Leptin deficiency per se dictates body composition and insulin action in ob/ob mice

Leptin deficiency per se dictates body composition and insulin action in ob/ob mice

van den Hoek, A.M.
Teusink, B.
Voshol, P.J.
Havekes, L.M.
Romijn, J.A.
Pijl, H.
TNO Kwaliteit van Leven

2008

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.

Biology
Adiposity hormone
Brain
Insulin resistance
Metabolism
Type 2 diabetes mellitus
glucose
insulin
leptin
animal experiment
animal tissue
article
body composition
body weight
caloric restriction
controlled study
diet restriction
female
gluconeogenesis
glucose clamp technique
glucose metabolism
hormone deficiency
insulin resistance
insulin sensitivity
lean body weight
leptin deficiency
male
mouse
mouse strain
nonhuman
obesity
pathophysiology
priority journal
quantitative analysis
signal transduction
wild type
Animals
Blood Glucose
Body Composition
Body Weight
Fatty Acids, Nonesterified
Female
Food Deprivation
Glucose
Glucose Clamp Technique
Growth and Development
Insulin
Leptin
Male
Mice
Mice, Inbred C57BL
Mice, Obese
Mice, Transgenic
Obesity

http://resolver.tudelft.nl/uuid:e7bfa372-1d76-4474-9c24-7318ed2a3b8d

https://doi.org/10.1111/j.1365-2826.2007.01626.x

240568

0953-8194

Journal of Neuroendocrinology, 20 (1), 120-127

article