title: [Monogenic forms of obesity: from mice to human].
abstract: The cloning of five rodent obesity genes has constituted a major advance in our understanding of body weight homeostasis. Breakthroughs in human molecular genetics have identified mutations disrupting either rodent homologue/analogue genes or genes involved in the same pathways in obese patients. Three rare cases of human morbid obesity of early onset associated with hypogodatropic hypogodanism are due to mutations in the leptin and the leptin receptor genes. These studies have confirmed that leptin plays not only a crucial role in the control of body weight in the human but also in several endocrine functions. Other Human obesity syndromes are linked to mutations in the genes encoding brain-expressed targets of leptin, particularly some key components of the melanocortin system. Patients compound heterozygous for mutations in the POMC gene display severe obesity of early onset, congenital adrenal insufficiency and red hair. Another genetic cause of obesity is due to mutation in the Proconvertase gene (PC1), the enzyme required for the cleavage of POMC into ACTH and alpha MSH, and also of Proinsulin to insulin. The subject compound heterozygous for the PC1 mutation displays besides obesity, a partial ACTH deficiency, elevated POMC and late post absorptive hypoglycemia due to the accumulation of high pro-insulinemia. Contrasting largely with these rare syndromic forms of obesity, several mutations located in the melanocortin 4 receptor gene have been showed to cause an early onset dominant form of obesity with no other associated abnormalities indifferent populations. These mutations in MC4-R could represent a "frequent" cause of common monogenic forms of obesity in human. More generally, these researches into human obesity have opened new exciting understandings in some of the pathways regulating body fat mass.
authors.affiliation: HHMI/Stanford University, Beckman Center RM B281, 270, Campus drive, Stanford, CA, USA. Karine.clement@td.ap-hop-paris.fr
authors.forename: K
authors.initials: K
authors.lastname: Clément
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005809:Genes, Regulator / Q000502:physiology; D006579:Heterozygote; D006801:Humans; D020738:Leptin / Q000097:blood / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D000521:alpha-MSH / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D020738:Leptin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D000521:alpha-MSH; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone