title: Disrupted Leptin Signaling in the Lateral Hypothalamus and Ventral Premammillary Nucleus Alters Insulin and Glucagon Secretion and Protects Against Diet-Induced Obesity.
abstract: Leptin signaling in the central nervous system, and particularly the arcuate hypothalamic nucleus, is important for regulating energy and glucose homeostasis. However, the roles of extra-arcuate leptin responsive neurons are less defined. In the current study, we generated mice with widespread inactivation of the long leptin receptor isoform in the central nervous system via Synapsin promoter-driven Cre (Lepr(flox/flox) Syn-cre mice). Within the hypothalamus, leptin signaling was disrupted in the lateral hypothalamic area (LHA) and ventral premammillary nucleus (PMV) but remained intact in the arcuate hypothalamic nucleus and ventromedial hypothalamic nucleus, dorsomedial hypothalamic nucleus, and nucleus of the tractus solitarius. To investigate the role of LHA/PMV neuronal leptin signaling, we examined glucose and energy homeostasis in Lepr(flox/flox) Syn-cre mice and Lepr(flox/flox) littermates under basal and diet-induced obese conditions and tested the role of LHA/PMV neurons in leptin-mediated glucose lowering in streptozotocin-induced diabetes. Lepr(flox/flox) Syn-cre mice did not have altered body weight or blood glucose levels but were hyperinsulinemic and had enhanced glucagon secretion in response to experimental hypoglycemia. Surprisingly, when placed on a high-fat diet, Lepr(flox/flox) Syn-cre mice were protected from weight gain, glucose intolerance, and diet-induced hyperinsulinemia. Peripheral leptin administration lowered blood glucose in streptozotocin-induced diabetic Lepr(flox/flox) Syn-cre mice as effectively as in Lepr(flox/flox) littermate controls. Collectively these findings suggest that leptin signaling in LHA/PMV neurons is not critical for regulating glucose levels but has an indispensable role in the regulation of insulin and glucagon levels and, may promote the development of diet-induced hyperinsulinemia and weight gain.
authors.affiliation: Laboratory of Molecular and Cellular Medicine (H.C.D., M.M.G., E.T., W.L.Q., M.P., H.M.B., T.J.K.) and Laboratory of the Genetics of Obesity and Diabetes (S.K., S.M.C.), Department of Cellular and Physiological Sciences, Life Sciences Institute, and Department of Surgery (T.J.K.), University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Denroche
authors.affiliation: Laboratory of Molecular and Cellular Medicine (H.C.D., M.M.G., E.T., W.L.Q., M.P., H.M.B., T.J.K.) and Laboratory of the Genetics of Obesity and Diabetes (S.K., S.M.C.), Department of Cellular and Physiological Sciences, Life Sciences Institute, and Department of Surgery (T.J.K.), University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Glavas
authors.affiliation: Laboratory of Molecular and Cellular Medicine (H.C.D., M.M.G., E.T., W.L.Q., M.P., H.M.B., T.J.K.) and Laboratory of the Genetics of Obesity and Diabetes (S.K., S.M.C.), Department of Cellular and Physiological Sciences, Life Sciences Institute, and Department of Surgery (T.J.K.), University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Eva
authors.initials: E
authors.lastname: Tudurí
authors.affiliation: Laboratory of Molecular and Cellular Medicine (H.C.D., M.M.G., E.T., W.L.Q., M.P., H.M.B., T.J.K.) and Laboratory of the Genetics of Obesity and Diabetes (S.K., S.M.C.), Department of Cellular and Physiological Sciences, Life Sciences Institute, and Department of Surgery (T.J.K.), University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Subashini
authors.initials: S
authors.lastname: Karunakaran
authors.affiliation: Laboratory of Molecular and Cellular Medicine (H.C.D., M.M.G., E.T., W.L.Q., M.P., H.M.B., T.J.K.) and Laboratory of the Genetics of Obesity and Diabetes (S.K., S.M.C.), Department of Cellular and Physiological Sciences, Life Sciences Institute, and Department of Surgery (T.J.K.), University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Whitney L
authors.initials: WL
authors.lastname: Quong
authors.affiliation: Laboratory of Molecular and Cellular Medicine (H.C.D., M.M.G., E.T., W.L.Q., M.P., H.M.B., T.J.K.) and Laboratory of the Genetics of Obesity and Diabetes (S.K., S.M.C.), Department of Cellular and Physiological Sciences, Life Sciences Institute, and Department of Surgery (T.J.K.), University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Marion
authors.initials: M
authors.lastname: Philippe
authors.affiliation: Laboratory of Molecular and Cellular Medicine (H.C.D., M.M.G., E.T., W.L.Q., M.P., H.M.B., T.J.K.) and Laboratory of the Genetics of Obesity and Diabetes (S.K., S.M.C.), Department of Cellular and Physiological Sciences, Life Sciences Institute, and Department of Surgery (T.J.K.), University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Britton
authors.affiliation: Laboratory of Molecular and Cellular Medicine (H.C.D., M.M.G., E.T., W.L.Q., M.P., H.M.B., T.J.K.) and Laboratory of the Genetics of Obesity and Diabetes (S.K., S.M.C.), Department of Cellular and Physiological Sciences, Life Sciences Institute, and Department of Surgery (T.J.K.), University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Clee
authors.affiliation: Laboratory of Molecular and Cellular Medicine (H.C.D., M.M.G., E.T., W.L.Q., M.P., H.M.B., T.J.K.) and Laboratory of the Genetics of Obesity and Diabetes (S.K., S.M.C.), Department of Cellular and Physiological Sciences, Life Sciences Institute, and Department of Surgery (T.J.K.), University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D059305:Diet, High-Fat; D005934:Glucagon / Q000378:metabolism*; D007026:Hypothalamic Area, Lateral / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D020738:Leptin / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014697:Ventromedial Hypothalamic Nucleus / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D054411:Receptors, Leptin; D005934:Glucagon