Intracerebroventricular Leptin Infusion Improves Glucose Homeostasis in Lean Type 2 Diabetic MKR Mice via Hepatic Vagal and Non-Vagal Mechanisms

MKR mice, lacking insulin-like growth factor 1 receptor (IGF-1R) signaling in skeletal muscle, are lean yet hyperlipidemic, hyperinsulinemic, and hyperglycemic, with severe insulin resistance and elevated hepatic and skeletal muscle levels of triglycerides. We have previously shown that chronic peripheral administration of the adipokine leptin improves hepatic insulin sensitivity in these mice independently of its effects on food intake. As central leptin signaling has been implicated in the control of peripheral glucose homeostasis, here we examined the ability of central intracerebroventricular leptin administration to affect energy balance and peripheral glucose homeostasis in non-obese diabetic male MKR mice. Central leptin significantly reduced food intake, body weight gain and adiposity, as well as serum glucose, insulin, leptin, free fatty acid and triglyceride levels relative to ACSF treated controls. These reductions were accompanied by increased fat oxidation as measured by indirect calorimetry, as well as increased oxygen consumption. Central leptin also improved glucose tolerance and hepatic insulin sensitivity determined using the euglycemic-hyperinsulinemic clamps relative to pair fed vehicle treated controls, as well as increasing the rate of glucose disappearance. Hepatic vagotomy only partially reversed the ability of central leptin to improve glucose tolerance. These results demonstrate that central leptin dramatically improves insulin sensitivity independently of its effects on food intake, in a lean mouse model of type 2 diabetes. The findings also suggest that: 1) both hepatic vagal and non-vagal pathways contribute to this improvement, and 2) central leptin alters glucose disposal in skeletal muscle in this model

Locomotor Activity And Metabolic Functions In Leptin Treated MKR Mice.

<p>Two week third intracerebroventricular leptin treatment (black bars) reduced light and dark phase locomotor activity (A,B), respiratory quotient (RER, C,D) and increased both light and dark phase oxygen consumption in male MKR mice relative to artificial cerebrospinal fluid (ACSF) vehicle treated controls (open bars) (E,F). All data presented as means ± SEM, N = 6/group. * p<0.05.</p

Glucose Tolerance Tests In Leptin And Vehicle Treated MKR Mice.

<p>Two week intracerebroventricular leptin treatment significantly improved glucose tolerance in male MKR mice relative to artificial cerebrospinal fluid (ACSF) vehicle treated controls and pair fed, ACSF treated MKR mice. A. Intraperitoneal glucose tolerance test (ipGTT, 2 g/kg), B. Area under the curve (AUC) during ipGTT. All data presented as means ± SEM, N = 6–7/group. * p<0.05, ** p<0.01.</p

Body Weights (A) And Fat Content (B), Before And After 14 Days Of ICV Leptin Treatment Compared With ACSF And Pair-Fed Control Mice.

<p>All data presented as means ± SEM, N = 6–7/group. * p<0.05. Different superscript letters indicate significant differences at p<0.05.</p

Body Weight, Food Intake, And Body Composition In Leptin Treated MKR Mice.

<p>Two week third intracerebroventricular leptin treatment (filled symbols) reduced body weight gain (A), 24 h daily food intake (B), fat mass (C) and produced a small reduction in lean mass (D) in male MKR mice, relative to artificial cerebrospinal fluid (ACSF) vehicle treated controls (open symbols). All data presented as means ± SEM, N = 6/group. * p<0.05, ** p<0.01.</p

Hyperinsulinemic-euglycemic clamps.

<p>Third intracerebroventricular leptin treatment (black bars) significantly improved hepatic insulin sensitivity and glucose disposal during hyperinsulinemic-euglycemic clamps in male MKR mice relative to artificial cerebrospinal fluid (ACSF) vehicle treated controls (open bars) and pair fed, ACSF treated male MKR mice (hatched bars). A. Glucose infusion rate (GIR) during the clamp, B. peripheral glucose disappearance rate (Rd), hepatic glucose production (GP) under basal conditions (C) or hyperinsulinemia (D). All data presented as means ± SEM. N = 5–6/group. Different superscript letters indicate significant differences at p<0.05.</p

Glucose tolerance in leptin-treated MKR mice with or without hepatic vagotomy.

<p>Selective hepatic branch vagotomy (VGX) partially reversed the ability of two week third intracerebroventricular leptin treatment to improve glucose tolerance in male MKR mice, relative to artificial cerebrospinal fluid (ACSF) vehicle treated controls. SHAM  =  sham surgical treatment. A. Intraperitoneal glucose tolerance (ipGTT, 2 g/kg), * p<0.05, B. Area under the curve (AUC) during ipGTT. All data presented as means ± SEM, N = 6–7/group. Different superscript letters indicate significant differences at p< 0.05. * p<0.05.</p