Monogenic disorders of obesity and body fat distribution

Recently, great progress has been made towards understanding the molecular basis of body fat regulation, Identification of mutations in several genes in spontaneous monogenic animal models of obesity and development of transg enic models have indicated the physiological roles of many genes in the reg ulation of body fat distribution. In humans, mutations in leptin, leptin re ceptor, prohormone convertase 1 (PC1), pro-opiomelanocortin (POMC), melanoc ortin 4-receptor (MC4R), and peroxisome proliferator-activated receptor (PP AR) gamma 2 gems have been described in patients with severe obesity. Most of these obesity disorders exhibit a distinct phenotype with varying degree s of hypothalamic and pituitary dysfunction and a recessive inheritance, wh ereas MC4R mutation has a nonsyndromic phenotype with dominant inheritance. These mutations suggest the critical role of central signaling systems com posed of leptin/leptin receptor and alpha-melanocyte stimulating hormone/MC 4-R in human energy homeostasis, Although the genetic basis of monogenic di sorders of body fat distribution, such as congenital generalized lipodystro phy and familial partial lipodystrophy, Dunnigan variety, is still unknown, the genes for these have recently been localized to chromosomes 9q34 and 1 q21-22, respectively. The advances in our knowledge of the phenotypic manif estations and underlying molecular mechanisms of genetic body fat disorders may lead to better treatment and prevention of obesity and other disorders of adipose tissue in the future.