Print Email Facebook Twitter Leptin deficiency per se dictates body composition and insulin action in ob/ob mice Title Leptin deficiency per se dictates body composition and insulin action in ob/ob mice Author van den Hoek, A.M. Teusink, B. Voshol, P.J. Havekes, L.M. Romijn, J.A. Pijl, H. TNO Kwaliteit van Leven Publication year 2008 Abstract Obese humans are often insulin- and leptin resistant. Since leptin can affect glucose metabolism, it is conceivable that a lack of leptin signal transduction contributes to insulin resistance. It remains unclear whether leptin affects glucose metabolism via peripheral and/or central mechanistic routes. In the present study, we aimed: (i) to determine the relative contributions of lack of leptin signal transduction and adiposity to insulin resistance and (ii) to establish the impact of central leptin action on glucose metabolism. To address the first point, ob/ob mice were subjected to severe calorie restriction, so that their body weight became similar to that of wild-type mice. Insulin sensitivity was measured in obese ob/ob, lean (food restricted) ob/ob and lean, weight-matched wild-type mice. To address the second point, leptin (or vehicle) was i.c.v. infused to the lateral cerebral ventricle of ob/ob mice and insulin sensitivity was determined. Hyperinsulinaemic euglyceamic clamps were used to quantify insulin sensitivity. Food restriction barely affected body composition, although it profoundly curtailed body weight. Insulin suppressed hepatic glucose production (HGP) to a greater extent in lean ob/ob than in obese ob/ob mice, but its impact remained considerably less than in wild-type mice (% suppression: 11.8 ± 8.9 versus 1.3 ± 1.1 versus 56.6 ± 13.0%/nmol, for lean, obese ob/ob and wild-type mice, respectively; P < 0.05). The insulin-mediated glucose disposal (GD) of lean ob/ob mice was also in between that of obese ob/ob and wild-type mice (37.5 ± 21.4 versus 25.1 ± 14.6 versus 59.6 ± 17.3 μmol/min/kg/nmol of insulin, respectively; P < 0.05 wild-type versus obese ob/ob mice). Leptin infusion acutely enhanced both hepatic insulin sensitivity (insulin-induced inhibition of HGP) and insulin-mediated GD (9.1 ± 2.4 versus 5.0± 2.7%/nmol of insulin, and 25.6 ± 5.6 versus 13.6 ± 4.8 μmol/min/kg/ nmol of insulin, respectively; P < 0.05 for both comparisons) in ob/ob mice. Both a lack of leptin signals and adiposity may contribute to insulin resistance in obese individuals. Diminution of central leptin signalling can critically affect glucose metabolism in these individuals. © 2008 The Authors. Journal Compilation © 2008 Blackwell Publishing Ltd. Subject BiologyAdiposity hormoneBrainInsulin resistanceMetabolismType 2 diabetes mellitusglucoseinsulinleptinanimal experimentanimal tissuearticlebody compositionbody weightcaloric restrictioncontrolled studydiet restrictionfemalegluconeogenesisglucose clamp techniqueglucose metabolismhormone deficiencyinsulin resistanceinsulin sensitivitylean body weightleptin deficiencymalemousemouse strainnonhumanobesitypathophysiologypriority journalquantitative analysissignal transductionwild typeAnimalsBlood GlucoseBody CompositionBody WeightFatty Acids, NonesterifiedFemaleFood DeprivationGlucoseGlucose Clamp TechniqueGrowth and DevelopmentInsulinLeptinMaleMiceMice, Inbred C57BLMice, ObeseMice, TransgenicObesity To reference this document use: http://resolver.tudelft.nl/uuid:e7bfa372-1d76-4474-9c24-7318ed2a3b8d DOI https://doi.org/10.1111/j.1365-2826.2007.01626.x TNO identifier 240568 ISSN 0953-8194 Source Journal of Neuroendocrinology, 20 (1), 120-127 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.