International Textbook of Obesity - part 3 pptx

Role of Neuropeptides and Leptin in Food Intake and Obesity Lilly Corporate Center, Indianapolis, Indiana, USA and Geneva University School of Medicine, Geneva, Switzerland Interrelation

Methods of evaluating adiposity and adipose tissue

distribution have advanced substantially in the past

decade Stimulated by the rising worldwide

preva-lence of obesity, new methods are under

develop-ment that promise to advance the field The point

has now been reached, however, at which excellent

methods of quantifying fatness are available for

application in field, clinical, and researchsettings

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21 McCrory MA, Gomez TD, Bernauer EM, Mole PA ation of a new air displacement plethysmograph for measur-

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24 Mazess, RB, Barden H, Bisek J, Hanson J, Dual energy X-ray absorptiometry for total-body and regional bone-

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96 INTERNATIONAL TEXTBOOK OF OBESITY

30 Chumlea WC, Guo SS Bioelectrical impedance and body

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34 Guo SS, Chumlea WC, Coockram DB Use of statistical

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35 Jensen MD, Kanaley JA, Reed JE, Sheedy PF Measurement

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37 Chettle DR, Fremlin JH Techniques of in vivo neutron

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40 Kehayias JJ, Heymsfield SB, LoMonte AF, Wang J, Pierson

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97 EVALUATION OF HUMAN ADIPOSITY

Part III

Appetite Regulation and Obesity

Prevention

MMMM

Role of Neuropeptides and Leptin

in Food Intake and Obesity

Lilly Corporate Center, Indianapolis, Indiana, USA and Geneva University School of Medicine,

Geneva, Switzerland

Interrelationships Between

Hypothalamic Neuropeptides and

Leptin in the Maintenance of Body

Weight Homeostasis, or Evolution to

Obesity

It is now accepted that body weight homeostasis is

maintained via a series of complex interactions that

occur between the brain, the hypothalamus in

par-ticular, and the periphery (1—3), notably via a

hor-mone, leptin, synthesized in and secreted from

adi-pose tissue (4) Secreted leptin, although it may have

direct peripheral effects, exerts its action principally

within the brain Following its transport through

the blood—brain barrier, possibly via the short

lep-tin receptor isoform (ObRa), leplep-tin reaches the

hy-pothalamic area where it binds to its long receptor

isoform (ObRb) Following a specific signaling

cas-cade, leptin inhibits many of the orexigenic

neur-opeptides, while favoring many of the anorexigenic

ones, as discussed below By doing so, leptin exerts

its effects of decreasing food intake and body

weight, increasing fat oxidation and energy

expen-diture, thus favoring leanness (5—11).

In the present review, the characteristics of the

main orexigenic and anorexigenic neuropeptides

will be summarized (Figure 7.1) and putative effects

of leptin thereon described or, when such effects of

leptin are defective, the main reasons for the

estab-lishment of a state of obesity will be outlined ure 7.2)

(Fig-OREXIGENIC NEUROPEPTIDES Effects of Neuropeptide Y (NPY)

NPY is a 36 amino acid neuropeptide that is widelydistributed in the brain In the hypothalamus, it issynthesized in the arcuate nucleus and released inthe paraventricular nucleus It stimulates food in-take by binding to Y1 and /or Y5 receptor subtypes

(12—14) This increase in feeding can be observed

upon infusing the peptide intracerebroventricularly(i.c.v.) in normal rats and is accompanied by a rapid,sustained and marked increase in body weight(15,16) Central NPY infusion also stimulates insu-lin secretion via an activation of the parasym-pathetic nervous system reaching the endocrinepancreas (17) Concomitantly, central NPY admin-istration increases the activity of the hypothalamo-pituitary-adrenal axis, with resulting hypercorticos-teronemia and increased susceptibility to stressfulsituations (15,17) Finally, central NPY reduces theactivity of the efferent sympathetic nerves reachingbrown adipose tissue, with resulting decrease inenergy dissipation as heat (18,19)

The metabolic consequences of the hormonal

International Textbook of Obesity Edited by Per Bjo¨rntorp.

International Textbook of Obesity Edited by Per Bjorntorp.

Copyright © 2001 John Wiley & Sons Ltd Print ISBNs: 0-471-988707 (Hardback); 0-470-846739 (Electronic)

Figure 7.1 Diagram of food intake regulation by orexigenic and anorexigenic neuropeptides Stimulators of food intake are depicted

as increasing the diameter of a tube by exerting a pressure ( ;) from inside, with agouti-related peptide (AGRP) mainly exerting its action by inhibiting the melanocortin system (
-MSH and MC4 receptor), the effect of which is to reduce this diameter Inhibitors of food intake are depicted as reducing ( 9) the diameter of the tube, with AGRP having little effect on the melanocortin system, allowing the latter to largely contribute to reducing this diameter NPY, neuropeptide Y; MCH, melanin concentrating hormone; ORE, orexins;

-MSH,
-melanocyte-stimulating hormone and the melanocortin-4 (MC4-R) receptor; CRH, corticotropin-releasing hormone, CART, cocaine- and amphetamine-regulated transcript; NT, neurotensin Not all neuropeptides are represented Solid lines indicate marked effects, dotted ones weak effects

changes produced by central NPY infusion

(in-creased plasma insulin and corticosterone levels)

are increased adipose tissue and liver lipogenic

ac-tivity, changes mainly due to hyperinsulinemia

(15,16), together with decreased insulin-stimulated

glucose utilization by muscles (15,16) This muscle

insulin resistance is likely to be due to the combined

NPY-induced

hyperinsulinemia/hypercorticostero-nemia (1)

It should be noted that the NPY-elicited effects

are very marked when exogenous NPY is

chroni-cally infused i.c.v., resulting in high central

concen-trations of the neuropeptide Physiologically,

how-ever, it is thought that these changes are modest,

occurring via the spontaneous fluctuations of

hy-pothalamic NPY levels, which transiently change

nutrient partitioning toward fat accretion and

de-creased oxidation processes This situation persists

until leptin is secreted into the blood as a result of

hormonal changes such as transient sulinemia in response to meal taking Secreted lep-tin reaches the brain and decreases hypothalamicNPY levels by exerting its negative feedback inhibi-tion on the expression and amount of this neur-

hyperin-opeptide (20—22) Experiments have shown,

how-ever, that in addition to NPY, other brainneuropeptidic systems play a role in the regulation

of food intake Thus, in transgenic mice made cient in NPY, the expected decrease in both foodintake and body weight fails to occur (23,24) Trans-genic mice lacking the NPY-Y1 or Y5 receptoractually gain more weight, not less, than the con-trols (25,26) This indicates that the regulation offood intake and body weight is redundant, i.e thatseveral pathways are implicated and that when one

defi-of them is knocked out, others take over to tain a normal body weight homeostasis

main-102 INTERNATIONAL TEXTBOOK OF OBESITY

Figure 7.2 Diagram of the central effects of leptin on food intake Leptin is depicted as decreasing the diameter of a tube relative to a

normal one (dotted lines), due to its dual effect of reducing ( ) the expression or amount of neuropeptides that stimulate food intake (neuropeptide Y, NPY; melanin concentrating hormone, MCH; orexin, ORE; agouti-related protein, AGRP) and of increasing ( !) the expression or amount of neuropeptides that inhibit food intake (cocaine- and amphetamine-regulated transcript, CART; corticotropin- releasing hormone, CRH; the melanocortin system with proopiomelanocortin, POMC,
-MSH and the melanocortin-4 receptor, MC4-R) The effect of leptin on food intake (FI) is accompanied by increased fat oxidation and energy (E) expendidure, the three parameters together producing leanness

NPY and Obesity

When considering the hormono-metabolic changes

produced by central NPY, one realizes that

experi-mentally produced increases in central levels of this

neuropeptide reproduce most of the abnormalities

observed in experimental or genetic obesity

syn-dromes (15,16), as well as in human obesity The

pathological relevance of increased hypothalamic

NPY levels in mimicking obesity syndromes is

sup-ported by the observation that NPY expression and

levels are indeed increased in the ob/ob, db/db obese

mice and in the fa/fa obese rat (1,20—22) Increased

NPY levels in ob/ob mice are due to the lack of

synthesis and secretion of leptin in adipose tissue,

the ob (leptin) gene being mutated As a result of this

mutation, plasma leptin levels are nil, leptin fails to

exert its negative feedback on hypothalamic NPY

levels which remain continually elevated

maintain-ing, probably with other neuropeptides that are

influenced by leptin, the obesity syndrome (1,27) In

the db/db and the fa/fa obese rodents, the ob gene of

adipose tissue is normal, but the long form leptin

receptor is mutated in its intracellular (db/db) (5) or extracellular (fa/fa) (28) domain Even though leptin

is overproduced by adipose tissue, bringing about astate of hyperleptinemia, it cannot act centrally andhypothalamic NPY levels remain high The latter,probably in concert with other neuropeptides,maintain the obesity syndrome (29)

Effects of Melanin Concentrating

Hormone (MCH)

MCH is a cyclic neuropeptide comprising 19 aminoacids which is present in many areas of the brain,notably in the lateral hypothalamus (30) Its namederives from its ability to cause melanosome aggre-gation in fish skin, an action which is antagonized

by
-MSH, the melanosome-dispersing factor cently, a role for MCH in the central regulation

Re-of food intake has been discovered, i.c.v MCH

103 ROLE OF NEUROPEPTIDES AND LEPTIN IN OBESITY

administration increasing food intake in normal

rats (31,32) As for the melanosome aggregation/

dispersion system, the action of
-MSH is the

oppo-site of that of MCH, resulting in decreased food

intake (33) The antagonistic action of MCH and

-MSH extends to the regulation of the

hy-pothalamo-pituitary-adrenal (HPA) axis, MCH

de-creasing plasma corticosterone and ACTH levels

relative to controls, while
-MSH does the contrary,

increasing plasma corticosterone and ACTH levels

(33)

I.c.v administration of a single dose of MCH

results in stimulation of food intake that is

dose-dependent, lasts for about 6 hours (32,33), but is

moderate in amplitude when compared to the effect

of NPY (34) The feeding effect of central MCH

administration is counteracted not only by
-MSH

as just mentioned, but also by glucagon-like peptide

(GLP-1) and neurotensin (34)

As is the case for NPY, central leptin

administra-tion decreases hypothalamic MCH expression and

prevents MCH-induced increase in food intake

(35,36) However, contrary to what is observed with

NPY, long-term central MCH administration fails

to produce sustained increases in food intake or in

body weight gain, thus obesity (32) This is in

con-trast with the observation that, in the obese ob/ob

mouse, hypothalamic MCH expression is increased

and may participate in the final development of the

obese phenotype (31)

To strengthen the physiological role of MCH in

food intake regulation, mice carrying a targeted

deletion of the MCH gene have been produced

When compared to controls, these mice are

hy-pophagic, leaner, have decreased carcass lipids, and

increased metabolic rate (37) Thus, MCH does

rep-resent an important hypothalamic pathway in the

regulation of body weight homeostasis, a pathway

further completed recently by the discovery of a 353

amino acid G-protein-coupled receptor, to which

MCH specifically binds (38,39) Such a receptor is

present in the hypothalamus and many other brain

regions, in keeping with the several functions,

be-yond the feeding behavior, that are under the

influ-ence of MCH (38,39)

Effects of Orexins

Orexin A and B (from the Greek word for appetite)

have been discovered recently and are also referred

to as ‘hypocretins’ (due to their hypothalamic tion and sequence analogy to secretin) (40,41).Orexin A (33 amino acids) and orexin B (28 aminoacids) neurons are restricted to the lateral and pos-terior hypothalamus, whereas both orexin A andorexin B fibers project widely into different areas of

loca-the brain (42—45) The corresponding cloned

recep-tors, OX1 and OX2, are found in the hypothalamus(ventromedial hypothalamic nucleus, paraventricu-lar nucleus) a distribution that is receptor-specific(41,46)

The stimulatory effect of central administration

of orexin on food intake is much weaker than that

of NPY, and is smaller than that elicited by MCH.Orexin A is more potent than orexin B in elicitingfeeding, and its effect is consistent, whereas that oforexin B is not (47, 48) When given peripherally,orexin A rapidly enters the brain by simple diffusion

as it is highly lipophilic, while orexin B with its lowlipophilicity is degraded, thus failing to reach thebrain adequately (49) The fact that orexin B iseasily inactivated by endopeptidases could be one

of the reasons for its relative inefficiency in ting food intake In a way similar to what has beenobserved with NPY, some of the centrally elicitedeffects of orexin A, e.g the stimulation of gastricacid secretion, are mediated by an activation of theparasympathetic nervous system, favoring anabolicprocesses (50)

regula-Leptin administration produces a diminution oforexin A levels in the lateral hypothalamus (51), afinding that is in keeping with the observation of thepresence of numerous leptin receptors on orexin-immunoreactive neurons in the lateral hy-pothalamus (52) Additional data must be gatheredfor the physiological role of the orexin system infood intake regulation to be better understood

Effects of Opioids

The endogenous opioid system has long beenknown to play a role in the regulation of ingestivebehavior The opioid peptides exert their action via

a complex receptor subtype system implicating ppa, mu and delta receptors for, respectively, dynor-phin, -endorphin and the enkephalins (53) Thespecific modulation of taste and food intake can bepartly understood by the use of selective receptorsubtype agonists and antagonists (54,55) Typically,

ka-104 INTERNATIONAL TEXTBOOK OF OBESITY

the central administration of opioid agonists

stimu-lates food intake, decreases the latency to feed,

in-creases the number of interactions with the food,

favors fat as well as sucrose ingestion, and increases

body weight gain (54,56—60) In contrast, the central

administration of opioid antagonists does the

re-verse, decreasing food intake and body weight

(55,60—62).

The three major types of opioid receptors, mu,

kappa, delta, have been cloned and belong to the

G-protein-coupled family Recently, another

recep-tor highly homologous to the opioid receprecep-tors, but

one that does not bind any opioid peptide with high

affinity, has been cloned (63) This opioid

receptor-like (ORL-1) is widely distributed within the central

nervous system (CNS), the hypothalamus,

hip-pocampus, and the amygdala, in particular (64)

The endogenous ligand for this opioid-like orphan

receptor has now been isolated (63) It is called

nociceptin (as it increases pain responsiveness), or

orphanin FQ It is an 18 amino acid peptide which

resembles dynorphin A and has a marked affinity

for ORL-1 (63—65) Nociceptin and ORL-1 thus

constitute a new peptidergic system within the

CNS, a system of potential interest as it is present

not only in rodents, but also in humans (64,65)

When given centrally, nociceptin stimulates food

intake in satiated rats, an effect that is blocked by an

opioid antagonist, naloxone As naloxone does not

act at the level of ORL-1, this indicates that

stimula-tion of food intake by nociceptin involves, at some

ill-defined steps, the function of the ‘classical’ opioid

system (65) Microinjection of nociceptin into two

brain areas implicated in food intake (the

ven-tromedial hypothalamic nucleus and the nucleus

accumbens) also results in increased in food intake

(64) The physiopathological implications of these

findings will soon be unraveled

Opioids and Obesity

The susceptibility to diet-induced obesity in the rat

is strain dependent For example, some strains of

rats (e.g Osborne-Mendel) overeat and become

obese when fed a diet rich in fat Other strains (e.g

S5B/P1) are resistant to high fat diet-induced

obes-ity (66) In this context, it is interesting that central

administration of a kappa opioid receptor

antagon-ist decreases the intake of a high fat diet in the

obesity-prone rats, while it does not do so in the

obesity-resistant ones In contrast, the central

ad-ministration of a kappa opioid receptor agonistincreases the intake of a high fat diet in obesity-prone rats, while it increases the intake of any type

of diet in obesity-resistant animals (66) It is thusconceivable that the sensitivity to opioids differsfrom strain to strain, possibly from species to spe-cies It is also possible that, within the brain areasconstituting the opioid system, the distribution ofthe opioids, that of their receptors, may vary fromstrain to strain This may lead to a strain-specificopioid dependency of the food intake process andevolution to obesity (66)

The likely importance of the opioid system inobesity is illustrated by the observation that theperipheral administration of compounds with po-tent opioid antagonistic activity to obese rats re-sults in rapid, marked and sustained decreases infood intake and body weight gain (67,68)

ANOREXIGENIC PEPTIDES Effects of Cocaine- and Amphetamine-Regulated Transcript

(CART)

Cocaine- and amphetamine-regulated transcript(CART) is a recently discovered hypothalamic pept-ide which is regulated by leptin and is endowed withappetite-suppressing activity (69,70) In the rat, theCART gene encodes a peptide of either 129 or 116amino acid residues (70) In contrast, only the shortform of CART exists in humans (70) The maturepeptide contains several potential cleavage sites andCART may be post-transcriptionally processedinto several biologically active fragments Thus, inmost tissues studied, CART peptides are short,

CART (42—89) being found in the rat hypothalamus

(71) This tissue processing of CART resulting inneuropeptides of different lengths may indicate thatdifferent CART peptides have different biologicalfunctions (71)

Acute i.c.v CART administration to normal ratsproduces a dose-dependent decrease in food intake(69,72) CART also transiently decreases the NPY-elicited feeding response in normal rats (69) Finally,CART appears to have a tonic inhibitory influence

on food intake, as treatment of rats with anti-CARTantiserum results in increased food intake (69).CART is regulated, in part, by leptin as chronic

105 ROLE OF NEUROPEPTIDES AND LEPTIN IN OBESITY

peripheral leptin administration to the

leptin-defi-cient ob/ob mice results in a definite augmentation

of the low expression of CART measured in the

hypothalamic arcuate nucleus of these animals, an

increase that is paralleled by the observed decrease

in body weight CART expression is also markedly

reduced in the genetically obese leptin-resistant fa/

fa rat, thus possibly playing a role in the

hyper-phagia of this animal (69) The physiological and

pathological importance of CART has yet to be

substantiated, although preliminary results with

chronic infusion of the neuropeptide appear to

indi-cate that it markedly reduces food intake and body

weight of both normal and obese rats

Effects of Corticotropin-releasing

Hormone (CRH)

Apart from its role as controller of the

hy-pothalamo-pituitary-adrenal (HPA) axis, CRH, a

41 amino acid neuropeptide, also functions as a

central effector molecule that brings about a state of

negative energy balance and weight loss This is due

to the ability of central CRH to decrease food

in-take (73), to increase the activity of the sympathetic

nervous system and to stimulate thermogenesis

(73—75) CRH also influences gastrointestinal

func-tions, inhibiting gastric acid secretion and gastric

emptying, processes that are controlled by the

para-sympathetic nervous system (76—79) Chronic i.c.v.

CRH administration in normal (73), genetically

obese fa/fa rats (80), as well as in monkeys (81),

decreases food intake and body weight, partly by

acting on energy dissipating mechanisms Central

microinjections of CRH were shown to inhibit

NPY-induced feeding (82), in keeping with the

no-tion that the locally released CRH could restrain

the effect of NPY and/or of other orexigenic signals

Leptin administration results in transient increases

in hypothalamic CRH levels, thus potentially

favor-ing the CRH effects just mentioned (22) The leptin

effect on CRH could occur via its increasing CRH

type 2 receptor (CRHR-2) expression in the

ven-tromedial hypothalamus, as these receptors are

po-tentially responsible for the CRH-mediated

de-crease in food intake and sympathetic nervous

a 13amino acid peptide which binds with differentaffinities to five different subtypes of G-protein-coupled receptors An involvement of
-MSH inbody weight homeostasis via an interaction withthe melanocortin-4 (MC4), possibly the MC3recep-tors, has been recently described MC3receptorsare present mainly in the hypothalamus, MC4 re-ceptors throughout the brain and in the sympath-etic nervous system (85,86) When administeredi.c.v to normal rats,
-MSH decreases food intake(34), as does the central administration of a stablelinear analog of
-MSH, NDP-MSH (87) The rela-tionships existing between the melanocortins, theirreceptor subtypes and feeding have been illustrated

by studying synthetic melanocortin receptor ists and antagonists, amongst which are the com-pounds called MTII and SHU9119 (85,88) Thei.c.v administration of the agonist MTII markedlyand dose-dependently inhibits food intake, whilethat of the antagonist SHU9119 markedly anddose-dependently stimulates food intake process(85,89) The co-injection of equal concentrations ofthe agonist and of the antagonist results in a foodintake that is identical to that of control rats (85) Inaddition, MTII inhibits or suppresses, depending

agon-on the dose, the feeding respagon-onse elicited by opeptide Y (85), in keeping with the observationthat both MC3and MC4 receptors are found inCNS sites in which NPY neurons are also present(90)

neur-The effect of
-MSH in decreasing food intake isunder the ‘tonic’ inhibitory influence from amelanocortin-receptor antagonist called ‘agouti-re-lated protein’ (AGRP) When an active fragment ofAGRP is administered i.c.v to rats, an increasedfood intake is observed Moreover, when
-MSH issimilarly administered, the observed decrease infood intake is blocked by the further addition ofAGRP (91)

The fundamental importance of the MC4 tors has been highlighted by obtaining transgenic

recep-106 INTERNATIONAL TEXTBOOK OF OBESITY

mice lacking the MC4 receptors (MC4-R-deficient

mice) These mice (female and male) exhibit

in-creased food intake and become obese Both sexes

have marked hyperinsulinemia, hyperleptinemia,

with either normoglycemia (females) or

hyper-glycemia (males), plasma corticosterone levels being

normal These data support the view that MC4

receptors are essential in the cascade of events

nor-mally leading to decreased food intake and leanness

(92) The decreased food intake produced by

-MSH and the subsequent cascade of events

sum-marized above is accompanied by a change in the

activity of the sympathetic nervous system Thus,

activation of the MC3/MC4-receptor system by the

agonist MTII administered centrally results in a

marked, specific, dose-dependent activation of the

sympathetic nerves innervating the brown adipose

tissue, as well as the renal and lumbar beds, while no

change in blood pressure or heart rate is observed

(93) The combination of decreased food intake and

increased sympathetic activation with likely

in-crease in energy dissipation suggests that the

melanocortin system is well adapted to play a role

in decreases in body weight

Since the main central effects of leptin are to

decrease food intake and body weight, and to

in-crease energy dissipation, it has been postulated

that this hormone could bring about these changes

by influencing the melanocortin system It is thus of

interest to observe that the effect of leptin in

de-creasing food intake is blocked by a MC4 receptor

antagonist (SHU9119), and that pretreatment with

the antagonist is able to prevent the effects of leptin

in decreasing both food intake and body weight

This effect is specific as the antagonist did not affect

the decreased food intake produced by another

peptide (GLP-1) (94) Thus, the MC4-receptor

sig-naling is important in mediating the effects of leptin

In keeping with this finding is the observation that

the MC4 receptor agonist, MTII, which decreases

food intake in normal animals, also suppresses the

hyperphagia of the leptin-deficient ob/ob mice This

suggests that leptin acts via MC4 receptors and that

in the absence of leptin, i.e in ob/ob mice, the lack of

signaling through MC4 receptors would be

respon-sible for the increased food intake (95), a viewpoint

that remains to be fully validated (96)

When considering POMC (the precursor of

melanocortins, of
-MSH) and AGRP (the

antag-onist of the MC4 receptor), it is of interest to

ob-serve that the lack of leptin in the ob/ob mouse (or

lack of leptin signaling in the db/db one) is

accom-panied by a decrease in POMC expression and an

increase in that of AGRP (97—99) Moreover, leptin

administration leads to an increase in POMC

ex-pression and a decrease in that of AGRP (100—103).

It may thus be concluded that leptin decreases foodintake and body weight, in part by favoring theaction of melanocortin neuropeptide(s) at the MC4receptor, while concomitantly preventing the in-hibitory influence of AGRP on this same receptor, aconcept excellently reviewed elsewhere (102) Thisspecific effect of leptin is probably additive to itsinhibitory one on hypothalamic NPY levels, NPYbeing one of the most potent food stimulators asdescribed above, and being co-expressed withAGRP within the arcuate nucleus of the hy-pothalamus (104)

The Melanocortin System and Obesity

Obesity, as mentioned above, may result from

alter-ed functions of the MC4 receptors This is trated in a global fashion by the observation thatwhen the melanocortin receptor agonist (MTII) is

illus-administered i.c.v to fasted—refed hyperphagic mice, to obese ob/ob mice, to yellow (Ay) obese mice,

to NPY hyperphagic mice, their respective phagia is largely canceled (95) In addition, it hasbeen recently demonstrated that mice lackingPOMC (hence lacking subsequent
-MSH syn-thesis and its inhibitory effect on feeding via itsbinding to MC4 receptors) overeat and becomeobese, a situation partly reversed by an
-MSHtreatment (105)

hyper-The yellow obese mouse is an interesting animalmodel that underlines the potential importance ofthe melanocortin system As reviewed recently, thepigment produced by melanocytes in the skin isunder the regulation of
-MSH and a paracrinemelanocyte signaling molecule called ‘agouti’ (fromAmerican Spanish ‘aguti’, meaning alternation oflight and dark bands of colors in the fur of variousanimals) Agouti binds to MC1 receptors and de-creases their signaling, resulting in decreased cAMPlevels, thereby inducing melanocytes to synthesize ayellow pigment (pheomelanin)
-MSH binds toMC1 receptors and increases their signaling, result-ing in increased cAMP, thereby stimulating the syn-thesis of a black pigment (eumelanin) The classicalagouti hair color of many species appears brown,although the ‘brown’ hairs are in fact black-yellow-

107 ROLE OF NEUROPEPTIDES AND LEPTIN IN OBESITY

black banded hairs, due to the joint effects of agouti

and
-MSH The yellow mouse (A) is heterozygous

for a mutation in the agouti gene This mutation

results in an ectopic expression of the agouti protein

throughout the body, while the non-mutated gene

induces the expression of the agouti protein only in

hair follicles The ectopic expression of agouti is at

the origin of many different effects, i.e yellow hairs,

increased linear growth, decreased fertility, obesity

Within the brain, ectopic agouti functions as an

antagonist of the MC4 receptor (with little effect on

MC3-R), preventing the action of endogenous MC4

receptor agonists, with resulting obesity (102)

From a physiopathological viewpoint, the agouti

protein turns out not to be as esoteric as it may

sound Indeed, a pathway very similar to that of the

agouti in the skin has been described in the

hy-pothalamus Moreover, a novel gene called AGRP

(agouti-related protein) or ART (agouti-related

transcript) has been discovered in the

hy-pothalamus of rodents as well as humans (97,98) It

encodes a melanocortin (MC3, MC4) receptor

an-tagonist comprising 132 amino acid residues which,

as mentioned above, is the likely natural antagonist

of the brain melanocortin system (97,98) The

im-portance of the AGRP pathway is supported by the

observation that over-expression of human AGRP

in transgenic mice induces obesity without

produc-ing a yellow color of the fur, ARGP havproduc-ing no effect

on MC1 receptors and therefore on the coat color

(97,106)

CONCLUSION

From the description of the effects of the

above-mentioned orexigenic and anorexigenic

neuropept-ides and their relationships with leptin, it is obvious

that the regulation of food intake is complex, as is

the evolution toward overeating and obesity This

complexity is even greater than described here, as

additional factors have not been mentioned For

example, the role of glucocorticoids has not been

discussed, although these hormones favor the

oc-currence of obesity through many different

mechan-isms, one of them being to inhibit the thinning

action of leptin (107—109) Insulin, once within the

brain after its passage though the blood—brain

bar-rier, appears to participate in the regulation of

en-ergy homeostasis by decreasing food intake and

body weight gain in several animal species ing monkeys (2) The hypothalamic neuropeptidegalanin is associated with preference for dietary fats(110) Other factors described as being able tomodulate food intake may, at the moment, be con-sidered of lesser importance, although they mayreemerge as being essential Several additionalneuropeptides will soon be discovered Possibly thestrongest candidates among current perceptions ofthe regulation of body weight homeostasis may beperceived differently in the months or years tocome, and be superseded by others Leptin appears

includ-to regulate many of the orexigenic and anorexigenicneuropeptides, and time will tell whether it canregulate all of them Its pivotal importance in themodulation of food intake, body weight and energyexpenditure is illustrated by the observation that itdecreases the expression or content of many neur-opeptides that favor food intake, while at the sametime favoring that of other neuropeptides that in-hibit these processes Leptin thus appears to bestrategically placed to modulate the dynamic equi-librium between neuropeptides with opposing finaleffects

It should be noted that many of the genes andneuropeptides involved in the regulation of bodyweight homeostasis in animals mentioned aboveare also encountered in humans Thus, families havebeen reported to have mutations in either the leptingene or the leptin receptor gene (111,112) Otherhuman mutations have an effect on orexigenic oranorexigenic neuropeptides and lead to obesity.These include mutation of the POMC gene

(113—115), as well as the MC4 receptor gene (116).

These rare cases provide support for the view thatmany of the pathways described here are likely to bepresent in humans This is the basis of the view that,

by the development of various antagonists or ists, the correction of at least some aspects of humanobesity is within reach

agon-ACKNOWLEDGEMENTS

The present work was carried out with grant No31-53719.98 of the Swiss National Science Founda-tion (Berne), and by grants in aid of Eli Lilly andCompany (Indianapolis, Indiana, USA) and ofNovartis (Basle, Switzerland)

108 INTERNATIONAL TEXTBOOK OF OBESITY

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112 INTERNATIONAL TEXTBOOK OF OBESITY

Regulation of Appetite and the

Management of Obesity

John E Blundell

Appetite control implies a control over energy

in-take Some researchers argue that it only requires a

habitual addition of 20—30kilocalories per day to

lead over a number of years to significant body

weight increases which, in turn, leads to an epidemic

of obesity If human beings are the most intelligent

life force on this planet, why is it that they cannot

adjust their (eating) behaviour by the very small

amounts which would be required for weight

stabil-ity rather than weight escalation? Some explanation

for this may be found through an examination of

the processes involved in the regulation of appetite

WHAT IS THE RELATIONSHIP

BETWEEN APPETITE AND OBESITY?

There are clear logical reasons for believing that the

expression of appetite—reflected in the pattern of

eating and overall energy intake—makes a large

contribution to the maintenance of a healthy

weight The impact of appetite on obesity is a

time-dependent process and will occur at least over many

months and usually years The relationship between

appetite and weight gain is therefore part of a

devel-opmental, or ageing, process and this perspective is

important (1)

Appetite fits into an energy balance model of

weight regulation but it is not necessary to believe

that appetite control is an outcome of the

regula-tion of energy balance Appetite is separately trolled and is relevant to energy balance since itmodulates the energy intake side of the equation.This happens because appetite includes various as-pects of eating patterns such as the frequency andsize of eating episodes (gorging versus nibbling),choices of high fat or low fat foods, energy density offoods consumed, variety of foods accepted, palat-ability of the diet and variability in day-to-day in-take All of these features can play a role in en-couraging energy intake to exceed energyexpenditure thereby creating a positive energy bal-ance If this persists then it will lead to weight gain.However, there appears to be no unique pattern ofeating or forms of energy intake that will exclusively

con-or invariably lead to an excess of energy intake overexpenditure Nevertheless, some characteristics ofthe expression of appetite do render individualsvulnerable to over-consumption of food—thesecharacteristics can be regarded as risk factors

These risk factors and other modulating features of

the expression of appetite will be disclosed by ananalysis of how appetite is regulated

CAN APPETITE BE CONTROLLED FOR THE MANAGEMENT OF OBESITY?

It is widely accepted that body weight control and,

by implication, a lack of control arises from an

International Textbook of Obesity Edited by Per Bjo¨rntorp.

International Textbook of Obesity Edited by Per Bjorntorp.

Copyright © 2001 John Wiley & Sons Ltd Print ISBNs: 0-471-988707 (Hardback); 0-470-846739 (Electronic)

interaction between biology and the environment—

particularly the food supply reflected in the

nutri-tional environment The link between the two

do-mains is eating behaviour and the associated

sub-jective sensations which make up the expression of

appetite It is this eating behaviour which transmits

the impact of biological events into the

environ-ment, and which also mediates the effects of the

nutrient environment on biology Appetite is not

nutrition, rather it is the expression of appetite

which allows nutrition to exert an effect on biology,

and vice versa Consequently, adjustments in the

processes regulating the expression of appetite

should have a significant impact on body weight

regulation

Of course obesity can be managed by direct

changes in the environment itself—to enforce an

increase in physical activity or to coercively prevent

food consumption Equally, pharmacological or

surgical interventions can be made directly in

biol-ogy to prevent the assimilation of food or to alter

the energy balance In addition, adjustments in the

environment and biology have the potential to

fluence body weight indirectly by altering food

in-take—often by acting on the signals involved in

processes regulating appetite The details of these

actions will be apparent as the regulation of

appe-tite is examined

Consequently, in principle, appetite can be

con-trolled for the management of obesity We can

en-visage interventions either in specific foods which

influence biology which in turn adjusts eating

be-haviour or through a direct and deliberate cognitive

control of behaviour There are many reasons to

believe that an adjustment to the expression of

ap-petite is the best chance we have to prevent the

persistent surfeit of energy consumed over energy

expended which is currently characterizing much of

the world’s population At the end of this chapter

we should be better informed about the possible

strategies for regulating appetite to prevent further

escalation of the obesity epidemic

BASIC CONCEPTS IN APPETITE

CONTROL

As a first step to recognizing how appetite can

contribute to the prevention of obesity, it is useful to

outline some basic principles which explain how the

expression of appetite can be understood This ceptual approach will indicate how the detailedmechanisms and processes contribute to the globalpicture

con-THE PSYCHOBIOLOGICAL SYSTEM

OF APPETITE CONTROL

It is now accepted that the control of appetite isbased on a network of interactions forming part of apsychobiological system The system can be con-ceptualized on three levels (Figure 8.1) These arethe levels of psychological events (hunger percep-tion, cravings, hedonic sensations) and behaviouraloperations (meals, snacks, energy and macronut-rient intakes); the level of peripheral physiology andmetabolic events; and the level of neurotransmitterand metabolic interactions in the brain (2) Appetitereflects the synchronous operation of events andprocesses in the three levels When appetite is dis-rupted as in certain eating disorders, these threelevels become desynchronised Neural events trig-ger and guide behaviour, but each act of behaviourinvolves a response in the peripheral physiologicalsystem; in turn, these physiological events are trans-lated into brain neurochemical activity This brainactivity represents the strength of motivation to eatand the willingness to refrain from feeding

The lower part of the psychobiological system(Figure 8.1) illustrates the appetite cascade whichprompts us to consider the events which stimulateeating and which motivate organisms to seek food

It also includes those behavioural actions whichactually form the structure of eating, and thoseprocesses which follow the termination of eatingand which are referred to as post-ingestive or post-prandial events

Even before food touches the mouth, cal signals are generated by the sight and smell offood These events constitute the cephalic phase ofappetite Cephalic-phase responses are generated inmany parts of the gastrointestinal tract; their func-tion is to anticipate the ingestion of food Duringand immediately after eating, afferent informationprovides the major control over appetite It hasbeen noted that ‘afferent information from ingestedfood acting in the mouth provides primarily posi-tive feedback for eating; that from the stomach andsmall intestine is primarily negative feedback’ (3)

physiologi-114 INTERNATIONAL TEXTBOOK OF OBESITY

Figure 8.1 Diagram showing the expression of appetite as the relationship between three levels of operations: the behavioural pattern,

peripheral physiology and metabolism, and brain activity PVN, paraventricular nucleus; NST, nucleus of the tractus solitarius; CCK, cholecystokinin; FFA, free fatty acids; T:LNAA, tryptophan: large neutral amino acids; GLP-1, glucagon-like peptide 1 (See Blundell (2) for detailed diagram)

SATIETY SIGNALS AND THE SATIETY

CASCADE

Scientifically important components of the appetite

system are those physiological events which are

triggered as responses to the ingestion of food and

which form the inhibitory processes that first of all

stop eating and then prevent the re-occurrence of

eating until another meal is triggered These logical responses are termed satiety signals, and can

physio-be represented by the satiety cascade (Figure 8.2)

Satiation can be regarded as the complex of

pro-cesses which brings eating to a halt (cause meal

termination) whilst satiety can be regarded as those

events which arise from food consumption andwhich serve to suppress hunger (the urge to eat) andmaintain an inhibition over eating for a particular

115 REGULATION OF APPETITE

Food

Satiation

Figure 8.2 The satiety cascade illustrating the classes of events

which constitute satiety signals arising from food consumption

period of time This characteristic form of an eating

pattern (size of meals, snacks etc.) is therefore

de-pendent upon the coordinated effects of satiation

and satiety which control the size and frequency of

eating episodes

Initially the brain is informed about the amount

of food ingested and its nutrient content via sensory

input The gastrointestinal tract is equipped with

specialized chemo- and mechano-receptors that

monitor physiological activity and pass

informa-tion to the brain mainly via the vagus nerve (4) This

afferent information constitutes one class of ‘satiety

signals’ and forms part of the pre-absorptive control

of appetite It is usual to identify a post-absorptive

phase that arises when nutrients have undergone

digestion and have crossed the intestinal wall to

enter the circulation These products, which

accu-rately reflect the food consumed, may be

metab-olized in the peripheral tissues or organs or may

enter the brain directly via the circulation In either

case, these products constitute a further class of

metabolic satiety signals Additionally, products of

digestion and agents responsible for their

metab-olism may reach the brain and bind to specific

chemoreceptors, influence neurotransmitter

syn-thesis or alter some aspect of neuronal metabolism

In each case the brain is informed about some

as-pects of the metabolic state resulting from food

consumption

It seems likely that chemicals released by gastric

stimuli or by food processing in the gastrointestinal

tract are involved in the control of appetite (5)

Many of these chemicals are peptide

neurotrans-mitters, and many peripherally administered

pept-ides cause changes in food consumption (6) There is

evidence for an endogenous role for cholecystokinin

(CCK), pancreatic glucagon, bombesin and

somatostatin Much recent research has confirmed

the status of CCK as a hormone mediating mealtermination (satiation) and possibly early phase sat-iety This can be demonstrated by administeringCCK intravenously (the mouth cannot be usedsince CCK would be inactivated as soon as itreached the stomach) and measuring changes infood intake and hunger CCK will reduce meal sizeand also suppress hunger before the meal; theseeffects do not depend on the nausea that sometimesaccompanies an intravenous infusion (7) Food con-sumption (mainly protein and fat) stimulates therelease of CCK (from duodenal mucosal cells)which in turn activates CCK-A type receptors in thepyloric region of the stomach This signal is trans-mitted via afferent fibres of the vagus nerve to thenucleus tractus solitarius (NTS) in the brainstem.From here the signal is relayed to the hypothalamicregion where integration with other signals occurs.The components of this system are set out in Figure8.3

Other potential peripheral satiety signals includepeptides such as enterostatin (8), neurotensin andglucagon-like peptide 1 (GLP-1) (9)

APPETITE AND THE DRIVE TO EAT

For years the focus of investigations of appetitecontrol has centred upon the termination of eating.This is because the termination of an eating epi-sode—being the endpoint of a behavioural act—was perceived to be an unambiguous event aroundwhich empirical studies could be organized Conse-quently satiety came to be the concept which for-med the basis for accounts of appetite

However, some 50years ago there was an equalemphasis on the excitatory or drive features of ap-petite This was embodied in Morgan’s ‘central mo-tive state’ and in Stellar’s location of this within thehypothalamus (10) One major issue was to explainwhat gave animals (and humans) the energy anddirection which motivated the seeking of food.These questions are just as relevant today but thelack of research has prevented much innovativethinking In the light of knowledge about the physi-ology of energy homeostasis, and the utilization ofdifferent fuel sources in the body, it is possible tomake some proposals One source of the drive forfood arises from the energy used to maintainphysiological integrity and behavioural adaptation

116 INTERNATIONAL TEXTBOOK OF OBESITY

Paraventricular hypothalamus

Decreased feeding

Vagal afferent

Receptor stimulation

Stomach Pylorus

Increased contraction

protease secretion

Figure 8.3 Peripheral—brain circuit indicating the postulated

mode of action of CCK (cholecystokinin) as a satiety signal

mediating the inhibition of eating

Consequently, there is a drive for food generated by

energy expenditure Approximately 60% of total

energy expenditure is contributed by the resting

metabolic rate (RMR) Consequently RMR

pro-vides a basis for drive and this resonates with the

older concept of ‘needs translated into drives’ In

addition, through adaptation, it can be envisaged

that other components of energy expenditure would

contribute to the drive for food The actual signals

that help to transmit this energy need into

behav-iour could be reflected in oxidated pathways of fuel

utilization (11), abrupt changes in the availability of

glucose in the blood (12) and eventually brain

neur-otransmitters such as neuropeptide Y (NPY) which

appears to be linked to metabolic processes Leptin

is also likely to play a role via this system

In turn this drive to seek food—arising from a

need generated by metabolic processing—is given

direction through specific sensory systems

asso-ciated with smell, but more particularly with taste

It is logical to propose that eating behaviour will be

directed to foods having obvious energy value Of

particular relevance to the current situation are thecharacteristics of sweetness and fattiness of foods

In general most humans possess a strong liking forthe sweet taste of foods and for the fatty texture.Both of these commodities indicate foods whichhave beneficial (energy yielding) properties

Accordingly, appetite can be considered as a ance between excitatory and inhibitory processes.The excitatory processes arise from bodily energyneeds and constitute a drive for food (which inhumans is reflected in the subjective experience ofhunger) The most obvious inhibitory processesarise from post-ingestive physiological processing

bal-of the consumed food—and these are reflected inthe subjective sensation of fullness and a sup-pression of the feeling of hunger However, the sen-sitivity of both the excitatory and inhibitory pro-cesses can be modulated by signals arising from thebody’s energy stores

It should be noted that the drive system probablyfunctions in order to ensure that energy intake atleast matches energy expenditure This has implica-tions for the maintenance of obesity since total en-ergy expenditure is proportional to body mass Thismeans that the drive for food may be strong inobese individuals in order to ensure that a greatervolume of energy is ingested to match the raisedlevel of expenditure At the same time whilst there is

a process to prevent energy intake falling belowexpenditure, there does not seem to be a strongprocess to prevent intake rising above expenditure.Consequently, any intrinsic physiological disturb-ance which leads to a rise in excitatory (drive) pro-cesses or a slight weakening of inhibitory (satiety)signals would allow consumption to drift upwardswithout generating a compensatory response Forsome reason a positive energy balance does notgenerate an error signal that demands correction.Consequently the balance between the excitatoryand inhibitory processes has implications for bodyweight regulation and for the induction of obesity

SIGNALS FROM ADIPOSE TISSUE: LEPTIN AND APPETITE CONTROL

One of the classical theories of appetite control hasinvolved the notion of a so-called long-term regula-tion involving a signal which informs the brainabout the state of adipose tissue stores This idea

117 REGULATION OF APPETITE

Figure 8.4 Diagram indicating the proposed role of the OB

protein (leptin) in a signal pathway linking adipose tissue to

central neural networks It has been postulated that leptin

inter-acts with neuropeptide Y in the brain (see text) to exert effects on

food intake (and indirectly on adipose tissue) and on the

pan-creas (release of insulin) The leptin link between adipose tissue

and the brain is only a part of a much more extensive

periph-eral—central circuit EE, energy expenditure; EI, energy intake

has given rise to the notion of a lipostatic or

pon-derstatic mechanism (13) Indeed this is a specific

example of a more general class of peripheral

appe-tite (satiety) signals believed to circulate in the

blood reflecting the state of depletion or repletion of

energy reserves which directly modulate brain

mechanisms Such substances may include satietin,

adipsin, tumour necrosis factor (TNF or

cachec-tin—so named because it is believed to be

respon-sible for cancer induced anorexia) together with

other substances belonging to the family of neural

active agents called cytokines

In 1994 a landmark scientific event occurred with

the discovery and identification of a mouse gene

responsible for obesity A mutation of this gene in

the ob/ob mouse produces a phenotype

character-ized by the behavioural trait of hyperphagia and the

morphological trait of obesity The gene controls

the expression of a protein (the OB protein) by

adipose tissue and this protein can be measured in

the peripheral circulation The identification andsynthesis of the protein made it possible to evaluatethe effects of experimental administration of theprotein either peripherally or centrally (14) Becausethe OB protein caused a reduction in food intake (aswell as an increase in metabolic energy expenditure)

it has been termed ‘leptin’ There is some evidencethat leptin interacts with NPY, one of the brain’smost potent neurochemicals involved in appetite,and with melanocortin-4 (MC4) Together theseand other neuromodulators may be involved in a

peripheral—central circuit which links an adipose

tissue signal with central appetite mechanisms andmetabolic activity (Figure 8.4)

In this way the protein called leptin probably acts

in a similar manner to insulin which has both tral and peripheral actions; for some years it hasbeen proposed that brain insulin represents a bodyweight signal with the capacity to control appetite

cen-At the present time the precise relationship tween the OB protein and weight regulation has notbeen determined However, it is known that in ani-mals and humans which are obese the measuredamount of OB protein in the plasma is greater than

be-in lean counterparts Indeed there is always a verygood correlation between the plasma levels of leptinand the degree of bodily fattiness (15) Thereforealthough the OB protein is perfectly positioned toserve as a signal from adipose tissue to the brain,high levels of the protein obviously do not preventobesity or weight gain However, the OB proteincertainly reflects the amount of adipose tissue in thebody Since the specific receptors for the protein(namely OB receptor) have been identified in thebrain (together with the gene responsible for itsexpression) a defect in body weight regulation couldreside at the level of the receptor itself rather thanwith the OB protein It is now known that a number

of other molecules are linked in a chain to transmitthe action of leptin in the brain These molecules arealso involved in the control of food intake, and insome cases a mutation in the gene controlling thesemolecules is known and is associated with the loss

of appetite control and obesity For example, theMC4-R mutation (melanocortin-4 receptor) leads

to an excessive appetite and massive obesity inchildren, just like the leptin deficiency (16)

These findings lead to a model of appetite controlbased on the classic two-process idea involving thestimulation (drive) to eat, and a quick-acting short-term inhibition of food consumption which decays

118 INTERNATIONAL TEXTBOOK OF OBESITY

rapidly The drive for food would be reflected in

high levels of hunger which are normally subjected

to episodic inhibitory (satiety) signals There are

strong logical reasons why the drive (need) for food

should be related to energy expenditure of

metab-olism and physical activity Evidence suggests a role

for NPY (which produces excessive food intake in

animal studies) and leptin (whose absence releases

the hunger drive in humans) This interpretation of

leptin action is consistent with the suggestion of a

dual role of leptin (24) Within the interaction

be-tween excitatory (drive) and inhibitory (satiety)

pro-cesses there is ample room for the operation of a

large number of mediating ‘orexic’ or ‘anorexic’

neuro-modulators (2)

LEPTIN DEFICIENCY AND APPETITE

CONTROL

It seems clear that for the majority of obese people,

the OB protein (leptin) system is not a major cause

of rapid or massive weight gain

However, for certain individuals very low levels

of leptin (or the absence of leptin) may constitute a

major risk factor Recently a number of individuals

have come to light For example, two young cousins

have been studied who displayed marked

hyper-phagia from a very early age This hyperhyper-phagia

took the form of a constant hunger accompanied by

food cravings and a continuous demand for food

(17) The eldest of the two cousins had reached a

body weight of more than 90kg by the age of 9 Her

serum leptin level (like that of the cousin) was very

low, and subsequently a mutation in the gene for

leptin was revealed This finding seems to implicate

leptin (OB protein) in the control of the drive for

food; that is, in the expression of hunger and active

food seeking rather than with satiety or the

short-term inhibition over eating Leptin therefore

ap-pears to modulate the tonic signal associated with

the translation of need into drive; when leptin levels

are low or absent then the drive is unleashed and

results in voracious food seeking The MC4

recep-tor is also part of the same system and the absence

of this receptor also abolishes restraint over

appe-tite leading to massive hyperphagia This

phenom-enon is quite different from the removal of a single

satiety signal which would lead only to an increase

in meal size or a modest increase in meal frequency

FAT PREFERENCE AS AN APPETITE

RISK FACTOR

It is clear that the expression of appetite—the ingness of people to eat or to refrain from eating—reflects an interaction between biology and the en-vironment (particularly the presence of salient food-related stimuli) The tendency of this eating to lead

will-to a positive or negative energy balance will bestrongly influenced by the energy density of thefoods selected Considering over-consumption, thehigh energy density of fatty foods means that die-tary fat intake is likely to lead to a positive energy(and fat) balance, and in turn to weight gain (18,19).Evidence for the effect of dietary fat on appetiteand weight gain arises from many different forms ofinvestigation including epidemiological surveys,nutrient balance studies in calorimeters, short-terminterventions on food intake and experiments on fatsubstitutes (20) One important issue in assessingthe effects of fat ingestion is the difference betweensatiation and satiety (see Figure 8.1) Satiation is theprocess in operation while foods are being eaten;satiety is the state engendered as a consequence ofconsumption In considering dietary fat as a riskfactor in over-consumption, the effect on satiation islikely to be much more important than that onpost-ingestive satiety

The experimental evidence has led to the closure of two phenomena—termed ‘passive over-consumption’ and the ‘fat paradox’ Use of an ex-perimental procedure called concurrent evaluationhas indicated that, when people eat to a state ofcomfortable fullness from a range of either high fat

dis-or high carbohydrate foods, they consume muchgreater quantities of energy from the fatty diet Thishas been termed high fat hyperphagia or passiveover-consumption The effect is almost certainlydue, in large part, to the high energy density of thehigh fat foods; hence it can be regarded as passiverather than active eating However, the term passivemeans only that there is no deliberate intention onthe part of the eater to over-consume, and does notmean that the phenomenon occurs without the me-diation of mechanisms Evidence indicates thatpeople can consume very large amounts of fat insingle meals and over a whole day (20) This is due

to a weak effect of fat on satiation and a tionately weak effect of fat on satiety (21) Somestudies have shown that human subjects obliged to

dispropor-119 REGULATION OF APPETITE

Table 8.1 Postulated interactions between behavioural risk factors and the obesigenic environment which generate a tendency for

over-consumption

Biological vulnerability (behavioural risk

Preference for fatty foods

Weak satiation (end of meal signals)

Oro-sensory responsiveness

Weak post-ingestive satiety

Abundance of high fat (high energy-dense) Large portion size

Availability of highly palatable foods with specific sensory-nutrient combinations Easy accessibility to foods and presence of potent priming stimuli

! tendency to re-initiate eating

eat a high fat diet for 3 weeks actually increased

their hunger and decreased feelings of fullness

be-fore a test meal (22) This finding resonates with

animal studies showing that when mice are fed a

high fat diet there is a consequent decrease in leptin

signalling in the hypothalamus Therefore a high fat

diet may weaken any inhibition over the tonic

sig-nal which translates needs into hunger drive

The capacity of some people to consume very

large quantities of fat creates a paradox On one

hand fat in the intestine generates potent satiety

signals (5) On the other hand, exposure to a high fat

diet leads to over-consumption (of energy)

suggest-ing that fat has a weak effect on satiety (21) The

resolution of this paradox is revealed by the

evi-dence that although individuals—in the

experimen-tal situation—eat greater energy from the high fat

foods, they may consume a smaller volume or

weight of food Since the function of a satiety signal

is to limit the amount of food people put into the

mouth, the signal has done its job but is

overwhel-med by the speed with which the large amount of

energy (from the high fat foods) can be delivered to

the stomach This dietary override of physiological

satiety signals has a number of implications

However, although there is a compelling

correla-tion between dietary fat and obesity, the relacorrela-tion-

relation-ship does not constitute a biological inevitability.

Some people eat a habitual high fat diet and remain

lean

RISK FACTORS FOR APPETITE

CONTROL

Most researchers do not have any trouble accepting

the idea that the state of a person’s metabolism

constitutes a major risk for developing weight gainand becoming obese However, as obesity develops,metabolic characteristics change so that the state ofobesity itself is associated with a different metabolicprofile to that accompanying the process of weightgain This makes it important to do longitudinalstudies (whilst weight is increasing) as well as cross-sectional studies (comparing lean and obese sub-jects) Recently, Ravussin and Gautier (23) havedrawn attention to this issue and have outlinedthose metabolic and physiological factors asso-ciated with weight gain and with the achievement ofobesity

The tendency to gain weight is associated with alow basal metabolic rate, low energy cost of physi-cal activity, a low capacity for fat oxidation (rela-tively high respiratory quotient—RQ), high insulinsensitivity, low sympathetic nervous system activityand a low plasma leptin concentration In the state

of obesity itself many of these risk factors (or dictors of weight again) are reversed

pre-Just as certain metabolic variables (risk factors)can lead to a positive energy balance, so we canenvisage certain behaviourally mediated processes

which themselves constitute the risk factors leading

to hyperphagia or ‘over-consumption’ (high energyintake leading to a positive energy balance) Theseprocesses may be patterns of eating behaviour, thesensory or hedonic events which guide behaviour,

or sensations which accompany or follow eating.For convenience this cluster of events can be refer-red to as behavioural risk factors These events mayinclude a preference for fatty foods, weakened sati-ation (end of meal signals), relatively weak satiety(post-ingestive inhibition over further eating),strong oro-sensory preferences (e.g for sweetnesscombined with fattiness in foods), a binge potential,and a high food-induced pleasure response In turn,

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Table 8.2 Characteristics of male high and low fat phenotypes

High fat phenotype (HF)

Low fat phenotype (LF)

* Significant difference between HF and LF, P:0.05 (2-tail).

these events may be subdivided to describe more

specific components leading to a risk of

over-con-sumption

These behavioural risk factors can be regarded as

biological dispositions which create a vulnerability

for weight gain and which manifest themselves

through behavioural acts themselves, or through

physiological processes which promote or permit

changes in behaviour

However, such risk factors alone would be

un-likely to lead to a positive energy balance in a

benign environment, i.e one in which the food

supply and the cultural habits worked against

ex-cessive consumption In most of today’s societies,

however, the food environment exploits

biologi-cally based dispositions and this promotes the

achievement of a high energy intake This

concep-tualization is set out in Table 8.1

INDIVIDUAL VARIABILITY IN

APPETITE CONTROL: THE HIGH FAT

PHENOTYPE

The concept of fat as an environmental risk factor is

reflected in a general agreement that the increased

energy intake which occurs on high fat diets is

reflected in body weight gain and increasing

obes-ity When individuals in a large national survey

were classified according to dietary fat intake,

obes-ity (BMI 9 30) among high fat consumers was 19

times that found in the low fat consumers (25)

Consequently, this supports the view that, in

gen-eral, a high intake of dietary fat tends to increase the

likelihood of weight gain However it is also clear

that obesity resulting from a high fat diet is not a

biological inevitability In all databases we have

examined, some high fat eaters remain normal

weight or lean This observation has led to a

charac-terization of people based on the nature of their

habitual dietary intake

Comparisons between groups characterized by

the amount of fat consumed in the diet has revealed

quite diverse responses to nutrient challenges and

to energy loading The degree of hunger

experi-enced and the behavioural responses were different

(26) These features are present in individuals (in this

case young male adults) indistinguishable in terms

of their BMIs, percentage body fat, age and general

lifestyle In an extension of these investigations

cer-tain physiological features have been examined.The outcome indicates that the high fat (high en-ergy) consumers with similar body weights to lowfat consumers have lower respiratory quotients(RQs—the respiratory quotient reflects the oxida-tion of fat or carbohydrate), as expected, but alsohave higher resting metabolic rates (Table 8.2).Taken together these two features would consti-tute physiological processes offering protectionagainst the weight-inducing potential of a high fatdiet This cluster of behavioural and physiologicalfeatures suggests the existence of a distinct pheno-type That is, a particular type of individual with thephysiological capacity to retain a stable lean body

A further interesting feature of the high fat type is the presence of a high level of plasma leptin.However, it is possible that the high circulatingleptin may not be translated into an effective hy-pothalamic signal

pheno-In addition, the investigation of the consequences

of the habitual consumption of a particular diet hasdrawn attention to the interplay between biologyand the environment The relationship is not 100%predictable In general it is clear that a high fat dietwill favour the generation of a positive energy bal-ance and weight gain, but some individuals who arephysiologically protected (through genetic disposi-tion or adaptation) will respond differently The factthat the relationship between dietary fat and bodyweight is not a biological inevitability means thatcorrelations from epidemiological studies (betweendietary fat and obesity) can be expected to be weak.The interpretation of these weak correlations ismade even more confusing because of the huge

121 REGULATION OF APPETITE

problem of mis-reporting food intake in large-scale

surveys (27)

FAT INTAKE AND ADIPOSITY IN

CHILDREN

Exposure to a diet containing high fat foods

consti-tutes a risk factor for body weight gain but this

relationship does not constitute a ‘biological

inevi-tability’ How does this relationship manifest itself

in children?

First, evidence suggests the existence of a

rela-tionship between parental obesity and obesity in the

offspring (28) In a retrospective cohort study of 854

subjects born between 1965 and 1971, obesity

(de-fined as a BMI of 27.8 for men and 27.3 for women)

in later adulthood was compared with the medical

records of the parents Among those who were

obese during childhood, the chance of obesity in

adulthood ranged from 8% (for 1- to 2-year-olds

without obese parents) to 79% (for 10- to

14-year-olds with at least one obese parent) Therefore obese

children under 3 years of age without obese parents

are at low risk for obesity in adulthood, but among

older children, obesity is an increasingly important

predictor of adult obesity In this study, parental

obesity more than doubled the risk of adult obesity

among children under 10years of age

One mediating factor (and possibly a mechanism)

in the development of adult obesity from childhood

involves the so-called ‘adiposity rebound’ (AR)

This is the name given to the second augmentation

of BMI after birth, and there is an inverse

relation-ship between adult BMI and the age of AR In a

longitudinal study of Czech children, followed from

1 month of age to adulthood, the heaviest adults

had an AR around 5 years and the leanest at 7.6

(29)

A number of studies have also examined the

die-tary fat intake of children and both the diet

compo-sition and adiposity of the parents In one study, a

high-risk group of children (one or two overweight

parents) was compared with a low-risk group (no

parent overweight) at 4.5 years of age The high-risk

group was consuming a higher percentage of fat in

their diet and a smaller percentage of carbohydrate

(30) In an unselected sample of 4- to 7-year-old

children (35 girls, 36 boys) there was an influence of

maternal adiposity on dietary fat intake in the

children, and, for the boys a correlation betweentheir own fat mass and fat intake (31) These datasuggest that mothers may contribute more stronglythan fathers to the development of obesity inchildren by influencing their dietary fat intake.Moreover, it is known that young children’s prefer-ences for particular foods are powerful predictors ofconsumption when self-selection is permitted (32).Interestingly, it has been demonstrated that the fatpreferences (and fat consumption) of 3- to 5-year-old children are related to parental adiposity (33).The fat intake from 18 children was obtained from30h weighed food intake records and comparedwith the body composition measures of childrenand parents Children’s fat intakes were correlatedwith preferences for high fat foods and to theirtriceps skinfold measurements In addition, therewere strong correlations between the children’s fatpreferences and fat intakes and the BMIs of theparents Children of heavier parents had strongerpreferences for (and higher consumption of) fattyfoods In a further study of 9- to 10-year-oldchildren, the fattest children consumed significantlymore energy from fat than the lean children (34).These findings strongly support an environment-

al impact of the habitual diet upon the development

of weight gain and obesity However, the data couldalso suggest a biological influence over the prefer-ences for those high fat foods which form part of thehabitual diet This scenario, which focuses attention

on the energy intake side of the energy balanceequation, should not obscure the role of physicalactivity and energy expenditure One major factor

in the ever-increasing frequency of sedentary iours is television viewing In a representative co-

behav-hort of 746 youths aged 10—15 years there was a strong dose—response relationship between the

prevalence of overweight and the hours of televisionviewed (35) The incidence of obesity was 8.3 timesgreater in those youths watching more than 5 hours

of television per day compared with those watching0to 2 hours As is the case with adults (36), over-weight in children appears to be strongly influenced

by the environmental factors of low physical ity (high frequency of sedentary activities) and expo-sure to a high energy-dense (high fat) diet However,

activ-we should be wary of assuming that the effect of TVwatching is necessarily due to sedentarism sinceviewing also provides an opportunity for furthereating Consequently, in children appetite controlcan play a significant role in weight gain and obes-

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