Chapter 074. Biology of Obesity (Part 5)

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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. ...

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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 Pra Lau Ahlst Coh Car ure der-Willi rence- rom en penter Moon- Biedl Inher Spor Aut Autos Prob Aut itance adic; two- osomal omal ably osomal thirds have recessive recessive autosomal recessive defect recessive Statu Shor Nor Norm Shor Nor
re t mal; al; t or tall mal infrequentl infrequently y short short Obes Gen Gen Trunc Tru Trun ity eralized eralized al ncal cal, gluteal Mod Earl Early Mid erate to y onset, 1– onset, 2–5 -childhood, severe 2 yrs yrs age 5 Ons et 1–3 yrs Cran Narr Not Not Hig Acr iofacies ow distinctive distinctive h nasal ocephaly bifrontal bridge Flat diameter Arc nasal Alm hed palate bridge ond-shaped Ope Hig eyes n mouth h-arched
Stra Shor palate bismus t philtrum V- shaped mouth High -arched palate Lim Sma Pol No Hyp Poly bs ll hands ydactyly abnormalitie otonia dactyly and feet s Narr Syn Hyp ow hands dactyly otonia and feet Gen u valgum Repr 1° 1° Hypo Nor 2° oductive Hypogonad Hypogona gonadism in mal Hypogonad status ism dism males but gonadal ism
not in function or females hypogonad otrophic hypogonad ism Othe Ena Dys r features mel plastic ears hypoplasia Dela Hyp yed erphagia puberty Tem per tantrums Nasa l speech Ment Mild Norm Mil Slig al to moderate al d ht
retardation intelligence