Monogenic disorders of obesity and body fat distribution
1999; Elsevier BV; Volume: 40; Issue: 10 Linguagem: Inglês
10.1016/s0022-2275(20)34890-2
ISSN1539-7262
Autores Tópico(s)Adipose Tissue and Metabolism
ResumoRecently, 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 transgenic models have indicated the physiological roles of many genes in the regulation of body fat distribution. In humans, mutations in leptin, leptin receptor, prohormone convertase 1 (PC1), pro-opiomelanocortin (POMC), melanocortin 4-receptor (MC4-R), and peroxisome proliferator-activated receptor (PPAR) γ2 genes have been described in patients with severe obesity. Most of these obesity disorders exhibit a distinct phenotype with varying degrees of hypothalamic and pituitary dysfunction and a recessive inheritance, whereas MC4-R mutation has a nonsyndromic phenotype with dominant inheritance. These mutations suggest the critical role of central signaling systems composed of leptin/leptin receptor and α-melanocyte stimulating hormone/MC4-R in human energy homeostasis. Although the genetic basis of monogenic disorders of body fat distribution, such as congenital generalized lipodystrophy and familial partial lipodystrophy, Dunnigan variety, is still unknown, the genes for these have recently been localized to chromosomes 9q34 and 1q21-22, respectively. The advances in our knowledge of the phenotypic manifestations 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.—Chen, D., and A. Garg. Monogenic disorders of obesity and body fat distribution. J. Lipid Res. 1999. 40: 1735–1746. 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 transgenic models have indicated the physiological roles of many genes in the regulation of body fat distribution. In humans, mutations in leptin, leptin receptor, prohormone convertase 1 (PC1), pro-opiomelanocortin (POMC), melanocortin 4-receptor (MC4-R), and peroxisome proliferator-activated receptor (PPAR) γ2 genes have been described in patients with severe obesity. Most of these obesity disorders exhibit a distinct phenotype with varying degrees of hypothalamic and pituitary dysfunction and a recessive inheritance, whereas MC4-R mutation has a nonsyndromic phenotype with dominant inheritance. These mutations suggest the critical role of central signaling systems composed of leptin/leptin receptor and α-melanocyte stimulating hormone/MC4-R in human energy homeostasis. Although the genetic basis of monogenic disorders of body fat distribution, such as congenital generalized lipodystrophy and familial partial lipodystrophy, Dunnigan variety, is still unknown, the genes for these have recently been localized to chromosomes 9q34 and 1q21-22, respectively. The advances in our knowledge of the phenotypic manifestations 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.—Chen, D., and A. Garg. Monogenic disorders of obesity and body fat distribution. J. Lipid Res. 1999. 40: 1735–1746. Overall excess of body fat as well as regional adiposity are recognized risk factors for type 2 diabetes, dyslipidemia, hypertension, and coronary heart disease. Other disorders with extreme abnormalities in body fat distribution, such as familial and acquired lipodystrophies, are also frequently associated with marked insulin resistance, early-onset diabetes mellitus, hypertriglyceridemia, and low serum concentrations of high density lipoprotein (HDL) cholesterol (1Foster D.W. The lipodystrophies and other rare disorders of adipose tissue.in: Fauci A.S. Braunwald E. Isselbacher K.J. Harrison's Principles of Internal Medicine. McGraw-Hill, New York1998: 2209-2214Google Scholar). Recently, great progress has been made in identifying several genes and in understanding the molecular mechanisms underlying spontaneous syndromes of obesity and abnormal body fat distribution in animal models and humans. Progress has also been made in establishing transgenic animal models with altered body adiposity and peculiar body fat distribution similar to that seen in familial forms of human lipodystrophy. This article reviews these advances in our knowledge of monogenic disorders of obesity and adipose tissue distribution in rodents and humans, and clinical features of these human disorders are reviewed in detail. Several well-described spontaneous monogenic rodent models of obesity syndromes have been known for over 4 decades, but only in the last 6 years have the molecular basis and the underlying pathophysiological mechanisms of obesity in these animals been elucidated (2Perusse L. Chagnon Y.C. Weisnagel J. Bouchard C. The human obesity gene map: the 1998 update.Obes. Res. 1999; 7: 111-129Google Scholar). The agouti gene mutation. The agouti was the first obesity gene cloned (3Bultman S.J. Michaud E.J. Woychik R.P. Molecular characterization of the mouse agouti locus.Cell. 1992; 71: 1195-1204Google Scholar). The gene product, agouti signaling protein (ASP), is a 133-amino acid (16 kD) polypeptide. 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Identification and characterization of the mouse obesity gene tubby: a member of a novel gene family.Cell. 1996; 85: 281-290Google Scholar). The tubby belongs to a tubby-like gene family whose function is not fully understood. The human homologues of mouse tubby includes TUB, tubby-like protein 1 (TULP 1), TULP 2 and TULP 3 (23North M.A. Naggert J.K. Yan Y. Noben-Trauth K. Nishina P.M. Molecular characterization of TUB, TULP1, and TULP2, members of the novel tubby gene family and their possible relation to ocular diseases.Proc. Natl. Acad. Sci. USA. 1997; 94: 3128-3133Google Scholar, 24Nishina P.M. North M.A. Ikeda A. Yan Y. Naggert J.K. Molecular characterization of a novel tubby gene family member, TULP3, in mouse and humans.Genomics. 1998; 54: 215-220Google Scholar). Although human obesity has not been associated with TUB family, mutations in TULP 1 and TULP 2, are implicated in the development of retinitis pigmentosa and cone-rod dystrophy, respectively (23North M.A. Naggert J.K. 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In addition, affected mice exhibit hyperphagia, hypothermia, hypercorticosteronemia, decreased linear growth, and infertility (30Coleman D.L. Burkart D.L. Plasma corticosterone concentrations in diabetic (db) mice.Diabetologia. 1977; 13: 25-26Google Scholar, 31Coleman D.L. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice.Diabetologia. 1978; 14: 141-148Google Scholar, 32Bray G.A. York D.A. Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis.Physiol. Rev. 1979; 59: 719-809Google Scholar). The Lep gene encodes a 167-amino acid (16-kD) protein, leptin, a member of class 1 cytokine superfamily. The primary structure of leptin is highly conserved, and there is 84% homology in amino acid sequences between the mouse and human homologues (33Zhang Y. Proenca R. Maffei M. Barone M. Leopold L. Friedman J.M. Positional cloning of the mouse obese gene and its human homologue.Nature. 1994; 372: 425-432Google Scholar). 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In contrast, the f/f mutation in Koletsky rats is a T2349A nonsense and null mutation resulting in virtually undetectable leptin receptor mRNA in the tissue (56Wu-Peng X.S. Chua Jr., S.C. Okada N. Liu S.M. Nicolson M. Leibel R.L. Phenotype of the obese Koletsky (f) rat due to Tyr763Stop mutation in the extracellular domain of the leptin receptor (Lepr): evidence for deficient plasma-to-CSF transport of leptin in both the Zucker and Koletsky obese rat.Diabetes. 1997; 46: 513-518Google Scholar). Besides the predicted diminished cellular response to leptin in f/f rats, lack of leptin receptor in the brain of f/f rats also leads to reduced transport of leptin from plasma to cerebrospinal fluid (56Wu-Peng X.S. Chua Jr., S.C. Okada N. Liu S.M. Nicolson M. Leibel R.L. Phenotype of the obese Koletsky (f) rat due to Tyr763Stop mutation in the extracellular domain of the leptin receptor (Lepr): evidence for deficient plasma-to-CSF transport of leptin in both the Zucker and Koletsky obese rat.Diabetes. 1997; 46: 513-518Google Scholar). The mechanism by which Lep and Lepr mutations cause obesity has not been totally elucidated. Molecular events downstream of leptin receptor may involve signaling via POMC/melanocortins (57Seeley R.J. Yagaloff K.A. Fisher S.L. Burn P. Thiele T.E. van Dijk G. Baskin D.G. Schwartz M.W. Melanocortin receptors in leptin effects.Nature. 1997; 390: 349Google Scholar), AGRP, and other neuropeptides, such as neuropeptide Y (NPY) (58Erickson J.C. Hollopeter G. Palmiter R.D. Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y.Science. 1996; 274: 1704-1707Google Scholar). Transgenic and knockout rodent models of altered body fat distribution. Table 1 displays several mouse models with either transgenic or knockout of specific genes that alter the amount or the distribution of body fat. These animal models not only reveal that certain genes may affect body adiposity by influencing energy balance, but also indicate the critical role of genes in adipocyte proliferation and differentiation. These g
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