title: Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3.
abstract: Leptin is an adipocyte-derived hormone that regulates energy balance and neuroendocrine function primarily by acting on specific hypothalamic pathways. Resistance to the weight reducing effects of leptin is a feature of most cases of human and rodent obesity, yet the molecular basis of leptin resistance is poorly understood. We have previously identified suppressor of cytokine signaling-3 (Socs3) as a leptin-induced negative regulator of leptin receptor signaling and potential mediator of leptin resistance. However, due to the non-viability of mice with targeted disruption of Socs3 (ref. 6), the importance of Socs3 in leptin action in vivo was unclear. To determine the functional significance of Socs3 in energy balance in vivo we undertook studies in mice with heterozygous Socs3 deficiency (Socs3(+/-)). We report here that Socs3(+/-) mice display greater leptin sensitivity than wild-type control mice: Socs3(+/-) mice show both enhanced weight loss and increased hypothalamic leptin receptor signaling in response to exogenous leptin administration. Furthermore, Socs3(+/-) mice are significantly protected against the development of diet-induced obesity and associated metabolic complications. The level of Socs3 expression is thus a critical determinant of leptin sensitivity and obesity susceptibility in vivo and this molecule is a potential target for therapeutic intervention.
authors.affiliation: Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Jane K
authors.initials: JK
authors.lastname: Howard
authors.forename: Belinda J
authors.initials: BJ
authors.lastname: Cave
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Oksanen
authors.forename: Iphigenia
authors.initials: I
authors.lastname: Tzameli
authors.forename: Christian
authors.initials: C
authors.lastname: Bjørbaek
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Flier
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D004041:Dietary Fats / Q000008:administration & dosage; D002149:Energy Intake; D004734:Energy Metabolism / Q000187:drug effects; D020738:Leptin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000517:prevention & control*; D011956:Receptors, Cell Surface / Q000502:physiology; D054411:Receptors, Leptin; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000502:physiology
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; C515448:LEPR protein, human; D020738:Leptin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D012097:Repressor Proteins; C106644:SOCS3 protein, human; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; C515447:leptin receptor, mouse