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Intracerebroventricular leptin infusion improves glucose homeostasis in lean type 2 diabetic MKR mice via hepatic vagal and non-vagal mechanisms.

Li X, Wu X, Camacho R, Schwartz GJ, LeRoith D - PLoS ONE (2011)

Bottom Line: 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.These reductions were accompanied by increased fat oxidation as measured by indirect calorimetry, as well as increased oxygen consumption.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.

View Article: PubMed Central - PubMed

Affiliation: Departments of Medicine and Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.

ABSTRACT
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.

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Body Weight, Food Intake, And Body Composition In Leptin Treated MKR Mice.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.
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pone-0017058-g001: Body Weight, Food Intake, And Body Composition In Leptin Treated MKR Mice.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.

Mentions: Chronic ICV leptin infusion caused a ∼10–15% reduction in body weight (BW) in MKR mice that began within 1–2 days of infusion onset, and remained stable thereafter (Figure 1A), while ACSF was without effect. This reduction in body weight was accompanied at weeks 1 and 2 by significantly reduced food intake and fat mass, a small but significant reduction in lean mass (Figure 1B–D). Body weight and fat mass were also measured in pair-fed controls (Figure 2 A and B) and only leptin treated mice showed a marked decrease in fat mass. A small but significant reduction in circulating plasma leptin levels (1.7±0.2 ng/ml versus 2.0±0.3 ng/ml, p<0.05) was seen. Central leptin treatment also significantly reduced serum insulin, FFA and TG levels relative to ACSF treated controls (insulin: 1.2±0.23 vs. 3.2±0.3 ng/ml; FFA: 0.35±08 vs 0.75±12 ng/dl, p<0.01; TG: 0.2±0.1 vs. 1.4±0.3 nM (all p<0.01)).


Intracerebroventricular leptin infusion improves glucose homeostasis in lean type 2 diabetic MKR mice via hepatic vagal and non-vagal mechanisms.

Li X, Wu X, Camacho R, Schwartz GJ, LeRoith D - PLoS ONE (2011)

Body Weight, Food Intake, And Body Composition In Leptin Treated MKR Mice.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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3040739&req=5

pone-0017058-g001: Body Weight, Food Intake, And Body Composition In Leptin Treated MKR Mice.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.
Mentions: Chronic ICV leptin infusion caused a ∼10–15% reduction in body weight (BW) in MKR mice that began within 1–2 days of infusion onset, and remained stable thereafter (Figure 1A), while ACSF was without effect. This reduction in body weight was accompanied at weeks 1 and 2 by significantly reduced food intake and fat mass, a small but significant reduction in lean mass (Figure 1B–D). Body weight and fat mass were also measured in pair-fed controls (Figure 2 A and B) and only leptin treated mice showed a marked decrease in fat mass. A small but significant reduction in circulating plasma leptin levels (1.7±0.2 ng/ml versus 2.0±0.3 ng/ml, p<0.05) was seen. Central leptin treatment also significantly reduced serum insulin, FFA and TG levels relative to ACSF treated controls (insulin: 1.2±0.23 vs. 3.2±0.3 ng/ml; FFA: 0.35±08 vs 0.75±12 ng/dl, p<0.01; TG: 0.2±0.1 vs. 1.4±0.3 nM (all p<0.01)).

Bottom Line: 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.These reductions were accompanied by increased fat oxidation as measured by indirect calorimetry, as well as increased oxygen consumption.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.

View Article: PubMed Central - PubMed

Affiliation: Departments of Medicine and Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus