Chapter 074. Biology of Obesity (Part 5) docx

Biology of Obesity Part 5 Figure 74-5 A central pathway through which leptin acts to regulate appetite and body weight.. Mutations that cause obesity in humans are indicated by the sol

Chapter 074 Biology of Obesity

(Part 5)

Figure 74-5

A central pathway through which leptin acts to regulate appetite and body weight Leptin signals through proopiomelanocortin (POMC) neurons in the

hypothalamus to induce increased production of α-melanocyte-stimulating hormone (α-MSH), requiring the processing enzyme PC-1 (proenzyme convertase 1) α-MSH acts as an agonist on melanocortin-4 receptors to inhibit appetite, and

the neuropeptide AgRp (Agouti-related peptide) acts as an antagonist of this receptor Mutations that cause obesity in humans are indicated by the solid green arrows

In addition to these human obesity genes, studies in rodents reveal several other molecular candidates for hypothalamic mediators of human obesity or

leanness The tub gene encodes a hypothalamic peptide of unknown function; mutation of this gene causes late-onset obesity The fat gene encodes

carboxypeptidase E, a peptide-processing enzyme; mutation of this gene is thought to cause obesity by disrupting production of one or more neuropeptides AgRP is coexpressed with NPY in arcuate nucleus neurons AgRP antagonizes α-MSH action at MC4 receptors, and its overexpression induces obesity In contrast,

a mouse deficient in the peptide MCH, whose administration causes feeding, is lean

A number of complex human syndromes with defined inheritance are associated with obesity (Table 74-2) Although specific genes are undefined at present, their identification will likely enhance our understanding of more common forms of human obesity In the Prader-Willi syndrome, obesity coexists with short stature, mental retardation, hypogonadotropic hypogonadism, hypotonia, small hands and feet, fish-shaped mouth, and hyperphagia Most patients have a chromosome 15 deletion, and reduced expression of the signaling protein necdin may be an important cause of defective hypothalamic neural

development in this disorder (Chap 63) Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized by obesity, mental retardation, retinitis pigmentosa, renal and cardiac malformations, polydactyly, and hypogonadotropic hypogonadism At least eight genetic loci have been identified, and BBS may involve defects in ciliary function

Table 74-2 A Comparison of Syndromes of Obesity—Hypogonadism and Mental Retardation

Syndrome

Feat

ure

Pra der-Willi

Lau rence- Moon-Biedl

Ahlst rom

Coh

en

Car penter

Inher

itance

Spor adic; two-thirds have defect

Aut osomal recessive

Autos omal

recessive

Prob ably

autosomal recessive

Aut osomal recessive

re t mal;

infrequentl

y short

al;

infrequently short

t or tall mal

Obes

ity

Gen eralized

Mod erate to severe

Ons

et 1–3 yrs

Gen eralized

Earl

y onset, 1–

2 yrs

Trunc

al

Early onset, 2–5 yrs

Tru ncal

Mid -childhood, age 5

Trun cal, gluteal

Cran

iofacies

Narr

ow bifrontal diameter

Alm ond-shaped eyes

Not distinctive

Not distinctive

Hig

h nasal bridge

Arc hed palate

Ope

n mouth

Acr ocephaly

Flat nasal bridge

Hig h-arched

Stra bismus

V-shaped mouth

High -arched palate

Shor

t philtrum

palate

Lim

bs

Sma

ll hands and feet

Hyp otonia

Pol ydactyly

No abnormalitie

s

Hyp otonia

Narr

ow hands and feet

Poly dactyly

Syn dactyly

Gen

u valgum

Repr

oductive

status

1°

Hypogonad ism

1°

Hypogona dism

Hypo gonadism in males but

Nor mal gonadal

2° Hypogonad ism

not in females

function or hypogonad otrophic hypogonad ism

Othe

r features

Ena mel hypoplasia

Hyp erphagia

Tem per

tantrums

Nasa

l speech

Dys plastic ears

Dela yed

puberty

Ment

al

Mild

to moderate

Norm

al

Mil

d

Slig

ht

retardation intelligence