Insulin Action and Its Disturbances in Disease - part 8 pdf

A genetic variant in intron 2, IVS2 + 181G → A, was signifi- cantly involved in a possible interaction between obesity and the association between T2DM and the SNP.171 A study that combin

proposed as a cause of T2DM42 possibly through an ectopic overload of fatty acids and lipotoxicity of non-adipose tissues.167 A role for resistin could there- fore be envisioned in the prediabetic syndrome of insulin resistance by virtue

of its ability to block adipocyte differentiation.

At the genic level, SNPS in non-coding regions of the human resistin gene were either not significantly associated with insulin resistance (G1326C in 3
UTR; −167C → T, 157C → T, 299G → A in introns)168, 169or associated with

an insulin sensitivity index in the case of a promoter SNP ( −394C → G)170(Table 13.3) A genetic variant in intron 2, IVS2 + 181G → A, was signifi- cantly involved in a possible interaction between obesity and the association between T2DM and the SNP.171 A study that combined population data from the Quebec Family Study and the Saguenay-Lac-St-Jean region of Quebec found two promoter SNPs ( −537A → C and −420C → G) to be associated with increased risk for BMI, but this result was not replicated in a population from Scandinavia.172 A trinucleotide (ATG) repeat at the 3
UTR of the gene was,

on the other hand, associated with a decreased risk of insulin resistance.173 It is too early at this point to draw any definitive conclusions regarding the role of resistin in the aetiology of the metabolic syndrome but its proposed physiological role and early genetic studies suggest a link between resistin and the metabolic syndrome However, its effects may be mediated by intermediate factors such

as oxidative stress or population-specific environmental factors.

PC-1

Plasma cell membrane glycoprotein-1 (PC-1) inhibits insulin receptor (IR) sine kinase activity and subsequent cellular signalling, possibly by inhibiting the IR by directly interacting with a specific region in the IR α-subunit.174

tyro-IR kinase activity is impaired in muscle, fibroblasts and other tissues of many patients with T2DM but abnormalities in the insulin receptor gene are not the cause of this decreased kinase activity Skin fibroblasts, however, from cer- tain insulin-resistant patients show increased enzymatic activity by PC-1, while overexpression of PC-1 in transfected cultured cells reduces insulin-stimulated tyrosine kinase activity.175 Using an assay to determine concentrations of cir- culating PC-1, it was shown that plasma PC-1 of 19 ng/ml or less identified a cluster of insulin-resistance-related alterations with 75 per cent accuracy, indi- cating that circulating PC-1 is related to insulin sensitivity.176, 177 In addition,

women with gestational diabetes mellitus and T2DM have an increased PC-1 content, which could contribute to lower phosphorylation levels of IRS-1 These post-receptor defects in the insulin signalling pathway are greater in these two groups of women than in women with normal pregnancy.178

At the genic level, an SNP (transversion A → C in codon 121) that resulted

in an amino-acid substitution, Lys121Gln, was strongly associated with insulin resistance179 (Table 13.3) The same SNP was associated with higher fasting

Table 13.4 Genome scans and linkages for metabolic syndrome phenotypesLocus or gene Phenotype(s) LOD score orp-value Reference2p21 (D2S1788) Leptin levels, fat mass LOD= 4.95 312

APO E Weight/fat factor in IR∗ p-value = 0.01 315

plasma glucose, higher systolic blood pressure and higher fasting insulin levels

in diabetic patients as well as normal individuals and, therefore, it may not be enough to increase susceptibility to T2DM.180The same SNP (Lys121Gly), how- ever, was not associated with T2DM among Danish Caucasians.181A haplotype

of three SNPs in the 3
UTR of PC-1 (G2897A, G2906C and C2948T) was ciated with increased PC-1 protein content and insulin resistance in Caucasians from Sicily182(Table 13.3) Furthermore, PC-1 maps to a region on chromosome 6q22–q23 that has been strongly linked to several insulin-resistance-related phenotypes in Mexican Americans183 (Table 13.4), which further suggests a potential role for PC-1 in the aetiology of the metabolic syndrome, possibly in interaction with genes that contribute to the aetiology of obesity and/or hyper- tension, using a rather direct pathway of action to inhibit insulin signalling.

asso-PPAR γ

Recently, several pedigrees have been described with severe insulin resistance, diabetes, and peripheral fat wasting The manifestation of this inherited partial lipodystrophy syndrome is quite similar to the metabolic syndrome-X, with the exception that these patients do not respond to the anti-diabetic thiazolidine- diones (TZDs) These families were found to have mutations in the PPAR- γ nuclear transcription factor gene at the ligand binding pocket.184 This results

in impaired activation of gene transcription by the TZDs PPAR- γ is a activated nuclear receptor that regulates adipocyte differentiation and possibly lipid metabolism and insulin sensitivity.185Predominantly expressed in the intes- tine and adipose tissue, it triggers adipocyte differentiation and promotes lipid storage.186 It could therefore play a significant role in the development of the metabolic syndrome through its ability to stimulate adipocyte differentiation and prevent lipid spillage to the liver and the muscle (i.e prevent ectopic lipotoxic- ity) PPAR- γ and its agonists are subjects of intense investigation as therapeutic agents for insulin resistance and the metabolic syndrome.187 Using a gain-of-

ligand-function approach, Wang et al showed that constitutive activation of PPAR- γ

was sufficient to prevent endothelial cells (ECs) from converting into a inflammatory phenotype, suggesting that genetic modification of the PPAR- γ activity in ECs may be a potential method for therapeutic intervention in inflam- matory disorders including the metabolic syndrome.188

pro-A common polymorphism, Pro12pro-Ala, was associated with adiposity and insulin resistance189 and decreased risk of the insulin resistance syndrome190(Table 13.3) Newer PPAR- γ ligands with a different structural backbone have

been shown to bypass CGL mutations in vitro.191 Agarwal and Garg describe

a C to T heterozygous mutation at nucleotide 1273 in exon 6 of the PPAR- γ gene with a phenotype of lipodystrophy.192 Although rare, these mutations are instructive in the sense that the metabolic sequelae are almost identical to the

‘garden-variety’ obesity and illustrate the utility of PPAR- γ agonists in the ment of the metabolic syndrome PPAR-γ is therefore a strong candidate gene for the metabolic syndrome with effects on adipocyte differentiation, as well

treat-as the development of obesity, dyslipidaemia and insulin resistance Its mode

of action may be indirect by means of regulating the transcriptional activation

of several adipose tissue-specific genes, thus altering adipose tissue mass and leading to insulin resistance.

β3-adrenoreceptor

Five adrenoreceptors are involved in the adrenergic regulation of fat cell tions: beta1- ( β1-), β2-, β3-, alpha1- (α1-) and α2-adrenergic receptors (ADRs) cAMP production and cAMP-related cellular responses are mediated through the control of adenyl cyclase activity that is stimulated by β1-, β2-, and β3- adrenoreceptors while activation of α1-adrenoreceptors stimulates phosphoinosi- tidase C activity so that a balance among adrenoreceptor subtypes determines the final effects of physiological amines in adipocytes.193

func-The cloning of the human β3-adrenoreceptor (β3-ADR) produced new ment in the field of obesity because of its thermogenic, anti-obesity and antidi- abetic activities in animal models.194 Structurally, the human β3-adrenoreceptor consists of two coding exons, and the pharmacological properties of the full length cDNA differ somewhat from those of the truncated receptor.195 The human β3-ADR gene is expressed predominantly in infant peripheral brown adipose tissue (which also expresses the thermogenic mitochondrial uncoupling protein UCP1), and in adults it is expressed at low levels in deep fat, such as perirenal and omental, but at much lower levels in subcutaneous fat.196It is also highly expressed in the gallbladder but to a lower extent in the colon, suggesting

excite-a potentiexcite-al role in the control of lipid metexcite-abolism excite-and triglyceride storexcite-age excite-and mobilization in adipose tissues.196, 197 However, doubts about its therapeutic effects were raised when it was found that β3-ADR is also expressed in human heart, where agonists for this receptor induce a negative inotropic effect, while

in blood vessels stimulation of β3-ADR produces a vasodilation.198

Transcriptionally, β3-ADR is regulated by C/EBP-α through a binding site in

an enhancer cis-acting element at position −3306.199 Mutational analysis of the human β3-ADR identified a missense polymorphism that resulted in an amino- acid substitution, Trp64Arg, that was associated with early onset of T2DM in the Pima Indians200 (Table 13.3) The Trp64Arg SNP was also found to con- tribute significantly to the accumulation of multiple risk factors in male subjects with hyperuricaemia,201 modulate the effects of β-blockers on triglyceride and HDL cholesterol concentrations in an Indo-Mauritian population,202 predict a greater tendency to develop abdominal adiposity and high blood pressure,203

be associated with visceral obesity but lower serum triglyceride204 and confer increased sensitivity to the pressor effect of noradrenaline.205On the other hand, the Trp64Arg SNP was not associated with obesity phenotypes in the Quebec Family Study and Swedish Obese Subjects cohorts,206 T2DM and features of the insulin resistance syndrome in a Finnish population207 or components of the metabolic syndrome in Chinese subjects.208

Taken together, the data show inconsistent associations of this SNP with the metabolic syndrome The end result may depend on population-specific char- acteristics such as ethnic origin, diet, exercise and environmental factors, i.e gene–gene or gene–environment interactions, that require further investigation.

Hepatic transcription of 11 β-HSD-1 is regulated by members of the C/EBP family of transcription factors providing a mechanism of cross-talk between C/EBP and the glucocorticoid signalling pathway.21111 β-HSD is highly expres- sed in all sodium-transporting epithelia, and mutations in the gene cause a rare monogenic juvenile hypertensive syndrome called apparent mineralocorticoid excess (AME).210Recent studies have shown a prolonged half-life of cortisol and

an increased ratio of urinary cortisol to cortisone metabolites in some patients with essential hypertension, similar to the effects of a CA-repeat polymorphism

in the first intron, although there was no correlation between this marker and blood pressure.210 The same CA-repeat, however, was associated with a mean arterial pressure difference between the sodium-loaded and the sodium-depleted states212, 213 (Table 13.3) In another study, a proband with AME was homozy-

gous for a mutation (Ala328Val) resulting in a protein devoid of activity,214while

a different individual with AME was homozygous for a Pro227Leu mutation215

(Table 13.3) In other cases, the polymorphism Arg213Cys was strongly ated with AME,216while two other mutations (Lys179Arg, Arg208His) resulted again in protein devoid of activity.217

associ-Other polymorphisms in 11 β-HSD-2 have also been associated with tial hypertension.218 – 220 From these data, we conclude that 11 β-HSD-2 plays a significant role in essential hypertension and is therefore an important candi- date gene that may contribute to the development of the metabolic syndrome Its mode of action may be independent of abnormal adipose tissue biology

essen-or the insulin signalling pathways, but it may exert its effects directly on the development of hypertension.

TNF- α

TNF-α is a cytokine that is produced by macrophages, monocytes, endothelial cells, neutrophils, smooth muscle cells, activated lymphocytes, astrocytes and adipocytes.221 TNF- α is a transmembrane glycoprotein and a cytotoxin with

a variety of functions, such as mediating expression of genes for growth tors, cytokines, transcription factors and receptors TNF- α suppresses adipocyte- specific genes and activates expression of preadipocyte genes in 3T3-L1 cells, with NF- κB being an obligatory mediator.222 TNF- α has been termed an adipo- stat because its adipose tissue expression is, like leptin, more or less proportional

fac-to the degree of adiposity.

TNF- α is synthesized as a 26 kDa transmembrane protein found on the face or processed to release the 17 kDa soluble form.223 The ways in which TNF- α may be involved in the aetiology of obesity include its inhibitory effect

sur-on lipoprotein lipase (LPL) activity, its effects sur-on glucose homeostasis and its effects on leptin There are significant positive relationships between TNF-

α expression, BMI and leptin, and a negative significant correlation between TNF- α and LPL activity, suggesting that TNF-α may be a homeostatic mech- anism that may prevent further fat deposition by regulating LPL activity and leptin production.224 Higher plasma levels of TNF- α are also associated with insulin resistance, higher BMI, higher fasting glucose levels and higher LDL-C levels.225 Using confirmatory factor analysis and structural equation modelling,

it was shown that obesity, dyslipidaemia and cytokines such as TNF- α were the principal explanatory variables for the various components of the metabolic syndrome.226 Human obesity and T2DM are associated with alterations in the sterol regulatory element binding protein (SREBP)-1 transcription factor that

is downregulated at the transcriptional level by TNF- α.227 TNF- α has also been proposed to link obesity with insulin resistance, with serine phospho- rylation of the insulin receptor substrate-1 being a prominent mechanism for TNF- α-induced insulin resistance.228 Physiologically, TNF- α could affect sev- eral metabolic functions (probably involving the adipose tissue) but its mode of action could be indirect, possibly requiring the development of insulin resistance for its effects to become evident (Figure 13.1).

In terms of genetic variants in TNF- α, there have been numerous tions, centred mostly on two promoter variants: −308G → A and −238G → A There are data that do not support an involvement of these two SNPs in the development of the metabolic syndrome229 – 235 but also a body of data that sup- ports an involvement of the two promoter variants in the aetiology of insulin resistance, obesity or T2DM236 – 242 (Table 13.3) A linkage between obesity and

publica-a mpublica-arker (dinucleotide repepublica-at) nepublica-ar the TNF- α locus in the Pima Indians has also been reported.243 Another promoter SNP ( −857C → T) was present at higher frequencies in obese patients with diabetes (T/T homozygotes) than in lean subjects244, 245(Table 13.3) Taking together the physiological functions of

TNF- α and the genetic variants, TNF-α may play a role in the development of the metabolic syndrome but the association studies are somewhat inconclusive.

Glucocorticoid receptor

The glucocorticoid receptor (GR) is the essential receptor by which ticoids exert their regulatory effects on gene expression GR is a member of the steroid family of nuclear receptors, and in the absence of its cognate lig- and it is transcriptionally inactive.246 There are two isoforms of GR (GR- α and GR- β), which are products of alternative splicing, but only GR-α has functional properties.246 Inside the DNA-binding domain of the receptor molecule, there are two zinc-finger structures, each containing four cysteines that are stabilized

glucocor-by bonds of Zn2+ions.247These zinc fingers enable GR homodimers to bind to palindromic DNA sequences and GR response elements found in the promot- ers of GR-regulated genes.248 The receptor then communicates with the basal transcriptional machinery to either enhance or repress transcription.246

Mutations in GR have often been associated with the metabolic syndrome in association with hyperactivity or abnormal regulation of the HPA axis.249, 250A restriction fragment length polymorphism (RFLP), Bcl I, has been studied exten- sively by several groups and appears to be associated with several subphenotypes

of the metabolic syndrome Specifically, in a study regarding the effects of GR in response to overfeeding, 2.3/2.3 kb homozygotes for the GR Bcl I RFLP expe- rience greater increases in body weight, blood pressure, cholesterol levels and visceral fat than 4.5/2.3 kb subjects251 (Table 13.3) In another study involving the Quebec Family Study, the 4.5 kb allele of the GR Bcl I RFLP was associ- ated with a higher amount of abdominal visceral fat (AVF) depot independent

of the levels of total body fat.252 The 4.5 kb allele of the GR Bcl I RFLP was also associated with elevated BMI, WHR, abdominal sagittal diameter, leptin and associated borderline with elevated systolic blood pressure.253 In a separate study, the 4.5 kb allele was again associated with higher AVF independently of total body fat, suggesting that the GR Bcl I RFLP or a locus in linkage disequi- librium with it may contribute to the accumulation of AVF.254 The Bcl I RFLP

in GR has also been associated with indices of glucose metabolism in obesity,

where 4.5 kb homozygotes had elevated both fasting insulin and an index of insulin resistance.255

Another RFLP in the 5
flanking region of the GR gene (3.8/3.4 kb) was associated (the 3.8 kb homozygotes) with elevated total and evening cortisol levels in a cohort of randomly selected middle-aged men.256 Heterozygotes for another SNP resulting in an amino-acid substitution, Asn363Ser, had higher BMI but normal blood pressure,257 but two other studies did not find an asso- ciation between the Asn363Ser SNP and altered sensitivity to glucocorticoids

or obesity258, 259 (Table 13.3) Yet a recent study reports an association of the Asn363Ser SNP with increased WHR in males for the 363Ser allele but no association with blood pressure, BMI, serum cholesterol, triglycerides, LDL

or glucose tolerance status.260 Other mutations in patients with primary cortisol resistance have been reported for GR due to complete lack or reduction of trans- activation capacity (Arg477His and Gly679Ser, respectively)261 (Table 13.3) Additional evidence for involvement of GR in the metabolic syndrome comes from a study for a haplogroup of the Glu22Arg/Glu23Lys SNPs where carriers

of the less frequent alleles had lower fasting insulin, HOMA-IR index and total LDL cholesterol concentrations.262 Other mutations in the promoter ( −22C → A) and 3
UTR exon 9 β (A → G in a AUUUA motif) have been reported263, 264

in GR, but they were not associated with phenotypes of the metabolic syndrome Taking together the functional properties of the GR and the various SNPs and RFLPs that have been associated with the metabolic syndrome, we conclude that DNA sequence variations in the GR gene play a significant role in the aetiology

as in other tissues.267, 268 Null mutations in MC4R in mice result in

hyperpha-gia, obesity and longitudinal growth while MC3R knockout mice exhibit 50–60 per cent increase in adipose mass and 50 per cent reduction in locomotory activity.269 A missense variant of the porcine MC4R gene was associated with backfat, growth rate and food intake,270 while frameshift mutations in humans were associated with dominantly inherited obesity271 – 275(Table 13.3) There are

in addition four other neuropeptides that have been shown to play significant roles in the regulation of food intake and energy balance: agouti-related protein (AgRP), neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART) and pro-opiomelanocortin (POMC).

AgRP binds competitively to the melanocortin receptors and is a potent appetite effector276and therefore represents a strong case as a candidate gene for obesity and consequently the metabolic syndrome The murine and human AgRP orthologs stimulate hyperphagia when administered intracerebroventricularly277 – 279or when overexpressed in transgenic mice.280The minimal promoter of the gene has been characterized and a functional polymorphism in the promoter ( −38C → T) was associated with decreased obesity in Blacks281(Table 13.3) AgRP plasma levels were elevated in obese individuals282or increased by 75 per cent after a two-hour fast.283Further studies in another cohort showed that the T allele of the −38C → T SNP in the promoter of AgRP was linked with reduced visceral adiposity, percent- age body fat and T2DM.281, 284A structural polymorphism (Ala67Thr) has been

strongly associated with resistance to late-onset obesity285(Table 13.3) The same SNP was also reported to be associated with anorexia nervosa.286This SNP rep- resents a rare example for a common polymorphism that was found in Caucasians only and was associated with resistance to obesity in the parental population but not

in the offspring.285 This parallels the syndromic characteristics of the metabolic syndrome, which is also a late onset disease, with components of its complex phenotype expressing gradually in the range of 35–55 years of age.

NPY is also a strong orexigenic gene287, 288 regulated by leptin and other peripheral signals.289There have been numerous studies linking NPY with feed- ing behaviour in several mammalian systems NPY knockout mice have an attenuated obese phenotype,289 while its receptors have important physiological functions.290 – 292 A polymorphism in the signal peptide (Leu7Pro) resulted in altered intracellular processing and release of NPY293 (Table 13.3) The same SNP has been associated with phenotypes of the metabolic syndrome including nephropathy in T2DM,294 enhanced carotid atherosclerosis in elderly patients with T2DM,294 carotid atherosclerosis, blood pressure, serum lipids in Finnish men295 and serum lipids in patients with coronary heart disease,296 as well as alcohol consumption and alcohol dependence.297, 298

CART is a hypothalamic anorectic peptide that is upregulated by leptin299, 300

and is also a candidate gene for the metabolic syndrome by virtue of its ability

to regulate food intake CART blocks the feeding response induced by NPY and its C-terminus is the active part of the protein.301 It has been shown to modulate the voltage-gated Ca2+ signalling in the hippocampal neurons,302 and expression studies in the brain further suggest a role for CART in the regula- tion of energy homeostasis.303, 304 CART is a drug target for obesity therapy, and polymorphisms in its promoter region have been associated with obesity in humans.305, 306 Specifically, SNP −156A → G in the promoter of the gene was associated with high BMI and was found at higher frequencies in obese individ- uals, while a neighbouring SNP ( −929G → C) was in linkage disequilibrium with the −156A → G SNP306 (Table 13.3) A mutation in the 3
UTR of the gene, A1475G, was significantly associated with WHR in heterozygous males,

thus suggesting a role by CART in fat distribution and variables related to the metabolic syndrome307 (Table 13.3).

POMC is the precursor of α-MSH, a strong anorectic peptide activated by leptin308 and therefore a candidate gene for the metabolic syndrome Post- translational processing of POMC results in five distinct proteins with different physiological functions: adrenocorticotropin, β-lipotropin, α-MSH, β-MSH and β-endorphin Mice lacking POMC have obesity and defective adrenal devel- opment and, when treated with α-MSH agonists, they lose weight.309, 310 A

missense mutation disrupting a dibasic prohormone processing site in hPOMC was associated with early onset obesity311 (Table 13.3).

A role for several hypothalamic neuropeptides can therefore be envisioned

in the development of the metabolic syndrome either as a result of elevated or diminished arousal of the hypothalamus or due to genetic alterations that may affect the expression levels or the activities of the protein products of these genes It must be noted that these neuropeptides are also expressed in peripheral tissues and, therefore, their mode of action is quite complex Hence, there are several routes by which these genes could influence the development of the metabolic syndrome (Figure 13.1).

There is abundant literature on linkage analyses and genome scans for the main subphenotypes of the metabolic syndrome (Figure 13.1) considered individu- ally In contrast, very few scans have been performed using a single integrated metabolic syndrome phenotype This is probably due to the complexity of the syndrome and the lack of comprehensive physiological and clinical data in fam- ily cohorts that would allow an adequate definition of the syndrome phenotype Yet there are reports providing suggestive linkages that may apply to the meta- bolic syndrome as a whole Comuzzie and colleagues have reported a significant LOD score on 2p21 (LOD = 4.95) for microsatellite D2S1788 that may deter-

mine serum leptin levels and fat mass in Mexican-Americans312 (Table 13.4) Indeed, this locus accounted for 47 per cent of the variation in serum leptin levels and contains several potential candidate genes including the glucokinase regula- tory protein and POMC However, it was not significantly linked to hypertension

in African-Americans.313

In a study that directly scanned the genome for QTLs for the metabolic syndrome, Kissebah and colleagues reported two QTLs with significant LOD scores.314 Specifically, using a 10 cM map in 2209 individuals distributed over

507 nuclear Caucasian families, a QTL on 3q27 was strongly linked with six traits characteristic of the metabolic syndrome, and this QTL was in possible epistatic interaction with a second QTL on 17p12314 (Table 13.4).

Another study used sib-pair linkage analysis with women twins in an effort

to identify lipoprotein candidate genes for multivariate factors of the insulin

resistance syndrome Specifically, quantitative sib-pair analysis based on factor scores with markers for nine candidate genes was carried out using 126 dizygotic women twins.315 There was suggestive evidence for linkage for the weight/fat factor and the APO E gene (0.01) and stronger evidence for linkage with the lipid factor and the cholesterol ester transfer protein ( p − value = 0.002)315(Table 13.4) A genome-wide scan in Indo-Mauritians for coronary heart dis- ease (CHD) identified a susceptibility locus on chromosome 16p13–pter and was able to replicate the previously reported linkage314with the metabolic syndrome

on 3q27316 (Table 13.4) A suggestive linkage was also identified for T2DM and high blood pressure on 8q23 (LOD = 2.55).316 A significant LOD score (LOD = 3.5) was identified on chromosome 6q22–q23 (D6S403, D6S264) for

fasting glucose, specific insulin values and other insulin resistance-related notypes with strong pleiotropic effects with obesity-related phenotypes in non- diabetic Mexican-Americans183(Table 13.4) It would therefore appear that there are suggestive linkages and candidate QTLs for the metabolic syndrome, but no single locus stands out as of yet Additional linkage studies are required to deter- mine whether there are any compelling QTLs for the metabolic syndrome In this regard, it may be useful to revisit previous genomic scan studies and re-analyse data from cohorts in which linkages with single phenotypes were reported, with the aim of testing more comprehensive metabolic syndrome phenotypes.

phe-13.7 Conclusions

The metabolic syndrome in humans is a multi-component disease whose dinal features include obesity, abnormal adipose tissue metabolism, ectopic fat deposition, insulin resistance, hyperinsulinaemia, dyslipidaemia and hyperten- sion The genetic causes for each of the components of the syndrome are under intense investigation A number of genes have emerged as possible regulators but no genetic master switch has been identified yet for the syndrome as a whole At this point the genetic data are not particularly robust, and intense work lies ahead in order to define the genetic aetiology of the disease The present review of epidemiological, Mendelian and syndromic data; candidate genes and polymorphisms; and linkage studies highlights several features and genetic hypotheses that deserve further research The field would benefit greatly from concertation among informative cohorts already assembled and from new collections of longitudinal data on large populations over an extended period of time Innovative genomic scan studies are also needed to identify key loci and QTLs for the syndrome defined as a single integrated phenotype Until then, the candidate gene approach appears to be the best way to identify functional SNPs that may contribute to the development of the metabolic syndrome.

car-References

1 Jahnke, K., Daweke, H., Liebermeister, H., Thamer, G., Preiss, H and Gries, F A.(1969) Hormonal and metabolic aspects of obesity in humans In: Milner, R D G., ed

Proceedings of the Sixth Congress of the International Diabetes Federation Amsterdam:

Excerpta Medica Foundation, 533 – 539

2 Williams, R R., Hunt, S C., Hopkins, P N., Stults, B M., Wu, L L., Hasstedt, S J.,Barlow, G K., Stephenson, S H., Lalouel, J M and Kuida, H (1988) Familialdyslipidemic hypertension Evidence from 58 Utah families for a syndrome present

in approximately 12% of patients with essential hypertension JAMA 259, 3579 – 3586.

3 Reaven, G M (1988) Banting Lecture 1988 Role of insulin resistance in human

cardiovascular disease Diabetes Care 14, 173 – 194.

6 Kaplan, N M (1989) The deadly quartet Upper-body obesity, glucose intolerance,

hypertriglyceridemia, and hypertension Arch Intern Med 149, 1514 – 1520.

7 Crepaldi, G., Tiengo, A and Manzato, E (1993) Diabetes, Obesity and

Hyperlipi-demias: V: the Plurimetabolic Syndrome Amsterdam: Excerpta Medica.

8 Flegal, K M., Carroll, M D., Ogden, C L and Johnson, C L (2002) Prevalence and

trends in obesity among US adults, 1999 – 2000 JAMA 288, 1723 – 1727.

9 Ford, E S., Giles, W H and Dietz, W H (2002) Prevalence of the metabolicsyndrome among US adults: findings from the third National Health and Nutrition

Examination Survey JAMA 287, 356 – 359.

10 Bouchard, C (1995) Genetics and the metabolic syndrome Int J Obes Relat Metab

Disord 19 (Suppl 1), S52 – 59.

11 Han, T S., Williams, K., Sattar, N., Hunt, K J., Lean, M E and Haffner, S M.(2002) Analysis of obesity and hyperinsulinemia in the development of metabolic

syndrome: San Antonio Heart Study Obes Res 10, 923 – 931.

12 Smith, S R (1999) Regional fat distribution In: Ryan, D H., ed Nutrition Genetic

and Obesity Baton Rouge, LA: LSU Press, 433 – 458.

13 Kissebah, A H and Peiris, A N (1989) Biology of regional body fat distribution:

relationship to non-insulin-dependent diabetes mellitus Diabetes Metab Rev 5, 83 – 109.

14 Despres, J P., Lemieux, S., Lamarche, B., Prud’homme, D., Moorjani, S., Brun, L D.,Gagne, C and Lupien, P J (1995) The insulin resistance– dyslipidemic syndrome:

contribution of visceral obesity and therapeutic implications Int J Obes Relat Metab

Disord 19 (Suppl 1), S76 – 86.

15 Banerji, M A., Chaiken, R L., Gordon, D., Kral, J G and Lebovitz, H E (1995)Does intra-abdominal adipose tissue in black men determine whether NIDDM is insulin-

resistant or insulin-sensitive? Diabetes 44, 141 – 146.

16 Albu, J B., Murphy, L., Frager, D H., Johnson, J A and Pi-Sunyer, F X (1997)Visceral fat and race-dependent health risks in obese nondiabetic premenopausal

women Diabetes 46, 456 – 462.

17 Albu, J B., Kovera, A J and Johnson, J A (2000) Fat distribution and health in

obesity Ann NY Acad Sci 904, 491 – 501.

18 Randle, P J., Garland, P B., Hales, C N and Newsholme, E A (1963) The glucosefatty acid cycle: its role in insulin sensitivity and metabolic disturbances of diabetes

mellitus Lancet i, 7285 – 7289.

19 Kelley, D E and Mandarino, L J (2000) Fuel selection in human skeletal muscle in

insulin resistance: a reexamination Diabetes 49, 677 – 683.

20 Bergman, R N and Ader, M (2000) Free fatty acids and pathogenesis of type 2

diabetes mellitus Trends Endocrinol Metab 11, 351 – 356.

21 Bjorntorp, P (1990) ‘Portal’ adipose tissue as a generator of risk factors for

cardiovascular disease and diabetes Arteriosclerosis 10, 493 – 496.

22 Frayn, K N., Samra, J S and Summers, L K (1997) Visceral fat in relation to health:

is it a major culprit or simply an innocent bystander? [letter] Int J Obes Relat Metab

Disord 21, 1191 – 1192.

23 Kelley, D E., Thaete, F L., Troost, F., Huwe, T and Goodpaster, B H (2000)

Subdivisions of subcutaneous abdominal adipose tissue and insulin resistance Am J

Physiol 278, E941.

24 Smith, S R., Lovejoy, J C., Greenway, F., Ryan, D., deJonge, L., de la Bretonne, J.,Volafova, J and Bray, G A (2001) Contributions of total body fat, abdominalsubcutaneous adipose tissue compartments, and visceral adipose tissue to the metabolic

complications of obesity Metabolism 50, 425 – 435.

25 Lundgren, C H., Brown, S L., Nordt, T K., Sobel, B E and Fujii, S (1996)Elaboration of type-1 plasminogen activator inhibitor from adipocytes A potential

pathogenetic link between obesity and cardiovascular disease Circulation 93, 106 – 110.

26 Bruun, J M., Pedersen, S B and Richelsen, B (2000) Interleukin-8 production

in human adipose tissue inhibitory effects of anti-diabetic compounds, the

thiazolidinedione ciglitazone and the biguanide metformin Horm Metab Res 32,

537 – 541

27 Straczkowski, M., Dzienis-Straczkowska, S., Stepien, A., Kowalska, I., Szelachowska,

M and Kinalska, I (2002) Plasma interleukin-8 concentrations are increased in obese

subjects and related to fat mass and tumor necrosis factor-alpha system J Clin

Endocrinol Metab 87, 4602 – 4606.

28 Engeli, S., Negrel, R and Sharma, A M (2000) Physiology and pathophysiology of

the adipose tissue renin – angiotensin system Hypertension 35, 1270 – 1277.

29 Steppan, C M., Bailey, S T., Bhat, S., Brown, E J., Banerjee, R R., Wright, C M.,Patel, H R., Ahima, R S and Lazar, M A (2001) The hormone resistin links obesity

to diabetes Nature 409, 307 – 312.

30 Harris, R B (1998) Acute and chronic effects of leptin on glucose utilization in lean

mice Biochem Biophys Res Commun 245, 502 – 509.

31 Muoio, D M., Dohm, G L., Fiedorek, F T., Jr., Tapscott, E B., Coleman, R A andDohn, G L (1997) Leptin directly alters lipid partitioning in skeletal muscle [published

erratum appears in Diabetes 1997 46 (10), 1663] Diabetes 46, 1360 – 1363.

32 Muoio, D M., Dohm, G L., Tapscott, E B and Coleman, R A (1999) Leptinopposes insulin’s effects on fatty acid partitioning in muscles isolated from obese ob/ob

mice Am J Physiol 276, E913 – 921.

33 Yamauchi, T., Kamon, J., Waki, H., Terauchi, Y., Kubota, N., Hara, K., Mori, Y.,Ide, T., Murakami, K., Tsuboyama-Kasaoka, N., Ezaki, O., Akanuma, Y., Gavrilova,O., Vinson, C., Reitman, M L., Kagechika, H., Shudo, K., Yoda, M., Nakano, Y.,Tobe, K., Nagai, R., Kimura, S., Tomita, M., Froguel, P and Kadowaki, T (2001)The fat-derived hormone adiponectin reverses insulin resistance associated with both

lipoatrophy and obesity Nat Med 7, 941 – 946.

34 Ouchi, N., Kihara, S., Arita, Y., Maeda, K., Kuriyama, H., Okamoto, Y., Hotta, K.,Nishida, M., Takahashi, M., Nakamura, T., Yamashita, S., Funahashi, T and Mat-suzawa, Y (1999) Novel modulator for endothelial adhesion molecules: adipocyte-

derived plasma protein adiponectin Circulation 100, 2473 – 2476.

35 Goldfine, I D., Maddux, B A., Youngren, J F., Frittitta, L., Trischitta, V and

Dohm, G L (1998) Membrane glycoprotein PC-1 and insulin resistance Mol Cell

Biochem 182, 177 – 184.

36 Shao, J., Catalano, P M., Yamashita, H., Ruyter, I., Smith, S., Youngren, J andFriedman, J E (2000) Decreased insulin receptor tyrosine kinase activity and plasma

cell membrane glycoprotein-1 overexpression in skeletal muscle from obese womenwith gestational diabetes mellitus (GDM): evidence for increased serine/threonine

phosphorylation in pregnancy and GDM Diabetes 49, 603 – 610.

37 Kahn, C R., Bruning, J C., Michael, M D and Kulkarni, R N (2000) Knockoutmice challenge our concepts of glucose homeostasis and the pathogenesis of diabetes

mellitus J Pediatr Endocrinol Metab 13 (Suppl 6), 1377 – 1384.

38 Mauvais-Jarvis, F., Kulkarni, R N and Kahn, C R (2002) Knockout models are

useful tools to dissect the pathophysiology and genetics of insulin resistance Clin

Endocrinol (Oxf) 57, 1 – 9.

39 Bogardus, C., Lillioja, S., Stone, K and Mott, D (1984) Correlation between muscle

glycogen synthase activity and in vivo insulin action in man J Clin Invest 73,

adiposity Diabetes 51, 1022 – 1027.

42 Danforth, E., Jr (2000) Failure of adipocyte differentiation causes type II diabetes

mellitus? Nat Genet 26, 13.

43 Smith, S R and Ravussin, E (2002) Increased fat intake, impaired fat oxidation, andfailure of fat cell proliferation result in ectopic fat storage, insulin resistance, and type

2 diabetes mellitus Ann NY Acad Sci 967, 363 – 378.

44 Colberg, S R., Simoneau, J A., Thaete, F L and Kelley, D E (1995) Skeletal muscle

utilization of free fatty acids in women with visceral obesity J Clin Invest 95,

1846 – 1853

45 Dobbins, R L., Szczepaniak, L S., Bentley, B., Esser, V., Myhill, J and McGarry,

J D (2001) Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes

intramyocellular lipid accumulation and insulin resistance in rats Diabetes 50, 123 – 130.

46 Kim, Y B., Shulman, G I and Kahn, B B (2002) Fatty acid infusion selectivelyimpairs insulin action on Akt1 and PKC lambda/zeta but not on glycogen synthase

kinase-3 J Biol Chem 277, 32 915 – 32 922.

47 Pasquali, R., Cantobelli, S., Casimirri, F., Capelli, M., Bortoluzzi, L., Flamia, R.,Labate, A M and Barbara, L (1993) The hypothalamic– pituitary – adrenal axis in

obese women with different patterns of body fat distribution J Clin Endocrinol Metab

77, 341 – 346.

48 Marin, P., Darin, N., Amemiya, T., Andersson, B., Jern, S and Bjorntorp, P (1992)Cortisol secretion in relation to body fat distribution in obese premenopausal women

Metabolism 41, 882 – 886.

49 Rosmond, R., Holm, G and Bjorntorp, P (2000) Food-induced cortisol secretion in

relation to anthropometric, metabolic and haemodynamic variables in men Int J Obes

Relat Metab Disord 24, 416 – 422.

50 Bujalska, I J., Kumar, S and Stewart, P M (1997) Does central obesity reflect

‘Cushing’s disease of the omentum’? Lancet 349, 1210 – 1213.

51 Masuzaki, H., Paterson, J., Shinyama, H., Morton, N M., Mullins, J J., Seckl, J R.and Flier, J S (2001) A transgenic model of visceral obesity and the metabolic

53 Bray, G A (1991) Obesity, a disorder of nutrient partitioning: the MONA LISA

hypothesis J Nutr 121, 1146 – 1162.

54 Astrup, A., Buemann, B., Christensen, N J., Toubro, S., Thorbek, G., Victor, O J andQuaade, F (1992) The effect of ephedrine/caffeine mixture on energy expenditure and

body composition in obese women Metabolism 41, 686 – 688.

55 Toubro, S., Astrup, A V., Breum, L and Quaade, F (1993) Safety and efficacy of

long-term treatment with ephedrine, caffeine and an ephedrine/caffeine mixture Int J

Obes Relat Metab Disord 17 (Suppl 1), S69 – 72.

56 Weyer, C., Tataranni, P., Snitker, S., Danforth, E and Ravussin, E (1998) Increase ininsulin action and fat oxidation after treatment with CL 316,243, a highly selective

beta3-adrenoceptor agonist in humans Diabetes 47, 1555 – 1561.

57 Berthoud, H R (2002) Multiple neural systems controlling food intake and body

weight Neurosci Biobehav Rev 26, 393 – 428.

58 Miles, P D G., Li, S., Hart, M., Romeo, O., Cheng, J., Cohen, A., Raafat, K.,Moossa, A R and Olefsky, J M (1998) Mechanisms of insulin resistance in

experimental hyperinsulinemic dogs J Clin Invest 101, 202 – 211.

59 Hamilton-Wessler, M., Ader, M., Dea, M K., Moore, D., Loftager, M., Markussen, J.and Bergman, R N (2002) Mode of transcapillary transport of insulin and insulin

analog NN304 in dog hindlimb: evidence for passive diffusion Diabetes 51, 574 – 582.

60 Pinkney, J H., Stehouwer, C D., Coppack, S W and Yudkin, J S (1997) Endothelial

dysfunction: cause of the insulin resistance syndrome Diabetes 46 (Suppl 2), S9 – 13.

61 Minokoshi, Y., Kim, Y B., Peroni, O D., Fryer, L G., Muller, C., Carling, D andKahn, B B (2002) Leptin stimulates fatty-acid oxidation by activating AMP-activated

protein kinase Nature 415, 339 – 343.

62 Fryer, L G., Parbu-Patel, A and Carling, D (2002) The anti-diabetic drugsrosiglitazone and metformin stimulate AMP-activated protein kinase through distinct

signaling pathways J Biol Chem 277, 25 226 – 25 232.

63 Aschenbach, W G., Hirshman, M F., Fujii, N., Sakamoto, K., Howlett, K F andGoodyear, L J (2002) Effect of AICAR treatment on glycogen metabolism in skeletal

muscle Diabetes 51, 567 – 573.

64 Hardie, D G and Carling, D (1997) The AMP-activated protein kinase – fuel gauge

of the mammalian cell? Eur J Biochem 246, 259 – 273.

65 Muoio, D M., Seefeld, K., Witters, L A and Coleman, R A (1999) AMP-activatedkinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liverand muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target

Biochem J 338, 783 – 791.

66 Hutber, C A., Hardie, D G and Winder, W W (1997) Electrical stimulationinactivates muscle acetyl-CoA carboxylase and increases AMP-activated protein kinase

Am J Physiol 272, E262 – 266.

67 Du, X L., Edelstein, D., Rossetti, L., Fantus, I G., Goldberg, H., Ziyadeh, F.,

Wu, J and Brownlee, M (2000) Hyperglycemia-induced mitochondrial superoxideoverproduction activates the hexosamine pathway and induces plasminogen activator

inhibitor-1 expression by increasing Sp1 glycosylation Proc Natl Acad Sci USA 97,

12 222 – 12 226

68 Hawkins, M., Barzilai, N., Liu, R., Hu, M., Chen, W and Rossetti, L (1997) Role of

the glucosamine pathway in fat-induced insulin resistance J Clin Invest 99, 2173 – 2182.

69 Prentki, M., Tornheim, K and Corkey, B E (1997) Signal transduction mechanisms

in nutrient-induced insulin secretion Diabetologia 40 (Suppl 2), S32 – 41.

70 Bouchard, C and Perusse, L (1994) Genetics of causes and manifestations of the

metabolic syndrome In: Crepaldi, G., ed 6th European Symposium on Metabolism:

the Plurimetabolic Syndrome Amsterdam: Elsevier, 67 – 74.

71 Nelson, T L., Vogler, G P., Pedersen, N L., Hong, Y and Miles, T P (2000) Geneticand environmental influences on body fat distribution, fasting insulin levels and CVD:

are the influences shared? Twin Res 3, 43 – 50.

72 Burke, G L., Savage, P J., Sprafka, J M., Selby, J V., Jacobs, D R., Jr., Perkins,

L L., Roseman, J M., Hughes, G H and Fabsitz, R R (1991) Relation of riskfactor levels in young adulthood to parental history of disease The CARDIA study

Circulation 84, 1176 – 1187.

73 Manson, J E., Colditz, G A., Stampfer, M J., Willett, W C., Krolewski, A S.,Rosner, B., Arky, R A., Speizer, F E and Hennekens, C H (1991) A prospectivestudy of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke

in women Arch Intern Med 151, 1141 – 1147.

74 Sarlund, H., Pyorala, K., Penttila, I and Laakso, M (1992) Early abnormalities incoronary heart disease risk factors in relatives of subjects with non-insulin-dependent

diabetes Arterioscler Thromb 12, 657 – 663.

75 Ukkola, O and Bouchard, C (2001) Clustering of metabolic abnormalities in obese

individuals: the role of genetic factors Ann Med 33, 79 – 90.

76 Carmelli, D., Cardon, L R and Fabsitz, R (1994) Clustering of hypertension, diabetes,

and obesity in adult male twins: same genes or same environments? Am J Hum Genet

55, 566 – 573.

77 Liese, A D., Mayer-Davis, E J., Tyroler, H A., Davis, C E., Keil, U., Schmidt, M I.,Brancati, F L and Heiss, G (1997) Familial components of the multiple metabolic

syndrome: the ARIC study Diabetologia 40, 963 – 970.

78 Selby, J V., Newman, B., Quiroga, J., Christian, J C., Austin, M A and

Fab-sitz, R R (1991) Concordance for dyslipidemic hypertension in male twins JAMA

265, 2079 – 2084.

79 Mitchell, B D., Kammerer, C M., Mahaney, M C., Blangero, J., Comuzzie, A G.,Atwood, L D., Haffner, S M., Stern, M P and MacCluer, J W (1996) Geneticanalysis of the IRS Pleiotropic effects of genes influencing insulin levels on lipoprotein

and obesity measures Arterioscler Thromb Vasc Biol 16, 281 – 288.

80 Hong, Y., Pedersen, N L., Brismar, K and de Faire, U (1997) Genetic and

environmental architecture of the features of the insulin-resistance syndrome Am J

Hum Genet 60, 143 – 152.

81 Katzmarzyk, P T., Perusse, L., Rice, T., Gagnon, J., Skinner, J S., Wilmore, J H.,Leon, A S., Rao, D C and Bouchard, C (2000) Familial resemblance for coronary

heart disease risk: the HERITAGE Family Study Ethn Dis 10, 138 – 147.

82 Katzmarzyk, P T., Perusse, L., Malina, R M., Bergeron, J., Despres, J P andBouchard, C (2001) Stability of indicators of the metabolic syndrome from childhood

and adolescence to young adulthood: the Quebec Family Study J Clin Epidemiol 54,

190 – 195

83 Ohlson, L O., Larsson, B., Bjorntorp, P., Eriksson, H., Svardsudd, K., Welin, L.,Tibblin, G and Wilhelmsen, L (1988) Risk factors for type 2 (non-insulin-dependent)diabetes mellitus Thirteen and one-half years of follow-up of the participants in a study

of Swedish men born in 1913 Diabetologia 31, 798 – 805.

84 Martin, B C., Warram, J H., Krolewski, A S., Bergman, R N., Soeldner, J S andKahn, C R (1992) Role of glucose and insulin resistance in development of type

2 diabetes mellitus: results of a 25-year follow-up study Lancet 340, 925 – 929.

85 Haffner, S M., Stern, M P., Hazuda, H P., Mitchell, B D and Patterson, J K (1988)

Increased insulin concentrations in nondiabetic offspring of diabetic parents N Engl J

Med 319, 1297 – 1301.

86 Eriksson, H., Welin, L., Wilhelmsen, L., Larsson, B., Ohlson, L O., Svardsudd, K andTibblin, G (1992) Metabolic disturbances in hypertension: results from the population

study ‘men born in 1913’ J Intern Med 232, 389 – 395.

87 Williams, R R., Hunt, S C., Hasstedt, S J., Hopkins, P N., Wu, L L., Berry, T D.,

Stults, B M., Barlow, G K., Schumacher, M C and Lifton, R P et al (1991) Are

there interactions and relations between genetic and environmental factors predisposing

to high blood pressure? Hypertension 18, I29 – 37.

88 Stamler, J., Vaccaro, O., Neaton, J D and Wentworth, D (1993) Diabetes, other riskfactors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor

Intervention Trial Diabetes Care 16, 434 – 444.

89 Schumacher, M C., Maxwell, T M., Wu, L L., Hunt, S C., Williams, R R andElbein, S C (1992) Dyslipidemias among normoglycemic members of familial

NIDDM pedigrees Diabetes Care 15, 1285 – 1289.

90 Laws, A., Stefanick, M L and Reaven, G M (1989) Insulin resistance andhypertriglyceridemia in nondiabetic relatives of patients with noninsulin-dependent

diabetes mellitus J Clin Endocrinol Metab 69, 343 – 347.

91 Selby, J V., Austin, M A., Newman, B., Zhang, D., Quesenberry, C P., Jr., Mayer,

E J and Krauss, R M (1993) LDL subclass phenotypes and the insulin resistance

syndrome in women Circulation 88, 381 – 387.

92 Haffner, S M., Stern, M P., Hazuda, H P., Mitchell, B D., Patterson, J K andFerrannini, E (1989) Parental history of diabetes is associated with increased

cardiovascular risk factors Arteriosclerosis 9, 928 – 933.

93 Rice, T., Province, M., Perusse, L., Bouchard, C and Rao, D C (1994) Cross-traitfamilial resemblance for body fat and blood pressure: familial correlations in the Quebec

Family Study Am J Hum Genet 55, 1019 – 1029.

94 Rice, T., Nadeau, A., Perusse, L., Bouchard, C and Rao, D C (1996) Familialcorrelations in the Quebec Family Study: cross-trait familial resemblance for body

fat with plasma glucose and insulin Diabetologia 39, 1357 – 1364.

95 Perusse, L., Rice, T., Despres, J P., Rao, D C and Bouchard, C (1997) Cross-traitfamilial resemblance for body fat and blood lipids: familial correlations in the Quebec

Family Study Arterioscler Thromb Vasc Biol 17, 3270 – 3277.

96 Hong, Y., Rice, T., Gagnon, J., Despres, J P., Nadeau, A., Perusse, L., Bouchard, C.,Leon, A S., Skinner, J S., Wilmore, J H and Rao, D C (1998) Familial clustering

of insulin and abdominal visceral fat: the HERITAGE Family Study J Clin Endocrinol

98 Mayer, E J., Newman, B., Austin, M A., Zhang, D., Quesenberry, C P., Jr., Edwards,

K and Selby, J V (1996) Genetic and environmental influences on insulin levels and

the insulin resistance syndrome: an analysis of women twins Am J Epidemiol 143,

323 – 332

99 Knutsen, S F and Knutsen, R (1990) Wives of coronary high-risk men – are they also

at higher risk? The Tromso Heart Study J Intern Med 228, 333 – 337.

100 Hamosh, A., Scott, A F., Amberger, J., Valle, D and McKusick, V A (2000) Online

Mendelian Inheritance in Man (OMIM) Hum Mutat 15, 57 – 61.

101 Bray, G (1998) Contemporary Diagnosis and Management of Obesity 1st edn.

Newtown, PA: Handbooks in Healthcare, 289

102 Hoybye, C., Hilding, A., Jacobsson, H and Thoren, M (2002) Metabolic profile and

body composition in adults with Prader– Willi syndrome and severe obesity J Clin

Endocrinol Metab 87, 3590 – 3597.

103 Nicholls, R D and Knepper, J L (2001) Genome organization, function, and

imprinting in Prader– Willi and Angelman syndromes Annu Rev Genomics Hum Genet

2, 153 – 175.

104 Gallagher, R C., Pils, B., Albalwi, M and Francke, U (2002) Evidence for the role

of PWCR1/HBII-85 C/D box small nucleolar RNAs in Prader– Willi syndrome Am J

Hum Genet 71, 669 – 678.

105 Cummings, D E., Clement, K., Purnell, J Q., Vaisse, C., Foster, K E., Frayo, R S.,Schwartz, M W., Basdevant, A and Weigle, D S (2002) Elevated plasma ghrelin

levels in Prader Willi syndrome Nat Med 8, 643 – 644.

106 Wren, A M., Seal, L J., Cohen, M A., Brynes, A E., Frost, G S., Murphy, K G.,Dhillo, W S., Ghatei, M A and Bloom, S R (2001) Ghrelin enhances appetite and

increases food intake in humans J Clin Endocrinol Metab 86, 5992.

107 Garg, A (2000) Lipodystrophies Am J Med 108, 143 – 152.

108 Scherer, P E., Williams, S., Fogliano, M., Baldini, G and Lodish, H F (1995) A

novel serum protein similar to C1q, produced exclusively in adipocytes J Biol Chem

270, 26 746 – 26 749.

109 Fruebis, J., Tsao, T S., Javorschi, S., Ebbets-Reed, D., Erickson, M R., Yen, F T.,Bihain, B E and Lodish, H F (2001) Proteolytic cleavage product of 30-kDaadipocyte complement-related protein increases fatty acid oxidation in muscle and

causes weight loss in mice Proc Natl Acad Sci USA 98, 2005 – 2010.

110 Berg, A H., Combs, T P., Du, X., Brownlee, M and Scherer, P E (2001) The

adipocyte-secreted protein Acrp30 enhances hepatic insulin action Nat Med 7,

947 – 953

111 Berg, A H., Combs, T P and Scherer, P E (2002) ACRP30/adiponectin: an

adipokine regulating glucose and lipid metabolism Trends Endocrinol Metab 13, 84 – 89.

112 Maeda, N., Shimomura, I., Kishida, K., Nishizawa, H., Matsuda, M., Nagaretani, H.,Furuyama, N., Kondo, H., Takahashi, M., Arita, Y., Komuro, R., Ouchi, N., Kihara, S.,Tochino, Y., Okutomi, K., Horie, M., Takeda, S., Aoyama, T., Funahashi, T and Mat-suzawa, Y (2002) Diet-induced insulin resistance in mice lacking adiponectin/ACRP30

Nat Med 8, 731 – 737.

113 Kondo, H., Shimomura, I., Matsukawa, Y., Kumada, M., Takahashi, M., Matsuda, M.,Ouchi, N., Kihara, S., Kawamoto, T., Sumitsuji, S., Funahashi, T and Matsuzawa, Y.(2002) Association of adiponectin mutation with type 2 diabetes: a candidate gene for

the insulin resistance syndrome Diabetes 51, 2325 – 2328.

114 Yamauchi, T., Kamon, J., Minokoshi, Y., Ito, Y., Waki, H., Uchida, S., Yamashita, S.,Noda, M., Kita, S., Ueki, K., Eto, K., Akanuma, Y., Froguel, P., Foufelle, F., Ferre, P.,Carling, D., Kimura, S., Nagai, R., Kahn, B B and Kadowaki, T (2002) Adiponectinstimulates glucose utilization and fatty-acid oxidation by activating AMP-activated

protein kinase Nat Med 8, 1288 – 1295.

115 Arita, Y., Kihara, S., Ouchi, N., Takahashi, M., Maeda, K., Miyagawa, J., Hotta, K.,Shimomura, I., Nakamura, T., Miyaoka, K., Kuriyama, H., Nishida, M., Yamashita, S.,Okubo, K., Matsubara, K., Muraguchi, M., Ohmoto, Y., Funahashi, T and Mat-suzawa, Y (1999) Paradoxical decrease of an adipose-specific protein, adiponectin,

in obesity Biochem Biophys Res Commun 257, 79 – 83.

116 Matsubara, M., Maruoka, S and Katayose, S (2002) Decreased plasma adiponectin

concentrations in women with dyslipidemia J Clin Endocrinol Metab 87, 2764 – 2769.

117 Stefan, N., Vozarova, B., Funahashi, T., Matsuzawa, Y., Weyer, C., Lindsay, R S.,Youngren, J F., Havel, P J., Pratley, R E., Bogardus, C and Tataranni, P A (2002)

Plasma adiponectin concentration is associated with skeletal muscle insulin receptortyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-

body insulin sensitivity in humans Diabetes 51, 1884 – 1888.

118 Ouchi, N., Kihara, S., Arita, Y., Nishida, M., Matsuyama, A., Okamoto, Y., Ishigami,M., Kuriyama, H., Kishida, K., Nishizawa, H., Hotta, K., Muraguchi, M., Ohmoto,Y., Yamashita, S., Funahashi, T and Matsuzawa, Y (2001) Adipocyte-derivedplasma protein, adiponectin, suppresses lipid accumulation and class A scavenger

receptor expression in human monocyte-derived macrophages Circulation 103,

specific gene, adiponectin Int J Obes Relat Metab Disord 24, 861 – 868.

121 Menzaghi, C., Ercolino, T., Di Paola, R., Berg, A H., Warram, J H., Scherer, P E.,Trischitta, V and Doria, A (2002) A haplotype at the adiponectin locus is associated

with obesity and other features of the insulin resistance syndrome Diabetes 51,

2306 – 2312

122 Stumvoll, M., Tschritter, O., Fritsche, A., Staiger, H., Renn, W., Weisser, M.,Machicao, F and Haring, H (2002) Association of the T-G polymorphism inadiponectin (exon 2) with obesity and insulin sensitivity: interaction with family history

of type 2 diabetes Diabetes 51, 37 – 41.

123 Hara, K., Boutin, P., Mori, Y., Tobe, K., Dina, C., Yasuda, K., Yamauchi, T.,Otabe, S., Okada, T., Eto, K., Kadowaki, H., Hagura, R., Akanuma, Y., Yazaki, Y.,Nagai, R., Taniyama, M., Matsubara, K., Yoda, M., Nakano, Y., Tomita, M., Kimura,S., Ito, C., Froguel, P and Kadowaki, T (2002) Genetic variation in the gene encodingadiponectin is associated with an increased risk of type 2 diabetes in the Japanese

population Diabetes 51, 536 – 540.

124 Vasseur, F., Helbecque, N., Dina, C., Lobbens, S., Delannoy, V., Gaget, S., Boutin, P.,Vaxillaire, M., Lepretre, F., Dupont, S., Hara, K., Clement, K., Bihain, B., Kad-owaki, T and Froguel, P (2002) Single-nucleotide polymorphism haplotypes in theboth proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secretedadiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in

French Caucasians Hum Mol Genet 11, 2607 – 2614.

125 Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L and Friedman, J M.(1994) Positional cloning of the mouse obese gene and its human homologue [published

erratum appears in Nature 1995 374 (6521), 479] [see comments] Nature 372,

425 – 432

126 Green, E D., Maffei, M., Braden, V V., Proenca, R., DeSilva, U., Zhang, Y.,Chua, S C., Jr., Leibel, R L., Weissenbach, J and Friedman, J M (1995) The humanobese (OB) gene: RNA expression pattern and mapping on the physical, cytogenetic,

and genetic maps of chromosome 7 Genome Res 5, 5 – 12.

127 Karvonen, M K., Pesonen, U., Heinonen, P., Laakso, M., Rissanen, A., nen, H., Valve, R., Uusitupa, M I and Koulu, M (1998) Identification of new sequence

Naukkari-variants in the leptin gene J Clin Endocrinol Metab 83, 3239 – 3242.

128 Akerman, F., Lei, Z M and Rao, C V (2002) Human umbilical cord and fetal

membranes co-express leptin and its receptor genes Gynecol Endocrinol 16, 299 – 306.

129 Leroy, P., Dessolin, S., Villageois, P., Moon, B C., Friedman, J M., Ailhaud, G and

Dani, C (1996) Expression of ob gene in adipose cells Regulation by insulin J Biol

Chem 271, 2365 – 2368.

130 Halaas, J L., Gajiwala, K S., Maffei, M., Cohen, S L., Chait, B T., Rabinowitz, D.,Lallone, R L., Burley, S K and Friedman, J M (1995) Weight-reducing effects of

the plasma protein encoded by the obese gene [see comments] Science 269, 543 – 546.

131 Vaisse, C., Halaas, J L., Horvath, C M., Darnell, J E., Jr., Stoffel, M and man, J M (1996) Leptin activation of Stat3 in the hypothalamus of wild-type and

Fried-ob/ob mice but not db/db mice Nat Genet 14, 95 – 97.

132 Shimon, I., Yan, X., Magoffin, D A., Friedman, T C and Melmed, S (1998) Intactleptin receptor is selectively expressed in human fetal pituitary and pituitary adenomas

and signals human fetal pituitary growth hormone secretion J Clin Endocrinol Metab

83, 4059 – 4064.

133 Spicer, L J (2001) Leptin: a possible metabolic signal affecting reproduction Domest

Anim Endocrinol 21, 251 – 270.

134 Brann, D W., Wade, M F., Dhandapani, K M., Mahesh, V B and Buchanan, C D

(2002) Leptin and reproduction Steroids 67, 95 – 104.

135 Ravussin, E., Pratley, R E., Maffei, M., Wang, H., Friedman, J M., Bennett, P H andBogardus, C (1997) Relatively low plasma leptin concentrations precede weight gain

in Pima Indians Nat Med 3, 238 – 240.

136 Hinney, A., Bornscheuer, A., Depenbusch, M., Mierke, B., Tolle, A., Middeke, K.,Ziegler, A., Roth, H., Gerber, G., Zamzow, K., Ballauff, A., Hamann, A., Mayer, H.,Siegfried, W., Lehmkuhl, G., Poustka, F., Schmidt, M H., Hermann, H., Herpertz-Dahlmann, B M., Fichter, M., Remschmidt, H and Hebebrand, J (1998) No evidencefor involvement of the leptin gene in anorexia nervosa, bulimia nervosa, underweight

or early onset extreme obesity: identification of two novel mutations in the coding

sequence and a novel polymorphism in the leptin gene linked upstream region Mol

Psychiatry 3, 539 – 543.

137 Hager, J., Clement, K., Francke, S., Dina, C., Raison, J., Lahlou, N., Rich, N.,Pelloux, V., Basdevant, A., Guy-Grand, B., North, M and Froguel, P (1998) Apolymorphism in the 5
untranslated region of the human ob gene is associated with

low leptin levels Int J Obes Relat Metab Disord 22, 200 – 205.

138 Ohshiro, Y., Ueda, K., Nishi, M., Ishigame, M., Wakasaki, H., Kawashima, H.,Furuta, H., Sasaki, H., Sanke, T., Takasu, N and Nanjo, K (2000) A polymorphic

marker in the leptin gene associated with Japanese morbid obesity J Mol Med 78,

516 – 520

139 Mammes, O., Betoulle, D., Aubert, R., Herbeth, B., Siest, G and Fumeron, F (2000)Association of the G-2548A polymorphism in the 5
region of the LEP gene with

overweight Ann Hum Genet 64, 391 – 394.

140 Hoffstedt, J., Eriksson, P., Mottagui-Tabar, S and Arner, P (2002) A polymorphism inthe leptin promoter region (−2548 g/a) influences gene expression and adipose tissue

secretion of leptin Horm Metab Res 34, 355 – 359.

141 Shintani, M., Ikegami, H., Fujisawa, T., Kawaguchi, Y., Ohishi, M., Katsuya, T.,Higaki, J., Shimamoto, K and Ogihara, T (2002) Leptin gene polymorphism is

associated with hypertension independent of obesity J Clin Endocrinol Metab 87,

2909 – 2912

142 Montague, C T., Farooqi, I S., Whitehead, J P., Soos, M A., Rau, H., ham, N J., Sewter, C P., Digby, J E., Mohammed, S N., Hurst, J A., Cheetham,

Ware-C H., Earley, A R., Barnett, A H., Prins, J B and O’Rahilly, S (1997) Congenital

leptin deficiency is associated with severe early-onset obesity in humans Nature 387,

903 – 908

143 Farooqi, I S., Keogh, J M., Kamath, S., Jones, S., Gibson, W T., Trussell, R.,Jebb, S A., Lip, G Y and O’Rahilly, S (2001) Partial leptin deficiency and human

adiposity Nature 414, 34 – 35.

144 Thompson, D B., Ravussin, E., Bennett, P H and Bogardus, C (1997) Structure andsequence variation at the human leptin receptor gene in lean and obese Pima Indians

Hum Mol Genet 6, 675 – 679.

145 Clement, K., Vaisse, C., Lahlou, N., Cabrol, S., Pelloux, V., Cassuto, D., len, M., Dina, C., Chambaz, J., Lacorte, J M., Basdevant, A., Bougneres, P., Lebouc,Y., Froguel, P and Guy-Grand, B (1998) A mutation in the human leptin receptor

Gourme-gene causes obesity and pituitary dysfunction Nature 392, 398 – 401.

146 Chagnon, Y C., Chung, W K., Perusse, L., Chagnon, M., Leibel, R L and Bouchard,

C (1999) Linkages and associations between the leptin receptor (LEPR) gene and

human body composition in the Quebec Family Study Int J Obes Relat Metab Disord

23, 278 – 286.

147 Lakka, H M., Oksanen, L., Tuomainen, T P., Kontula, K and Salonen, J T (2000)The common pentanucleotide polymorphism of the 3
-untranslated region of the leptinreceptor gene is associated with serum insulin levels and the risk of type 2 diabetes in

non-diabetic men: a prospective case– control study J Intern Med 248, 77 – 83.

148 Chagnon, Y C., Wilmore, J H., Borecki, I B., Gagnon, J., Perusse, L., Chagnon, M.,Collier, G R., Leon, A S., Skinner, J S., Rao, D C and Bouchard, C (2000)Associations between the leptin receptor gene and adiposity in middle-aged Caucasian

males from the HERITAGE family study J Clin Endocrinol Metab 85, 29 – 34.

149 de Silva, A M., Walder, K R., Aitman, T J., Gotoda, T., Goldstone, A P., Hodge,

A M., de Courten, M P., Zimmet, P Z and Collier, G R (1999) Combination ofpolymorphisms in OB-R and the OB gene associated with insulin resistance in Nauruan

males Int J Obes Relat Metab Disord 23, 816 – 822.

150 Quinton, N D., Lee, A J., Ross, R J., Eastell, R and Blakemore, A I (2001) Asingle nucleotide polymorphism (SNP) in the leptin receptor is associated with BMI, fat

mass and leptin levels in postmenopausal Caucasian women Hum Genet 108, 233 – 236.

151 Wauters, M., Mertens, I., Chagnon, M., Rankinen, T., Considine, R V., Chagnon,

Y C., Van Gaal, L F and Bouchard, C (2001) Polymorphisms in the leptin receptor

gene, body composition and fat distribution in overweight and obese women Int J Obes

Relat Metab Disord 25, 714 – 720.

152 Wauters, M., Mertens, I., Rankinen, T., Chagnon, M., Bouchard, C and Van Gaal, L.(2001) Leptin receptor gene polymorphisms are associated with insulin in obese women

with impaired glucose tolerance J Clin Endocrinol Metab 86, 3227 – 3232.

153 Mammes, O., Aubert, R., Betoulle, D., Pean, F., Herbeth, B., Visvikis, S., Siest, G andFumeron, F (2001) LEPR gene polymorphisms: associations with overweight, fat mass

and response to diet in women Eur J Clin Invest 31, 398 – 404.

154 Gotoda, T., Manning, B S., Goldstone, A P., Imrie, H., Evans, A L., Strosberg,

A D., McKeigue, P M., Scott, J and Aitman, T J (1997) Leptin receptor gene

variation and obesity: lack of association in a white British male population Hum

Mol Genet 6, 869 – 876.

155 Silver, K., Walston, J., Chung, W K., Yao, F., Parikh, V V., Andersen, R., skin, L J., Elahi, D., Muller, D., Leibel, R L and Shuldiner, A R (1997) TheGln223Arg and Lys656Asn polymorphisms in the human leptin receptor do not associate

Che-with traits related to obesity Diabetes 46, 1898 – 1900.

156 Rand, L., Winchester, E C., Millwood, I Y., Penny, M A and Kessling, A M.(2001) Maternal leptin receptor gene variant Gln223Arg is not associated with variation

in birth weight or maternal body mass index in UK and South Asian populations Int J

Obes Relat Metab Disord 25, 753 – 755.

157 Heo, M., Leibel, R L., Fontaine, K R., Boyer, B B., Chung, W K., Koulu, M., vonen, M K., Pesonen, U., Rissanen, A., Laakso, M., Uusitupa, M I., Chagnon, Y.,Bouchard, C., Donohoue, P A., Burns, T L., Shuldiner, A R., Silver, K., Ander-sen, R E., Pedersen, O., Echwald, S., Sorensen, T I., Behn, P., Permutt, M A.,Jacobs, K B., Elston, R C., Hoffman, D J., Gropp, E and Allison, D B (2002) Ameta-analytic investigation of linkage and association of common leptin receptor

Kar-(LEPR) polymorphisms with body mass index and waist circumference Int J Obes

Relat Metab Disord 26, 640 – 646.

158 Holcomb, I N., Kabakoff, R C., Chan, B., Baker, T W., Gurney, A., Henzel, W.,Nelson, C., Lowman, H B., Wright, B D., Skelton, N J., Frantz, G D., Tumas, D B.,Peale, F V., Jr., Shelton, D L and Hebert, C C (2000) FIZZ1, a novel cysteine-richsecreted protein associated with pulmonary inflammation, defines a new gene family

EMBO J 19, 4046 – 4055.

159 Way, J M., Gorgun, C Z., Tong, Q., Uysal, K T., Brown, K K., Harrington, W W.,Oliver, W R., Jr., Willson, T M., Kliewer, S A and Hotamisligil, G S (2001)Adipose tissue resistin expression is severely suppressed in obesity and stimulated

by peroxisome proliferator-activated receptor gamma agonists J Biol Chem 276,

161 Nagaev, I and Smith, U (2001) Insulin resistance and type 2 diabetes are not related to

resistin expression in human fat cells or skeletal muscle Biochem Biophys Res Commun

285, 561 – 564.

162 Lay, S L., Boucher, J., Rey, A., Castan-Laurell, I., Krief, S., Ferre, P., Valet, P andDugail, I (2001) Decreased resistin expression in mice with different sensitivities to a

high-fat diet Biochem Biophys Res Commun 289, 564 – 567.

163 Janke, J., Engeli, S., Gorzelniak, K., Luft, F C and Sharma, A M (2002) Resistin

gene expression in human adipocytes is not related to insulin resistance Obes Res 10,

165 McTernan, C L., McTernan, P G., Harte, A L., Levick, P L., Barnett, A H and

Kumar, S (2002) Resistin, central obesity, and type 2 diabetes Lancet 359, 46 – 47.

166 Kim, K H., Lee, K., Moon, Y S and Sul, H S (2001) A cysteine-rich adipose

tissue-specific secretory factor inhibits adipocyte differentiation J Biol Chem 276,

11 252 – 11 256

167 Unger, R H and Orci, L (2000) Lipotoxic diseases of nonadipose tissues in obesity

Int J Obes Relat Metab Disord 24 (Suppl 4), S28 – 32.

168 Sentinelli, F., Romeo, S., Arca, M., Filippi, E., Leonetti, F., Banchieri, M., DiMario, U and Baroni, M G (2002) Human resistin gene, obesity, and type 2 diabetes:

mutation analysis and population study Diabetes 51, 860 – 862.

169 Osawa, H., Onuma, H., Murakami, A., Ochi, M., Nishimiya, T., Kato, K., Shimizu, I.,Fujii, Y., Ohashi, J and Makino, H (2002) Systematic search for single nucleotidepolymorphisms in the resistin gene: the absence of evidence for the association of three

identified single nucleotide polymorphisms with Japanese type 2 diabetes Diabetes 51,

863 – 866

170 Wang, H., Chu, W S., Hemphill, C and Elbein, S C (2002) Human resistin gene:molecular scanning and evaluation of association with insulin sensitivity and type 2

diabetes in Caucasians J Clin Endocrinol Metab 87, 2520 – 2524.

171 Ma, X., Warram, J H., Trischitta, V and Doria, A (2002) Genetic variants at the

resistin locus and risk of type 2 diabetes in Caucasians J Clin Endocrinol Metab 87,

4407 – 4410

172 Engert, J C., Vohl, M C., Williams, S M., Lepage, P., Loredo-Osti, J C., Faith, J.,Dore, C., Renaud, Y., Burtt, N P., Villeneuve, A., Hirschhorn, J N., Altshuler, D.,Groop, L C., Despres, J P., Gaudet, D and Hudson, T J (2002) 5
flanking variants

of resistin are associated with obesity Diabetes 51, 1629 – 1634.

173 Pizzuti, A., Argiolas, A., Di Paola, R., Baratta, R., Rauseo, A., Bozzali, M.,Vigneri, R., Dallapiccola, B., Trischitta, V and Frittitta, L (2002) An ATG repeat inthe 3
-untranslated region of the human resistin gene is associated with a decreased risk

of insulin resistance J Clin Endocrinol Metab 87, 4403 – 4406.

174 Maddux, B A and Goldfine, I D (2000) Membrane glycoprotein PC-1 inhibition ofinsulin receptor function occurs via direct interaction with the receptor alpha-subunit

Diabetes 49, 13 – 19.

175 Maddux, B A., Sbraccia, P., Kumakura, S., Sasson, S., Youngren, J., Fisher, A.,

Spencer, S., Grupe, A., Henzel, W and Stewart, T A et al (1995) Membrane

glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus

[see comments] Nature 373, 448 – 451.

176 Frittitta, L., Spampinato, D., Solini, A., Nosadini, R., Goldfine, I D., Vigneri, R andTrischitta, V (1998) Elevated PC-1 content in cultured skin fibroblasts correlates withdecreased in vivo and in vitro insulin action in nondiabetic subjects: evidence that

PC-1 may be an intrinsic factor in impaired insulin receptor signaling Diabetes 47,

1095 – 1100

177 Frittitta, L., Camastra, S., Baratta, R., Costanzo, B V., D’Adamo, M., Graci, S.,Spampinato, D., Maddux, B A., Vigneri, R., Ferrannini, E and Trischitta, V (1999)

A soluble PC-1 circulates in human plasma: relationship with insulin resistance and

associated abnormalities J Clin Endocrinol Metab 84, 3620 – 3625.

178 Tomazic, M., Janez, A., Sketelj, A., Kocijancic, A., Eckel, J and Sharma, P M (2002)Comparison of alterations in insulin signalling pathway in adipocytes from Type II

diabetic pregnant women and women with gestational diabetes mellitus Diabetologia

45, 502 – 508.

179 Pizzuti, A., Frittitta, L., Argiolas, A., Baratta, R., Goldfine, I D., Bozzali, M.,Ercolino, T., Scarlato, G., Iacoviello, L., Vigneri, R., Tassi, V and Trischitta, V (1999)

A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is

strongly associated with insulin resistance Diabetes 48, 1881 – 1884.

180 Gu, H F., Almgren, P., Lindholm, E., Frittitta, L., Pizzuti, A., Trischitta, V andGroop, L C (2000) Association between the human glycoprotein PC-1 gene and

elevated glucose and insulin levels in a paired-sibling analysis Diabetes 49, 1601 – 1603.

181 Rasmussen, S K., Urhammer, S A., Pizzuti, A., Echwald, S M., Ekstrom, C T.,Hansen, L., Hansen, T., Borch-Johnsen, K., Frittitta, L., Trischitta, V and Pedersen, O.(2000) The K121Q variant of the human PC-1 gene is not associated with insulin

resistance or type 2 diabetes among Danish Caucasians Diabetes 49, 1608 – 1611.

182 Frittitta, L., Ercolino, T., Bozzali, M., Argiolas, A., Graci, S., Santagati, M G.,Spampinato, D., Di Paola, R., Cisternino, C., Tassi, V., Vigneri, R., Pizzuti, A andTrischitta, V (2001) A cluster of three single nucleotide polymorphisms in the

3
-untranslated region of human glycoprotein PC-1 gene stabilizes PC-1 mRNAand is associated with increased PC-1 protein content and insulin resistance-related

abnormalities Diabetes 50, 1952 – 1955.

183 Duggirala, R., Blangero, J., Almasy, L., Arya, R., Dyer, T D., Williams, K L.,Leach, R J., O’Connell, P and Stern, M P (2001) A major locus for fasting insulinconcentrations and insulin resistance on chromosome 6q with strong pleiotropic effects

on obesity-related phenotypes in nondiabetic Mexican Americans Am J Hum Genet 68,

1149 – 1164

184 Barroso, I., Gurnell, M., Crowley, V E., Agostini, M., Schwabe, J W., Soos, M A.,Maslen, G L., Williams, T D., Lewis, H., Schafer, A J., Chatterjee, V K andO’Rahilly, S (1999) Dominant negative mutations in human PPARgamma asso-

ciated with severe insulin resistance, diabetes mellitus and hypertension Nature 402,

880 – 883

185 Yen, C J., Beamer, B A., Negri, C., Silver, K., Brown, K A., Yarnall, D P.,Burns, D K., Roth, J and Shuldiner, A R (1997) Molecular scanning of the humanperoxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic

Caucasians: identification of a Pro12Ala PPAR gamma 2 missense mutation Biochem

Biophys Res Commun 241, 270 – 274.

186 Bocher, V., Chinetti, G., Fruchart, J C and Staels, B (2002) Role of the peroxisomeproliferator-activated receptors (PPARS) in the regulation of lipids and inflammation

control J Soc Biol 196, 47 – 52.

187 Olefsky, J M and Saltiel, A R (2000) PPAR gamma and the treatment of insulin

resistance Trends Endocrinol Metab 11, 362 – 368.

188 Wang, N., Verna, L., Chen, N G., Chen, J., Li, H., Forman, B M and man, M B (2002) Constitutive activation of peroxisome proliferator-activated receptor-gamma suppresses pro-inflammatory adhesion molecules in human vascular endothelial

Stemer-cells J Biol Chem 277, 34176 – 34181.

189 Gonzalez Sanchez, J L., Serrano Rios, M., Fernandez Perez, C., Laakso, M andMartinez Larrad, M T Effect of the Pro12Ala polymorphism of the peroxisomeproliferator-activated receptor gamma-2 gene on adiposity, insulin sensitivity and lipid

profile in the Spanish population Eur J Endocrinol 147, 495 – 501.

190 Frederiksen, L., Brodbaek, K., Fenger, M., Jorgensen, T., Borch-Johnsen, K., bad, S and Urhammer, S A (2002) Comment: studies of the Pro12Ala polymorphism

Mads-of the PPAR-gamma gene in the Danish MONICA cohort: homozygosity Mads-of the Ala

allele confers a decreased risk of the insulin resistance syndrome J Clin Endocrinol

Metab 87, 3989 – 3992.

191 Fischer, P., Moller, P., Bindl, L., Melzner, I., Tornqvist, H., Debatin, K M andWabitsch, M (2002) Induction of adipocyte differentiation by a thiazolidinedione incultured, subepidermal, fibroblast-like cells of an infant with congenital generalized

lipodystrophy J Clin Endocrinol Metab 87, 2384 – 2390.

192 Agarwal, A K and Garg, A (2002) A novel heterozygous mutation in peroxisomeproliferator-activated receptor-gamma gene in a patient with familial partial

lipodystrophy J Clin Endocrinol Metab 87, 408 – 411.

193 Lafontan, M and Berlan, M (1993) Fat cell adrenergic receptors and the control of

white and brown fat cell function J Lipid Res 34, 1057 – 1091.

194 Emorine, L J., Marullo, S., Briend-Sutren, M M., Patey, G., Tate, K., Klutchko, C and Strosberg, A D (1989) Molecular characterization of the human beta

Delavier-3-adrenergic receptor Science 245, 1118 – 1121.

195 Granneman, J G., Lahners, K N and Chaudhry, A (1993) Characterization of the

human beta 3-adrenergic receptor gene Mol Pharmacol 44, 264 – 270.

196 Krief, S., Lonnqvist, F., Raimbault, S., Baude, B., Van Spronsen, A., Arner, P.,Strosberg, A D., Ricquier, D and Emorine, L J (1993) Tissue distribution of beta

3-adrenergic receptor mRNA in man J Clin Invest 91, 344 – 349.

197 Lafontan, M (1994) Differential recruitment and differential regulation by physiologicalamines of fat cell beta-1, beta-2 and beta-3 adrenergic receptors expressed in native fat

cells and in transfected cell lines Cell Signal 6, 363 – 392.

198 Balligand, J L (2000) Beta 3 adrenergic receptor: physiologic role and potential

therapeutic applications Bull Mem Acad R Med Belg 155, 311 – 317; discussion

317 – 319

199 Dixon, T M., Daniel, K W., Farmer, S R and Collins, S (2001) binding protein alpha is required for transcription of the beta 3-adrenergic receptor gene

CCAAT/enhancer-during adipogenesis J Biol Chem 276, 722 – 728.

200 Walston, J., Silver, K., Bogardus, C., Knowler, W C., Celi, F S., Austin, S.,

Man-ning, B., Strosberg, A D., Stern, M P and Raben, N et al (1995) Time of onset of

non-insulin-dependent diabetes mellitus and genetic variation in the beta

3-adrenergic-receptor gene N Engl J Med 333, 343 – 347.

201 Hayashi, H., Nagasaka, S., Ishikawa, S., Kawakami, A., Rokkaku, K., Nakamura, T.,Saito, T., Kusaka, I., Higashiyama, M., Kubota, K and Murakami, T (1998)Contribution of a missense mutation (Trp64Arg) in beta3-adrenergic receptor gene to

multiple risk factors in Japanese men with hyperuricemia Endocr J 45, 779 – 784.

202 Manraj, M., Francke, S., Hebe, A., Ramjuttun, U S and Froguel, P (2001) Geneticand environmental nature of the insulin resistance syndrome in Indo-Mauritian subjectswith premature coronary heart disease: contribution of beta3-adrenoreceptor gene

polymorphism and beta blockers on triglyceride and HDL concentrations Diabetologia

44, 115 – 122.

203 Strazzullo, P., Iacone, R., Siani, A., Cappuccio, F P., Russo, O., Barba, G., bato, A., D’Elia, L., Trevisan, M and Farinaro, E (2001) Relationship of the Trp64Argpolymorphism of the beta3-adrenoceptor gene to central adiposity and high blood pres-sure: interaction with age Cross-sectional and longitudinal findings of the Olivetti

Bar-Prospective Heart Study J Hypertens 19, 399 – 406.

204 Kim-Motoyama, H., Yasuda, K., Yamaguchi, T., Yamada, N., Katakura, T., Shuldiner,

A R., Akanuma, Y., Ohashi, Y., Yazaki, Y and Kadowaki, T (1997) A mutation ofthe beta 3-adrenergic receptor is associated with visceral obesity but decreased serum

in the Quebec Family Study and Swedish Obese Subjects cohorts J Clin Invest 98,

2086 – 2093

207 Rissanen, J., Kuopusjarvi, J., Pihlajamaki, J., Sipilainen, R., Heikkinen, S., hala, M., Kekalainen, P., Kuusisto, J and Laakso, M (1997) The Trp64Arg polymor-phism of the beta 3-adrenergic receptor gene Lack of association with NIDDM and

Van-features of insulin resistance syndrome Diabetes Care 20, 1319 – 1323.

208 Thomas, G N., Tomlinson, B., Chan, J C., Young, R P and Critchley, J A (2000)The Trp64Arg polymorphism of the beta3-adrenergic receptor gene and obesity in

Chinese subjects with components of the metabolic syndrome Int J Obes Relat Metab

Disord 24, 545 – 551.

209 Vogeser, M., Zachoval, R., Felbinger, T W and Jacob, K (2002) Increased ratio of

serum cortisol to cortisone in acute-phase response Horm Res 58, 172 – 175.

210 Ferrari, P and Krozowski, Z (2000) Role of the 11beta-hydroxysteroid dehydrogenase

type 2 in blood pressure regulation Kidney Int 57, 1374 – 1381.

211 Williams, L J., Lyons, V., MacLeod, I., Rajan, V., Darlington, G J., Poli, V.,Seckl, J R and Chapman, K E (2000) C/EBP regulates hepatic transcription of11beta-hydroxysteroid dehydrogenase type 1 A novel mechanism for cross-talk

between the C/EBP and glucocorticoid signaling pathways J Biol Chem 275,

30 232 – 30 239

212 White, P C., Agarwal, A K., Nunez, B S., Giacchetti, G., Mantero, F and art, P M (2000) Genotype– phenotype correlations of mutations and polymorphisms

Stew-in HSD11B2, the gene encodStew-ing the kidney isozyme of 11beta-hydroxysteroid

dehy-drogenase Endocr Res 26, 771 – 780.

213 Agarwal, A K., Giacchetti, G., Lavery, G., Nikkila, H., Palermo, M., Ricketts, M.,McTernan, C., Bianchi, G., Manunta, P., Strazzullo, P., Mantero, F., White, P C andStewart, P M (2000) CA-repeat polymorphism in intron 1 of HSD11B2: effects on

gene expression and salt sensitivity Hypertension 36, 187 – 194.

214 Li, A., Li, K X., Marui, S., Krozowski, Z S., Batista, M C., Whorwood, C B.,Arnhold, I J., Shackleton, C H., Mendonca, B B and Stewart, P M (1997) Apparentmineralocorticoid excess in a Brazilian kindred: hypertension in the heterozygote state

mineralocorticoid excess Hypertension 34, 638 – 642.

218 Odermatt, A., Dick, B., Arnold, P., Zaehner, T., Plueschke, V., Deregibus,

M N., Repetto, H., Frey, B M., Frey, F J and Ferrari, P (2001) A mutation

in the cofactor-binding domain of 11beta-hydroxysteroid dehydrogenase type 2

asso-ciated with mineralocorticoid hypertension J Clin Endocrinol Metab 86, 1247 –

1252

219 Sugiyama, T., Kato, N., Ishinaga, Y., Yamori, Y and Yazaki, Y (2001) Evaluation ofselected polymorphisms of the Mendelian hypertensive disease genes in the Japanese

population Hypertens Res 24, 515 – 521.

220 Poch, E., Gonzalez, D., Giner, V., Bragulat, E., Coca, A and de La Sierra, A.(2001) Molecular basis of salt sensitivity in human hypertension Evaluation

of renin – angiotensin – aldosterone system gene polymorphisms Hypertension 38,

1204 – 1209

221 Smith, A D., (2000) Oxford Dictionary of Biochemistry and Molecular Biology.

Revised edn Oxford: Oxford University Press

222 Ruan, H., Hacohen, N., Golub, T R., Van Parijs, L and Lodish, H F (2002) Tumornecrosis factor-alpha suppresses adipocyte-specific genes and activates expression ofpreadipocyte genes in 3T3-L1 adipocytes: nuclear factor-kappaB activation by TNF-

alpha is obligatory Diabetes 51, 1319 – 1336.

223 Xu, H., Uysal, K T., Becherer, J D., Arner, P and Hotamisligil, G S (2002) Alteredtumor necrosis factor-alpha (TNF-alpha) processing in adipocytes and increased

expression of transmembrane TNF-alpha in obesity Diabetes 51, 1876 – 1883.

224 Bullo, M., Garcia-Lorda, P., Peinado-Onsurbe, J., Hernandez, M., Del Castillo, D.,Argiles, J M and Salas-Salvado, J (2002) TNFalpha expression of subcutaneousadipose tissue in obese and morbid obese females: relationship to adipocyte LPL activity

and leptin synthesis Int J Obes Relat Metab Disord 26, 652 – 658.

225 Nilsson, J., Jovinge, S., Niemann, A., Reneland, R and Lithell, H (1998) Relationbetween plasma tumor necrosis factor-alpha and insulin sensitivity in elderly men with

non-insulin-dependent diabetes mellitus Arterioscler Thromb Vasc Biol 18, 1199 – 1202.

226 Chan, J C., Cheung, J C., Stehouwer, C D., Emeis, J J., Tong, P C., Ko, G T andYudkin, J S (2002) The central roles of obesity-associated dyslipidaemia, endothelialactivation and cytokines in the Metabolic Syndrome – an analysis by structural equation

modelling Int J Obes Relat Metab Disord 26, 994 – 1008.

227 Sewter, C., Berger, D., Considine, R V., Medina, G., Rochford, J., Ciaraldi, T.,Henry, R., Dohm, L., Flier, J S., O’Rahilly, S and Vidal-Puig, A J (2002) Humanobesity and type 2 diabetes are associated with alterations in SREBP1 isoform

expression that are reproduced ex vivo by tumor necrosis factor-alpha Diabetes 51,

1035 – 1041

228 Sykiotis, G P and Papavassiliou, A G (2001) Serine phosphorylation of insulin

receptor substrate-1: a novel target for the reversal of insulin resistance Mol Endocrinol

syndrome or altered birth weight in Danish Caucasians J Clin Endocrinol Metab 85,

polymorphism in the metabolic syndrome Metabolism 49, 1021 – 1024.

233 Romeo, S., Sentinelli, F., Capici, F., Arca, M., Berni, A., Vecci, E., Mario, U D andBaroni, M G (2001) The G− 308A variant of the Tumor Necrosis Factor-alpha (TNF-alpha) gene is not associated with obesity, insulin resistance and body fat distribution

236 Fernandez-Real, J M., Gutierrez, C., Ricart, W., Casamitjana, R., Fernandez-Castaner,M., Vendrell, J., Richart, C and Soler, J (1997) The TNF-alpha gene Nco Ipolymorphism influences the relationship among insulin resistance, percent body fat,

and increased serum leptin levels Diabetes 46, 1468 – 1472.

237 Herrmann, S M., Ricard, S., Nicaud, V., Mallet, C., Arveiler, D., Evans, A., ets, J B., Luc, G., Bara, L., Parra, H J., Poirier, O and Cambien, F (1998) Polymor-phisms of the tumour necrosis factor-alpha gene, coronary heart disease and obesity

Ruidav-Eur J Clin Invest 28, 59 – 66.

238 Hoffstedt, J., Eriksson, P., Hellstrom, L., Rossner, S., Ryden, M and Arner, P (2000)Excessive fat accumulation is associated with the TNF alpha −308 G/A promoter

polymorphism in women but not in men Diabetologia 43, 117 – 120.

239 Padovani, J C., Pazin-Filho, A., Simoes, M V., Marin-Neto, J A., Zago, M A andFranco, R F (2000) Gene polymorphisms in the TNF locus and the risk of myocardial

infarction Thromb Res 100, 263 – 269.

240 Brand, E., Schorr, U., Kunz, I., Kertmen, E., Ringel, J., Distler, A and Sharma, A M.(2001) Tumor necrosis factor-alpha−308 G/A polymorphism in obese Caucasians Int

J Obes Relat Metab Disord 25, 581 – 585.

241 Nicaud, V., Raoux, S., Poirier, O., Cambien, F., O’Reilly, D S and Tiret, L (2002)The TNF alpha/G− 308A polymorphism influences insulin sensitivity in offspring ofpatients with coronary heart disease: the European Atherosclerosis Research Study II

Atherosclerosis 161, 317 – 325.

242 Dalziel, B., Gosby, A K., Richman, R M., Bryson, J M and Caterson, I D (2002)Association of the TNF-alpha−308 G/A promoter polymorphism with insulin resistance

in obesity Obes Res 10, 401 – 407.

243 Norman, R A., Bogardus, C and Ravussin, E (1995) Linkage between obesity and a

marker near the tumor necrosis factor-alpha locus in Pima Indians J Clin Invest 96,

158 – 162

244 Kamizono, S., Yamada, K., Seki, N., Higuchi, T., Kimura, A., Nonaka, K and Itoh, K.(2000) Susceptible locus for obese type 2 diabetes mellitus in the 5
-flanking region of

the tumor necrosis factor-alpha gene Tissue Antigens 55, 449 – 452.

245 Skoog, T., Eriksson, P., Hoffstedt, J., Ryden, M., Hamsten, A and Arner, P (2001)Tumour necrosis factor-alpha (TNF-alpha) polymorphisms −857 C/A and −863 C/A

are associated with TNF-alpha secretion from human adipose tissue Diabetologia 44,

654 – 655

246 Rosmond, R (2002) The glucocorticoid receptor gene and its association to metabolic

syndrome Obes Res 10, 1078 – 1086.

247 Beato, M., Herrlich, P and Schutz, G (1995) Steroid hormone receptors: many actors

in search of a plot Cell 83, 851 – 857.

248 Beato, M., Chavez, S and Truss, M (1996) Transcriptional regulation by steroid

hormones Steroids 61, 240 – 251.

249 DeRijk, R H., Schaaf, M and de Kloet, E R (2002) Glucocorticoid receptor variants:

clinical implications J Steroid Biochem Mol Biol 81, 103 – 122.

250 Bjorntorp, P and Rosmond, R (2000) The metabolic syndrome – a neuroendocrine

disorder? Br J Nutr 83 (Suppl 1), S49 – 57.

251 Ukkola, O., Rosmond, R., Tremblay, A and Bouchard, C (2001) Glucocorticoidreceptor Bcl I variant is associated with an increased atherogenic profile in response to

long-term overfeeding Atherosclerosis 157, 221 – 224.

252 Ukkola, O., Perusse, L., Chagnon, Y C., Despres, J P and Bouchard, C (2001)Interactions among the glucocorticoid receptor, lipoprotein lipase and adrenergic

receptor genes and abdominal fat in the Quebec Family Study Int J Obes Relat Metab

Disord 25, 1332 – 1339.

253 Rosmond, R., Chagnon, Y C., Holm, G., Chagnon, M., Perusse, L., Lindell, K.,Carlsson, B., Bouchard, C and Bjorntorp, P (2000) A glucocorticoid receptor genemarker is associated with abdominal obesity, leptin, and dysregulation of the

hypothalamic– pituitary – adrenal axis Obes Res 8, 211 – 218.

254 Buemann, B., Vohl, M C., Chagnon, M., Chagnon, Y C., Gagnon, J., Perusse, L.,Dionne, F., Despres, J P., Tremblay, A., Nadeau, A and Bouchard, C (1997)Abdominal visceral fat is associated with a BclI restriction fragment length

polymorphism at the glucocorticoid receptor gene locus Obes Res 5, 186 – 192.

255 Weaver, J U., Hitman, G A and Kopelman, P G (1992) An association between aBclI restriction fragment length polymorphism of the glucocorticoid receptor locus and

hyperinsulinaemia in obese women J Mol Endocrinol 9, 295 – 300.

256 Rosmond, R., Chagnon, Y C., Chagnon, M., Perusse, L., Bouchard, C and torp, P (2000) A polymorphism of the 5
-flanking region of the glucocorticoid recep-

Bjorn-tor gene locus is associated with basal cortisol secretion in men Metabolism 49,

1197 – 1199

257 Huizenga, N A., Koper, J W., De Lange, P., Pols, H A., Stolk, R P., Burger, H.,Grobbee, D E., Brinkmann, A O., De Jong, F H and Lamberts, S W (1998) Apolymorphism in the glucocorticoid receptor gene may be associated with an increased

sensitivity to glucocorticoids in vivo J Clin Endocrinol Metab 83, 144 – 151.

258 Lin, R C., Wang, W Y and Morris, B J (1999) Association and linkage analyses

of glucocorticoid receptor gene markers in essential hypertension Hypertension 34,

1186 – 1192

259 Rosmond, R., Bouchard, C and Bjorntorp, P (2001) Tsp509I polymorphism in exon 2

of the glucocorticoid receptor gene in relation to obesity and cortisol secretion: cohort

study BMJ 322, 652 – 653.

260 Dobson, M G., Redfern, C P., Unwin, N and Weaver, J U (2001) The N363Spolymorphism of the glucocorticoid receptor: potential contribution to central obesity

in men and lack of association with other risk factors for coronary heart disease and

diabetes mellitus J Clin Endocrinol Metab 86, 2270 – 2274.

261 Ruiz, M., Lind, U., Gafvels, M., Eggertsen, G., Carlstedt-Duke, J., Nilsson, L.,Holtmann, M., Stierna, P., Wikstrom, A C and Werner, S (2001) Characterization oftwo novel mutations in the glucocorticoid receptor gene in patients with primary cortisol

resistance Clin Endocrinol (Oxf) 55, 363 – 371.

262 van Rossum, E F., Koper, J W., Huizenga, N A., Uitterlinden, A G., Janssen, J A.,Brinkmann, A O., Grobbee, D E., de Jong, F H., van Duyn, C M., Pols, H A andLamberts, S W (2002) A polymorphism in the glucocorticoid receptor gene, whichdecreases sensitivity to glucocorticoids in vivo, is associated with low insulin and

cholesterol levels Diabetes 51, 3128 – 3134.

263 Ikeda, Y., Suehiro, T., Tsuzura, S., Shiinoki, T., Kaneda, T., Kumon, Y andHashimoto, K (2001) A polymorphism in the promoter region of the glucocorticoid

receptor gene is associated with its transcriptional activity Endocr J 48, 723 – 726.

264 Schaaf, M J and Cidlowski, J A (2002) AUUUA motifs in the 3
UTR of humanglucocorticoid receptor alpha and beta mRNA destabilize mRNA and decrease receptor

protein expression Steroids 67, 627 – 636.

265 Bjorntorp, P and Rosmond, R (1999) Hypothalamic origin of the metabolic syndrome

X Ann NY Acad Sci 892, 297 – 307.

266 Bjorntorp, P., Holm, G and Rosmond, R (1999) Hypothalamic arousal, insulin

resistance and Type 2 diabetes mellitus Diabet Med 16, 373 – 383.

267 Hagan, M M., Rushing, P A., Schwartz, M W., Yagaloff, K A., Burn, P., Woods,

S C and Seeley, R J (1999) Role of the CNS melanocortin system in the response

to overfeeding J Neurosci 19, 2362 – 2367.

268 Marks, D L and Cone, R D (2001) Central melanocortins and the regulation of

weight during acute and chronic disease Recent Prog Horm Res 56, 359 – 375.

269 Butler, A A., Kesterson, R A., Khong, K., Cullen, M J., Pelleymounter, M A.,Dekoning, J., Baetscher, M and Cone, R D (2000) A unique metabolic syndrome

causes obesity in the melanocortin-3 receptor-deficient mouse Endocrinology 141,

3518 – 3521

270 Kim, K S., Larsen, N., Short, T., Plastow, G and Rothschild, M F (2000) A missensevariant of the porcine melanocortin-4 receptor (MC4R) gene is associated with fatness,

growth, and feed intake traits Mamm Genome 11, 131 – 135.

271 Yeo, G S., Farooqi, I S., Aminian, S., Halsall, D J., Stanhope, R G and O’Rahilly,

S (1998) A frameshift mutation in MC4R associated with dominantly inherited human

obesity Nat Genet 20, 111 – 112.

272 Vaisse, C., Clement, K., Guy-Grand, B and Froguel, P (1998) A frameshift mutation

in human MC4R is associated with a dominant form of obesity Nat Genet 20, 113 – 114.

273 Yeo, G S., Farooqi, I S., Challis, B G., Jackson, R S and O’Rahilly, S (2000) Therole of melanocortin signalling in the control of body weight: evidence from human

and murine genetic models QJM 93, 7 – 14.

274 Vaisse, C., Clement, K., Durand, E., Hercberg, S., Guy-Grand, B and Froguel, P.(2000) Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of

morbid obesity J Clin Invest 106, 253 – 262.

275 Ho, G and MacKenzie, R G (1999) Functional characterization of mutations

in melanocortin-4 receptor associated with human obesity J Biol Chem 274,

35 816 – 35 822

276 Schwartz, M W., Woods, S C., Porte, D., Jr., Seeley, R J and Baskin, D G (2000)

Central nervous system control of food intake Nature 404, 661 – 671.

277 Rossi, M., Kim, M S., Morgan, D G., Small, C J., Edwards, C M., Sunter, D., nana, S., Goldstone, A P., Russell, S H., Stanley, S A., Smith, D M., Yagaloff, K.,Ghatei, M A and Bloom, S R (1998) A C-terminal fragment of Agouti-related proteinincreases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone

Abus-in vivo EndocrAbus-inology 139, 4428 – 4431.

278 Hagan, M M., Rushing, P A., Pritchard, L M., Schwartz, M W., Strack, A M., VanDer Ploeg, L H., Woods, S C and Seeley, R J (2000) Long-term orexigenic effects

of AgRP-(83 – 132) involve mechanisms other than melanocortin receptor blockade Am

J Physiol Regul Integr Comp Physiol 279, R47 – 52.

279 Rosenfeld, R D., Zeni, L., Welcher, A A., Narhi, L O., Hale, C., Marasco, J.,Delaney, J., Gleason, T., Philo, J S., Katta, V., Hui, J., Baumgartner, J., Graham, M.,Stark, K L and Karbon, W (1998) Biochemical, biophysical, and pharmacological

characterization of bacterially expressed human agouti-related protein Biochemistry

37, 16 041 – 16 052.

280 Graham, M., Shutter, J R., Sarmiento, U., Sarosi, I and Stark, K L (1997)

Overexpression of Agrt leads to obesity in transgenic mice Nat Genet 17, 273 – 274.

281 Mayfield, D K., Brown, A M., Page, G P., Garvey, W T., Shriver, M D andArgyropoulos, G (2001) A role for the agouti related protein promoter in obesity and

type 2 diabetes Biochem Biophys Res Commun 287, 568 – 573.

282 Katsuki, A., Sumida, Y., Gabazza, E C., Murashima, S., Tanaka, T., Furuta, M.,Araki-Sasaki, R., Hori, Y., Nakatani, K., Yano, Y and Adachi, Y (2001) Plasma levels

of agouti-related protein are increased in obese men J Clin Endocrinol Metab 86,

284 Argyropoulos, G., Rankinen, T., Bai, F., Rice, T., Province, M., Leon, A., Skinner, J.,Wilmore, J., Rao, D and Bouchard, B (2003) The agouti related protein promoter and

body fatness in humans Int J Obes Relat Metab Disord 27, 276 – 280.

285 Argyropoulos, G., Rankinen, T., Neufeld, D R., Rice, T., Province, M A., Leon,

A S., Skinner, J S., Wilmore, J H., Rao, D C and Bouchard, C (2002) Apolymorphism in the human agouti-related protein is associated with late-onset obesity

J Clin Endocrinol Metab 87, 4198 – 4202.

286 Vink, T., Hinney, A., van Elburg, A A., van Goozen, S H., Sandkuijl, L A.,Sinke, R J., Herpertz-Dahlmann, B M., Hebebrand, J., Remschmidt, H., van Enge-land, H and Adan, R A (2001) Association between an agouti-related protein gene

polymorphism and anorexia nervosa Mol Psychiatry 6, 325 – 328.

287 Raposinho, P D., Pierroz, D D., Broqua, P., White, R B., Pedrazzini, T andAubert, M L (2001) Chronic administration of neuropeptide Y into the lateralventricle of C57BL/6J male mice produces an obesity syndrome including hyperphagia,

hyperleptinemia, insulin resistance, and hypogonadism Mol Cell Endocrinol 185,

195 – 204

288 Halford, J C (2001) Pharmacology of appetite suppression: implication for the

treatment of obesity Curr Drug Targets 2, 353 – 370.

289 Erickson, J C., Hollopeter, G and Palmiter, R D (1996) Attenuation of the obesity

syndrome of ob/ob mice by the loss of neuropeptide Y Science 274, 1704 – 1707.

290 Naveilhan, P., Canals, J M., Arenas, E and Ernfors, P (2001) Distinct roles of the Y1

and Y2 receptors on neuropeptide Y-induced sensitization to sedation J Neurochem 78,

1201 – 1207

291 Chamorro, S., Della-Zuana, O., Fauchere, J L., Feletou, M., Galizzi, J P andLevens, N (2002) Appetite suppression based on selective inhibition of NPY receptors

Int J Obes Relat Metab Disord 26, 281 – 298.

292 Sainsbury, A., Schwarzer, C., Couzens, M., Fetissov, S., Furtinger, S., Jenkins, A.,Cox, H M., Sperk, G., Hokfelt, T and Herzog, H (2002) Important role ofhypothalamic Y2 receptors in body weight regulation revealed in conditional knockout

mice Proc Natl Acad Sci USA 99, 8938 – 8943.

293 Kallio, J., Pesonen, U., Kaipio, K., Karvonen, M K., Jaakkola, U., Heinonen, O J.,Uusitupa, M I and Koulu, M (2001) Altered intracellular processing and release ofneuropeptide Y due to leucine 7 to proline 7 polymorphism in the signal peptide of

preproneuropeptide Y in humans FASEB J 15, 1242 – 1244.

294 Niskanen, L., Voutilainen-Kaunisto, R., Terasvirta, M., Karvonen, M K., Valve, R.,Pesonen, U., Laakso, M., Uusitupa, M I and Koulu, M (2000) Leucine 7 to proline

7 polymorphism in the neuropeptide y gene is associated with retinopathy in type 2

diabetes Exp Clin Endocrinol Diabetes 108, 235 – 236.

295 Karvonen, M K., Valkonen, V P., Lakka, T A., Salonen, R., Koulu, M., Pesonen, U.,Tuomainen, T P., Kauhanen, J., Nyyssonen, K., Lakka, H M., Uusitupa, M I andSalonen, J T (2001) Leucine7 to proline7 polymorphism in the preproneuropeptide

Y is associated with the progression of carotid atherosclerosis, blood pressure and

serum lipids in Finnish men Atherosclerosis 159, 145 – 151.

296 Erkkila, A T., Lindi, V., Lehto, S., Laakso, M and Uusitupa, M I (2002) Association

of leucine 7 to proline 7 polymorphism in the preproneuropeptide Y with serum lipids

in patients with coronary heart disease Mol Genet Metab 75, 260 – 264.

297 Kauhanen, J., Karvonen, M K., Pesonen, U., Koulu, M., Tuomainen, T P., tupa, M I and Salonen, J T (2000) Neuropeptide Y polymorphism and alcohol con-

Uusi-sumption in middle-aged men Am J Med Genet 93, 117 – 121.

298 Lappalainen, J., Kranzler, H R., Malison, R., Price, L H., Van Dyck, C., heck, R A., Cramer, J., Southwick, S., Charney, D., Krystal, J and Gelernter, J (2002)

Rosen-A functional neuropeptide Y Leu7Pro polymorphism associated with alcohol

depen-dence in a large population sample from the United States Arch Gen Psychiatry 59,

825 – 831

299 Jequier, E (2002) Leptin signaling, adiposity, and energy balance Ann NY Acad Sci

967, 379 – 388.

300 Elmquist, J K (2001) Hypothalamic pathways underlying the endocrine, autonomic,

and behavioral effects of leptin Physiol Behav 74, 703 – 708.

301 Ludvigsen, S., Thim, L., Blom, A M and Wulff, B S (2001) Solution structure of the

satiety factor, CART, reveals new functionality of a well-known fold Biochemistry 40,

9082 – 9088

302 Yermolaieva, O., Chen, J., Couceyro, P R and Hoshi, T (2001) Cocaine- andamphetamine-regulated transcript peptide modulation of voltage-gated Ca2 + signaling

in hippocampal neurons J Neurosci 21, 7474 – 7480.

303 Elias, C F., Lee, C E., Kelly, J F., Ahima, R S., Kuhar, M., Saper, C B andElmquist, J K (2001) Characterization of CART neurons in the rat and human

hypothalamus J Comp Neurol 432, 1 – 19.

304 Elias, C F., Lee, C., Kelly, J., Aschkenasi, C., Ahima, R S., Couceyro, P R.,Kuhar, M J., Saper, C B and Elmquist, J K (1998) Leptin activates hypothalamic

CART neurons projecting to the spinal cord Neuron 21, 1375 – 1385.

305 Dhillo, W S and Bloom, S R (2001) Hypothalamic peptides as drug targets for

obesity Curr Opin Pharmacol 1, 651 – 655.

306 Yamada, K., Yuan, X., Otabe, S., Koyanagi, A., Koyama, W and Makita, Z (2002)Sequencing of the putative promoter region of the cocaine- and amphetamine-regulated-

transcript gene and identification of polymorphic sites associated with obesity Int J

Obes Relat Metab Disord 26, 132 – 136.

307 Challis, B G., Yeo, G S., Farooqi, I S., Luan, J., Aminian, S., Halsall, D J.,Keogh, J M., Wareham, N J and O’Rahilly, S (2000) The CART gene and human

obesity: mutational analysis and population genetics Diabetes 49, 872 – 875.

308 Cowley, M A., Smart, J L., Rubinstein, M., Cerdan, M G., Diano, S., Horvath, T L.,Cone, R D and Low, M J (2001) Leptin activates anorexigenic POMC neurons

through a neural network in the arcuate nucleus Nature 411, 480 – 484.

309 Butler, A A and Cone, R D (2001) Knockout models resulting in the development

of obesity Trends Genet 17, S50 – 54.

310 Yaswen, L., Diehl, N., Brennan, M B and Hochgeschwender, U (1999) Obesity in themouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin

Nat Med 5, 1066 – 1070.

311 Challis, B G., Pritchard, L E., Creemers, J W., Delplanque, J., Keogh, J M., Luan,J., Wareham, N J., Yeo, G S., Bhattacharyya, S., Froguel, P., White, A., Farooqi, I S.and O’Rahilly, S (2002) A missense mutation disrupting a dibasic prohormoneprocessing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset

obesity through a novel molecular mechanism Hum Mol Genet 11, 1997 – 2004.

312 Comuzzie, A G., Hixson, J E., Almasy, L., Mitchell, B D., Mahaney, M C., Dyer,

T D., Stern, M P., MacCluer, J W and Blangero, J (1997) A major quantitative traitlocus determining serum leptin levels and fat mass is located on human chromosome

2 Nat Genet 15, 273 – 276.

313 Rutkowski, M P., Klanke, C A., Su, Y R., Reif, M and Menon, A G (1998)Genetic markers at the leptin (OB) locus are not significantly linked to hypertension in

African Americans Hypertension 31, 1230 – 1234.

314 Kissebah, A H., Sonnenberg, G E., Myklebust, J., Goldstein, M., Broman, K.,James, R G., Marks, J A., Krakower, G R., Jacob, H J., Weber, J., Martin, L.,