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 Statu Shor Nor Norm Shor Nor 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 . Chapter 074. Biology of Obesity (Part 5) Figure 74-5 A central pathway through which leptin acts to regulate. 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. 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