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• W2016979581 abstract "Only three fundamental mechanisms can underlie the development of obesity: 1) relative increase in energy intake; 2) relative decrease in energy expenditure; and 3) preferential partitioning of ingested calories to fat storage. That any one of these defects is sufficient to cause obesity is demonstrated by the phenotypes of animals produced by specific transgenic manipulations as follows. 1) Disruption of the 5HT2c serotonin receptor results in hyperphagia and obesity (1Tecott L.H. Sun L.M. Akana S.F. Strack A.M. Lowenstein D.H. Dallman M.F. Julius D. Nature. 1995; 374: 542-546Crossref PubMed Scopus (1144) Google Scholar). 2) Defective nonshivering thermogenesis (energy expenditure) is the major abnormality in obese mice with ablation of brown adipose tissue due to tissue-specific expression of the diphtheria toxin gene driven by the uncoupling protein promoter (2Lowell B.S.-B. Susulic V. Hamann A. Lawitts J.A. Himms-Hagen J. Boyer B.B. Kozak L.P. Flier J.S. Nature. 1993; 366: 740-742Crossref PubMed Scopus (920) Google Scholar). 3) Partitioning of calories to adipose tissue is the sole metabolic abnormality in obese mice carrying a human GLUT4 transgene that is constitutively expressed exclusively in fat (3Shepherd P.R. Gnudi L. Tozzo E. Yang H. Leach F. Kahn B.B. J. Biol. Chem. 1993; 268: 22243-22246Abstract Full Text PDF PubMed Google Scholar). By virtue of their effects on critical regulatory pathways of energy homeostasis, the rodent single gene obesities represent complex admixtures of these mechanisms and provide important insights into the molecular physiology of weight regulation. All six of the autosomal dominant yellow mutations in the agouti (A) gene (e.g. A y, lethal yellow;A vy, viable yellow; A sy, sienna yellow; A iy, intermediate yellow;A hvy, hypervariable yellow;A iapy, intracisternal A particle yellow) are promoter mutations characterized by obesity, hyperphagia, hyperinsulinemia, hypercorticosteronism, and increased linear growth (4Yen T.T. Gill A.M. Frigeri L.G. Barsh G.S. Wolff G.L. FASEB J. 1994; 8: 479-488Crossref PubMed Scopus (278) Google Scholar). The degree of obesity correlates with the amount and intensity of the yellow hair pigment, which results from overexpression of the agouti gene. yellow mice are distinguishable by coat color from normal littermates at birth, but their obesity does not develop until postweaning (6–8 weeks). Plasma insulin and corticosterone concentrations are not elevated until the obesity is manifest. Hyperphagia is a major contributor to the obesity, since food restriction to 80% of normal intake can decrease body weight and body fat content to near ad libitum levels (4Yen T.T. Gill A.M. Frigeri L.G. Barsh G.S. Wolff G.L. FASEB J. 1994; 8: 479-488Crossref PubMed Scopus (278) Google Scholar). However, restriction to 60% of normal intake does not decrease fractional body fat content beyond the reduction induced by the restriction to 80% of usual calories, indicating that there are metabolic alterations which increase metabolic efficiency and/or partitioning to adipose tissue of the yellow mutants. However, unlike the Lep ob or Lepr db mice, the yellow mutants display no defect in temperature control under cold stress. The agouti locus encodes ASP, a 131-amino acid peptide with a 22-amino acid signal peptide, a central basic region, and a cysteine-rich C terminus, which resembles the conotoxins (5Bultman S.J. Michaud E.J. Woychik R.P. Cell. 1992; 71: 1195-1204Abstract Full Text PDF PubMed Scopus (704) Google Scholar, 6Manne J. Argeson A.C. Siracusa L.D. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4721-4724Crossref PubMed Scopus (72) Google Scholar). ASP is normally produced only in the hair follicle and testes. The dominant yellow mutations in agouti result in ectopic overexpression (including brain) of a structurally unaltered ASP protein. The promiscuous overexpression results from a deletion (A y only) or insertions of transposable elements (e.g. A vy, A iapy, and others) in non-coding sequence that place agouti under the control of heterologous promoters, which drive its overexpression in usual (e.g. hair follicle) and ectopic (e.g. brain) sites (7Siracusa L.D. Trends Genet. 1994; 10: 423-428Abstract Full Text PDF PubMed Scopus (110) Google Scholar). ASP in the hair follicle acts to switch pigment synthesis from eumelanin (black) to pheomelanin (yellow) production by blocking the action of melanocortin-stimulating hormone (MSH) at its receptor (MC1R). Obesity induction by the yellow mutations, however, does not require the MC1R receptor since A y e/e mice (lacking extension (e) = Mc1r) (8Poole T.W. Silvers W.K. Dev. Biol. 1976; 48: 377-381Crossref PubMed Scopus (14) Google Scholar) are still obese (and black) (9.Lamoreux, M. L. (1973) A Study of Gene Interactions Using Coat Color Mutants in the Mouse and Selected Mammals. Doctoral thesis, University of Maine.Google Scholar). In parabiosis (joined circulation) studies and transgenic experiments in which mice overexpress ASP solely in the skin, animals do not become obese (10Kucera G.T. Bortner D.M. Rosenberg M.P. Dev. Biol. 1996; 173: 162-173Crossref PubMed Scopus (70) Google Scholar). However, transgenic mice ubiquitously overexpressing ASP mimic the phenotype of A y mice (11Klebig M.L. Wilkison J.E. Geisler J.G. Woychik R.P. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4728-4732Crossref PubMed Scopus (245) Google Scholar). Thus, the ectopic overexpression of ASP likely acts through autocrine or paracrine, rather than endocrine, mechanisms to produce its pleiotropic effects. Since the Mc1r gene product is not required for A y -induced obesity, the ASP synthesized in the brains of mutant animals must be producing its effects by another pathway. Recently, the melanocortin 4 receptor (MC4R) in the brain has been shown to mediate effects on food intake. Knockout animals homozygous for a disruption of the Mc4r gene are as obese as A y animals (12Fan W. Boston B.A. Kesterson R.A. Hruby V.J. Cone R.D. Nature. 1997; 9: 165-168Crossref Scopus (1670) Google Scholar, 13Huszar D. Lynch C.A. Fairchild-Huntress V. Dunmore J.H. Fang Q. Berkemeier L.R. Gu W. Kesterson R.A. Boston B.A. Cone R.D. Smith F.J. Campfield L.A. Burn P. Lee F. Cell. 1997; 88: 131-141Abstract Full Text Full Text PDF PubMed Scopus (2575) Google Scholar). The normal ligand(s) for this brain receptor is not known. However, ASP competes with high affinity against MSH at MC4R (4Yen T.T. Gill A.M. Frigeri L.G. Barsh G.S. Wolff G.L. FASEB J. 1994; 8: 479-488Crossref PubMed Scopus (278) Google Scholar). Thus, it appears likely that some of the obesity-producing effects of ASP expression in the brain may be due to its interference with signal generation by MSH at MC4R, a signal which normally acts to suppress food intake. ASP also appears to induce lipogenesis in adipocytes by enhancing insulin sensitivity via a pathway that increases intracellular calcium (6Manne J. Argeson A.C. Siracusa L.D. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4721-4724Crossref PubMed Scopus (72) Google Scholar). ASIP (gene symbol for the human homolog of agouti) maps to 20q11.2 in humans and is normally expressed at low levels in skin, adipose tissue, testes, ovary, heart, liver, and kidney, suggesting that it may have roles in humans which are different from the mouse (14Wilson B.D. Ollmann M.M. Kang L. Stoffel M. Bell G.I. Barsh G.S. Hum. Mol. Genet. 1995; 4: 223-230Crossref PubMed Scopus (161) Google Scholar). Whether ASIP is normally expressed in human brain is not known. ASIP has not yet been directly linked to human obesity (15Xu W. Reed D.R. Ding Y. Price R.A. Obes. Res. 1995; 3: 559-562Crossref PubMed Scopus (10) Google Scholar) or to variation in skin pigmentation or hair color (16Valverde P. Healy E. Jackson I. Rees J.L. Thody A.J. Nat. Genet. 1995; 11: 328-330Crossref PubMed Scopus (845) Google Scholar). agouti-related protein (AGRP), also known as agouti-related transcript (16q22 in human; 8D1-D2 in mouse), a 132-aa protein 25% identical to agouti, is normally expressed primarily in the adrenal and the arcuate nucleus of the hypothalamus. The gene is overexpressed in Lep ob and Lepr db homozygotes, and AGRP selectively antagonizes α-MSH binding to MC3R and MC4R. Thus, AGRP acting via MCRs is a potential distal mediator of leptin effects on energy homeostasis (17Ollmann M. Wilson B. Yang Y.-K. Kerns J. Chen Y. Gantz I. Barsh G. Science. 1997; 278: 135-138Crossref PubMed Scopus (1558) Google Scholar, 18Shutter J. Graham M. Kinsey A. Scully S. Luthy R. Stark K. Genes Dev. 1997; 11: 593-602Crossref PubMed Scopus (560) Google Scholar). The distinguishing characteristic of mice homozygous for the Cpe fat mutation is early and severe hyperproinsulinemia (19Naggert J.K. Fricker L.D. Varlamov O. Nishin R.M. Rouille T. Steiner D.F. Carroll R.J. Raigen B.J. Leiter E.H. Nat. Genet. 1995; 10: 135-142Crossref PubMed Scopus (612) Google Scholar), which is evident as early as 4 weeks of age (20Coleman D.L. Eicher E.M. J. Hered. 1990; 81: 424-427Crossref PubMed Scopus (233) Google Scholar). These animals display transient hyperglycemia, which is characteristic of the Lep ob and Lepr db mutants, but no hypercorticosteronemia (21Leiter E.H. Herberg L. Diabetes Rev. 1997; 5: 131-148Google Scholar). Moderate obesity develops progressively, starting between 8 and 12 weeks of age, with females becoming obese earlier than males. The specific metabolic/behavioral mechanism(s) by which these mice become obese is not known. CPE is required for the excision of paired dibasic residues remaining at the C terminus of peptide prohormone intermediates such as proinsulin. Naggert et al. (19Naggert J.K. Fricker L.D. Varlamov O. Nishin R.M. Rouille T. Steiner D.F. Carroll R.J. Raigen B.J. Leiter E.H. Nat. Genet. 1995; 10: 135-142Crossref PubMed Scopus (612) Google Scholar) identified a single S202P mutation in Cpe in the Cpe fat mouse that abolishes virtually all activity of the enzyme and accounts for the elevation in plasma proinsulin (19Naggert J.K. Fricker L.D. Varlamov O. Nishin R.M. Rouille T. Steiner D.F. Carroll R.J. Raigen B.J. Leiter E.H. Nat. Genet. 1995; 10: 135-142Crossref PubMed Scopus (612) Google Scholar). Site-specific mutagenesis to introduce the S202P into wild-type Cpe resulted in no CPE activity above background. Residual carboxypeptidase activity from the presence of other carboxypeptidases apparently prevents the loss of CPE activity from resulting in lethality (21Leiter E.H. Herberg L. Diabetes Rev. 1997; 5: 131-148Google Scholar). The molecular mechanism by which inactivation of CPE leads to obesity in these animals is unclear. Transgenic replacement of CPE activity in the islets of Cpe fat animals does not alter the obesity, indicating that the obesity is not caused by the hyperproinsulinemia per se (21Leiter E.H. Herberg L. Diabetes Rev. 1997; 5: 131-148Google Scholar). The putative role of CPE in processing other prohormones and proneuropeptides such as neurotensin, GLP, MSH, POMC, TRH, CCK, gastrin, CRF, and melanin-concentrating hormone suggests possible mechanisms for the obesity in Cpe fat animals via effects on these neuropeptides that mediate food intake and energy expenditure. The enzyme also acts as a secretory pathway sorting receptor for pro-opiomelanocortin and probably other endocrine proteins and proinsulin (22Cool D.R. Normant E. Shen F. Chen H.-C. Pannell L. Zhang Y. Loh Y.P. Cell. 1997; 88: 73-83Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar), and derangement in such sorting is another potential mechanism for the protean phenotypic manifestations of the Cpe fat mutation. Although no instance of human obesity related to sequence variation in CPE (4q32) has yet been identified, obesity due to compound heterozygosity for mutations in prohormone convertase 1 has been recently described in a 47-year-old woman (23Jackson R.S. Creemers J. Ohagi S. Raffin-Sanson M. Sanders L. Montague C. Hutton J. O'Rahilly S. Nat. Genet. 1997; 16: 303-306Crossref PubMed Scopus (939) Google Scholar). Prohormone convertase 1 cleaves prohormones at pairs of basic amino acids, leaving C-terminal basic residues, which are then excised by CPE. The phenotype of this individual, moderate obesity, hyperproinsulinemia, infertility, and lack of hypercortisolism, is very similar to that seen in the Cpe fat mouse. Thus, the CPE pathway has been implicated in the control of body weight in humans. The tubby (tub) mouse does not develop obesity until at least 12 weeks of age, and the obesity is much milder in degree than any of the other rodent single gene mutations (20Coleman D.L. Eicher E.M. J. Hered. 1990; 81: 424-427Crossref PubMed Scopus (233) Google Scholar). Hyperinsulinemia is initially mild but progresses steadily until insulin concentrations are 10–20-fold higher than in lean mice with pancreatic islet hypertrophy/hyperplasia. Hyperglycemia is never present. In fact, older tubby mice have blood glucose concentrations somewhat lower than lean control mice (20Coleman D.L. Eicher E.M. J. Hered. 1990; 81: 424-427Crossref PubMed Scopus (233) Google Scholar). Similar to fat, tub does not elicit hyperadrenocorticism (21Leiter E.H. Herberg L. Diabetes Rev. 1997; 5: 131-148Google Scholar). The physiologic mechanism(s) for the obesity in these animals is not known. The tubby gene product shows 62% amino acid similarity to a putative phosphodiesterase but may actually be a member of a novel protein family. Based upon the associated phenotypes of retinal degeneration and degeneration of the organ of Corti and the ganglion cells of the cochlea at the earliest age examined (3 weeks), it has been hypothesized that lack of the tubby gene product may result in apoptosis of neural cells (24Noben-Trauth K. Naggert J.K. North M.A. Nishina P.M. Nature. 1996; 380: 534-538Crossref PubMed Scopus (296) Google Scholar, 25Kleyn P.W. Fan W. Kovats S.G. Lee J.J. Pulido J.C. Wu Y. Berkemeier L.R. Misumi D.J. Holmgren L. Charlat O. Woolf E.A. Tayber O. Brody T. Shu P. Hawkins F. Kennedy B. Baldini L. Ebeling C. Alperin G.D. Deeds J. Lakey N.D. Culpepper J. Chen H. Glucksmann-Kuis A.A. Carlson G.A. Duyk G.M. Moore K.J. Cell. 1996; 85: 281-290Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar).tub is expressed at high levels in the hypothalamus, a region of the brain that plays a critical role in control of food intake and energy expenditure (25Kleyn P.W. Fan W. Kovats S.G. Lee J.J. Pulido J.C. Wu Y. Berkemeier L.R. Misumi D.J. Holmgren L. Charlat O. Woolf E.A. Tayber O. Brody T. Shu P. Hawkins F. Kennedy B. Baldini L. Ebeling C. Alperin G.D. Deeds J. Lakey N.D. Culpepper J. Chen H. Glucksmann-Kuis A.A. Carlson G.A. Duyk G.M. Moore K.J. Cell. 1996; 85: 281-290Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar). Apoptosis of specific cells within the ventromedial nucleus might recapitulate the phenotype of increased adiposity observed when these nuclei are physically or chemically ablated (26Bray G. York D. Physiol. Rev. 1979; 59: 719-809Crossref PubMed Scopus (967) Google Scholar). Allelic variation at the tub locus may also play a role in dietary-induced obesity, since one of the mouse quantitative trait loci for this phenotype maps to the genetic interval that contains tub (25Kleyn P.W. Fan W. Kovats S.G. Lee J.J. Pulido J.C. Wu Y. Berkemeier L.R. Misumi D.J. Holmgren L. Charlat O. Woolf E.A. Tayber O. Brody T. Shu P. Hawkins F. Kennedy B. Baldini L. Ebeling C. Alperin G.D. Deeds J. Lakey N.D. Culpepper J. Chen H. Glucksmann-Kuis A.A. Carlson G.A. Duyk G.M. Moore K.J. Cell. 1996; 85: 281-290Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar, 27Warden C. Fisler J. Shoemaker S.M. Wen P.-Z. Svenson K.L. Pace M.J. Luis A.J. J. Clin. Invest. 1995; 95: 1545-1552Crossref PubMed Scopus (171) Google Scholar). The human tub homolog is 94% identical to the mouse gene at the amino acid level with particularly high conservation within the final 260 amino acids. The human homolog maps to 11p15 in a region of synteny homology with mouse 7. 2Chung, W. K., Goldberg-Berman, J., Power-Kehoe, L., and Leibel, R. L. (1996) Genomics 32,210–217. To date, no mutations in the human homolog have been reported. Considering that the Lep ob and Lepr db (or Lepr fa) mutant rodents share a mutation in a ligand (ob)-receptor (db/fa) pair, it is not surprising that these mutations produce identical phenotypes when carried on the same inbred strains (28Coleman D.L. Diabetologia. 1978; 14: 141-148Crossref PubMed Scopus (1089) Google Scholar). The earliest manifestation of these mutations is a defect in thermogenesis detectable within the first few days of life as a lower core temperature and a more rapid decline in body temperature upon cold stress (29Himms-Hagen J. Annu. Rev. Nutr. 1985; 5: 69-94Crossref PubMed Scopus (183) Google Scholar). At 2 weeks of age, somatic fat mass is increased (30Joosten H.F.P. vanderKroon P.H.W. Metabolism. 1974; 23: 59-66Abstract Full Text PDF PubMed Scopus (31) Google Scholar, 31Boulange A. Planche E. deGasquet P. J. Lipid Res. 1979; 20: 857-864Abstract Full Text PDF PubMed Google Scholar). The mutants are obese and hyperphagic at the time of weaning (21 days). High concentrations of circulating corticosterone are a hallmark of the Lep ob and Lepr db phenotypes. Adrenalectomy can arrest the progression of the obesity and the diabetes (26Bray G. York D. Physiol. Rev. 1979; 59: 719-809Crossref PubMed Scopus (967) Google Scholar), whereas extremely low doses of corticosterone after adrenalectomy are sufficient to bring back the full-blown obesity/diabetes syndrome (32Tokuyama K. Himms-Hagen J. Am. J. Physiol. 1987; 252: E202-E208PubMed Google Scholar, 33Smith C.K. Romsos D.R. Am. J. Physiol. 1985; 249: R13-R22PubMed Google Scholar). It is unclear whether glucocorticoid or mineralocorticoid receptors, or both, convey the striking steroid dependence of the obese phenotype in these animals and most of the other genetic and experimental models of rodent obesity (26Bray G. York D. Physiol. Rev. 1979; 59: 719-809Crossref PubMed Scopus (967) Google Scholar, 34Devenport L. Thomas T. Knehans A. Sundstrom A. Physiol. Behav. 1990; 47: 1221-1228Crossref PubMed Scopus (29) Google Scholar). Leptin is synthesized as a 167-amino acid protein and secreted from adipose tissue after excision of a 21-aa signal peptide (35Friedman J.M. Leibel R.L. Siegel D.A. Walsh J. Bahary N. Genomics. 1991; 11: 1054-1062Crossref PubMed Scopus (155) Google Scholar, 36Zhang Y. Proenca R. Maffei M. Barone M. Leopold L. Friedman J.M. Nature. 1994; 372: 425-432Crossref PubMed Scopus (11807) Google Scholar). For reasons indicated below, leptin is a plausible afferent signal of somatic fat stores. Leptin has a cytokine-like predicted tertiary structure, which includes 4 α-helices, 2 β-sheets, and a single disulfide bond between cysteines 96 and 146 (37Stephens T. Basinski M. Bristow P.K. Bue-Valleskey J.M. Burgett S.G. Craft L. Hale J. Hoffmann J. Hsiung H.M. Kriauciunas A. MacKellar Jr., W. Rosteck P.R. Schoner B. Smith D. Tinsley F.C. Zhang X.-Y. Helman M. Nature. 1995; 377: 530-532Crossref PubMed Scopus (1478) Google Scholar). Replacement of leptin in Lep ob homozygous mice via either intraperitoneal or intracerebroventricular injection results in weight loss, decreased food intake, and increased physical activity. These effects are immediately reversed upon termination of leptin administration (38Campfield L.A. Smith F.J. Guisez Y. Devos R. Burn P. Science. 1995; 269: 546-549Crossref PubMed Scopus (3072) Google Scholar, 39Pelleymounter M. Cullen M. Baker M. Hecht R. Winters D. Boone T. Collins F. Science. 1995; 269: 540-543Crossref PubMed Scopus (3884) Google Scholar, 40Halaas J.L. Gajiwala K.S. Maffei M. Cohen S.L. Chait B.T. Rabinowitz D. Lallone R.L. Burley S.K. Friedman J.M. Science. 1995; 269: 543-546Crossref PubMed Scopus (4256) Google Scholar). Leptin treatment of normal mice, with or without diet-induced obesity, also decreases adipose tissue mass, whereas Lepr db mice are unaffected by leptin treatment, suggesting that they are resistant to the hormone as originally suggested by Coleman's parabiosis experiments (28Coleman D.L. Diabetologia. 1978; 14: 141-148Crossref PubMed Scopus (1089) Google Scholar). Intracerebroventricular administration of leptin in Lep ob mice rectifies systemic glucose disposal to a degree not fully accounted for by weight loss (41Schwartz M. Baskin D. Bukowski T. Kuijper J. Foster D. Lasser G. Prunkard D. Porte D. Woods S. Seeley R. Weigle D. Diabetes. 1996; 45: 531-535Crossref PubMed Google Scholar), suggesting that leptin may affect peripheral insulin sensitivity by neurally mediated effects. Intraperitoneal administration of leptin to non-obese male mice during starvation normalizes many of the (neuro)endocrine changes (e.g. decreased thyroxine and testosterone, increased corticosterone), which occur as a result of food deprivation (42Ahima R.S. Prabakaran D. Mantzoros C. Qu D.Q. Lowell B. Matos-Flier E. Flier J.S. Nature. 1996; 382: 250-252Crossref PubMed Scopus (2693) Google Scholar), but does not significantly alter the rate of weight loss. Administration to female mice accelerates the onset of sexual maturity (43Chehab F.F. Mounzih K. Lu R. Lim M.E. Science. 1997; 275: 88-90Crossref PubMed Scopus (738) Google Scholar, 44Ahima R.S. Dushay J. Flier S.N. Prabakaran D. Flier J.S. J. Clin. Invest. 1997; 99: 391-395Crossref PubMed Scopus (654) Google Scholar). The human leptin gene (LEP) is 85% identical to the murine gene at the amino acid level (36Zhang Y. Proenca R. Maffei M. Barone M. Leopold L. Friedman J.M. Nature. 1994; 372: 425-432Crossref PubMed Scopus (11807) Google Scholar) and maps to 7q31.3 as predicted based on synteny with proximal mouse chromosome 6 (45Green E.D. Maffei M. Braden V.V. Procena R. DeSilva U. Zhang Y. Chua S.C. Leibel R.L. Weissenbach J. Friedman J.M. Genome Res. 1995; 5: 5-12Crossref PubMed Scopus (188) Google Scholar). Extreme obesity in humans has been linked to genetic markers near LEP (46Reed D.R. Ding Y. Xu W. Cather C. Green E.D. Price R.A. Diabetes. 1996; 45: 691-694Crossref PubMed Scopus (0) Google Scholar, 47Clement K. Garner C. Hager J. Philippi A. Leduc C. Carey A. Harris T.J.R. Jury C. Cardon L.R. Basdevant A. Demanais F. Guygrand B. North M. Froguel P. Diabetes. 1996; 45: 687-690Crossref PubMed Scopus (0) Google Scholar, 48Duggirala R. Stern M.P. Mitchell B.D. Reinhart L.J. Shipman P.A. Uresandi O.C. Chung W.K. Leibel R.L. Hales C.N. O'Connell P. Blangero J. Am. J. Hum. Genet. 1996; 59: 694-703PubMed Google Scholar). A definite role for leptin in human energy balance was recently confirmed by the demonstration of homozygosity for a frameshift mutation in LEP in two cousins (2 and 8 years old) with massive, early onset obesity (49Montague C. Farooqi I. Whitehead J. Soos M. Rau H. Wareham N. Sewter C. Digby J. Mohammed S. Hurst J. Cheetham C. Earley A. Barnett A. Prins J. O'Rahilly S. Nature. 1997; 387: 903-908Crossref PubMed Scopus (2462) Google Scholar). The phenotypes of the two children (from a consanguineous pedigree) differ in some very interesting ways from those seen in ob/ob mice. For example, the children do not show evidence of stunting, reduced lean body mass, or hypothermia. Such mutations are, however, apparently rare since earlier direct coding sequence analysis of a large number of human subjects has failed to identify any functionally significant coding sequence variation in this gene (50Considine R.V. Considine E.L. Williams C.J. Nyce M.R. Magosin S.A. Bauer T.L. Rosato E.L. Colberg J. Caro J.F. J. Clin. Invest. 1995; 95: 2986-2988Crossref PubMed Scopus (427) Google Scholar, 51Considine R.V. Considine E.L. Williams C.J. Nyce M.R. Zhang P. Opentanova I. Ohannesian J.P. Kolaczynski J.W. Bauer T.L. Moore J.H. Caro J.F. Biochem. Biophys. Res. Commun. 1996; 220: 735-739Crossref PubMed Scopus (82) Google Scholar, 52Maffei M. Stoffel M. Barone M. Moon M. Dammerman M. Ravussin E. Bogardus C. Ludwig D.S. Flier J.S. Talley M. Auerbach S. Friedman J.M. Diabetes. 1996; 45: 679-682Crossref PubMed Scopus (178) Google Scholar). Plasma leptin concentrations (normal, 3–15 ng/ml) are increased in obese humans (53Rosenbaum M. Nicolson M. Hirsch J. Heymsfield S.B. Gallagher D. Chu F. Leibel R.L. J. Clin. Endocrinol. Metab. 1996; 81: 3424-3427Crossref PubMed Scopus (771) Google Scholar) and some rodents (other than Lep ob) (54Frederich R.C. Lollmann B. Hamann A. Napolitano-Rosen A. Kahn B.B. Lowell B.B. Flier J.S. J. Clin. Invest. 1995; 96: 1658-1663Crossref PubMed Scopus (557) Google Scholar, 55Frederich R. Hamann A. Anderson S. Lollmann B. Lowell B.B. Flier J.S. Nat. Med. 1995; 1: 1311-1314Crossref PubMed Scopus (1422) Google Scholar) in proportion to body fat mass. Within a given fat depot, leptin mRNA expression is proportional to adipocyte volume (56Hamilton B. Paglia D. Kwan A. Deitel M. Nat. Med. 1995; 9: 953-956Crossref Scopus (513) Google Scholar). However, there is no evidence of a primary difference between obese and never-obese humans in rates of leptin production per unit of fat mass or of leptin clearance (57Klein S. Coppack S.W. Mohamed-Ali V. Landt M. Diabetes. 1996; 45: 984-987Crossref PubMed Google Scholar). Subcutaneous adipose tissue appears to produce more leptin than intraabdominal fat (58Montague C. Prins J. Sanders L. Digby J. O'Rahilly S. Diabetes. 1997; 46: 342-347Crossref PubMed Scopus (0) Google Scholar). Circulating concentrations of leptin and adipose tissue leptin mRNA expression are reduced by fasting and restored to normal levels by feeding in rats (59Saladin R. DeVos P. Guerre-Millo M. Leturque A. Girard J. Staels B. Auwerx J. Nature. 1995; 377: 527-529Crossref PubMed Scopus (1095) Google Scholar). These changes are seen within a few hours in rodents and in 12–36 h in humans (60Kolaczynski J.W. Nyce M.R. Considine R.V. Boden G. Nolan J.J. Henry R. Mudaliar S.R. Olefsky J. Caro J.F. Diabetes. 1996; 45: 699-701Crossref PubMed Scopus (0) Google Scholar). Whereas systemic administration of leptin to Lep ob mice restores insulin-sensitive glucose disposal (41Schwartz M. Baskin D. Bukowski T. Kuijper J. Foster D. Lasser G. Prunkard D. Porte D. Woods S. Seeley R. Weigle D. Diabetes. 1996; 45: 531-535Crossref PubMed Google Scholar), insulin resistance to glucose disposal in obese humans occurs in the presence of high ambient leptin. Thus, both total leptin deficiency and extreme leptin excess are associated with resistance to insulin action. In human hepatocytes, leptin attenuates certain insulin-induced processes such as tyrosine phosphorylation of IRS-1, association of GRB2 with IRS-1, and down-regulation of gluconeogenesis (61Cohen B. Novick D. Rubinstein M. Science. 1996; 274: 1185-1188Crossref PubMed Scopus (655) Google Scholar). The findings in humans suggest that leptin may mediate some of the effects of obesity on insulin resistance. Recombinant leptin inhibits basal insulin release in perfused pancreata of Lep ob mice but not Lepr fa (LEPR-deficient) Zucker rats (62Emilsson V. Liu Y. Cawthorne M. Morton N. Davenport M. Diabetes. 1997; 46: 313-316Crossref PubMed Scopus (0) Google Scholar). The mechanism for this effect may be via leptin-mediated reduction in the amount of “lipotoxic” intracellular triglycerides in the islets of Langerhans (63Shimabukuro M. Koyama K. Chen G. Wang M.-Y. Trieu F. Lee Y. Newgard C.B. Unger R. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 4637-4641Crossref PubMed Scopus (622) Google Scholar). Thus, leptin may also play a role in maintaining islet metabolic integrity. It is not yet clear whether leptin must enter the cerebrospinal fluid to affect the regions of the brain that receive its putative signal regarding fat mass. One of the circumventricular organs (vascular elements lacking the blood brain barrier) is located in the median eminence, just below the arcuate nucleus of the hypothalamus. The arcuate, which mediates aspects of ingestive behavior, projects axons to the median eminence, and it is possible that arcuate cell bodies are exposed directly to the circulation. In non-obese humans and animals, cerebrospinal fluid leptin concentration is about 5% of the plasma concentration, whereas in obese individuals, the ratio of cerebrospinal fluid to plasma leptin concentration is diminished, apparently due to saturation of the transport system at a plasma leptin concentration of approximately 25 ng/ml, well below the circulating concentration of leptin in most obese individuals (64Caro J.F. Kolaczynski J.W. Nyce M.R. Ohannesian J.P. Opentanova I. Goldman W.H. Lynn R.B. Zhang P.L. Sinha M.K. Considine R.V. Lancet. 1996; 348: 159-161Abstract Full Text Full Text PDF PubMed Scopus (1062) Google Scholar). The resulting curvilinear relationship between plasma and cerebrospinal fluid leptin concentrations has been proposed as the mechanism for apparent “leptin resistance” of the obese. Leptin's effects on body weight appear to be mediated primarily via effects on the hypothalamus (38Campfield L.A. Smith F.J. Guisez Y. Devos R. Burn P. Science. 1995; 269: 546-549Crossref PubMed Scopus (3072) Google Scholar). Some of leptin's effects on energy homeostasis are apparently conveyed by suppression of expression or action in the arcuate nucleus (41Schwartz M. Baskin D. Bukowski T. Kuijper J. Foster D. Lasser G. Prunkard D. Porte D. Woods S. Seeley R. Weigle D. Diabetes. 1996; 45: 531-535Crossref PubMed Google Scholar, 65Smith F.J. Campfield L.A. Moschera J.A. Bailon P.S. Burn P. Nature. 1996; 382: 307Crossref PubMed Scopus (68) Google Scholar) of neuropeptide Y (NPY), a potent stimulator of food intake. However, since mice without the Npy gene also respond to the anorexigenic effects of leptin (66Erickson J.C. Clegg K.E. Palmiter R.D. Nature. 1996; 381: 414-418Crossref Scopus (948) Google Scholar) and since animals doubly mutant for Lep ob and Npy are still obese (∼50% of Lep ob with i" @default.
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• W2016979581 date "1997-12-01" @default.
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• W2016979581 title "The Molecular Genetics of Rodent Single Gene Obesities" @default.
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• W2016979581 doi "https://doi.org/10.1074/jbc.272.51.31937" @default.
• W2016979581 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/9405382" @default.
• W2016979581 hasPublicationYear "1997" @default.

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