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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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Glucose tolerance in leptin-treated MKR mice with or without hepatic vagotomy.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.
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pone-0017058-g006: Glucose tolerance in leptin-treated MKR mice with or without hepatic vagotomy.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.

Mentions: Five hr. fasted blood glucose levels were lower in all leptin treated MKR mice compared to ACSF and ACSF pair fed controls, but this leptin-induced reduction was unaffected by hepatic branch vagotomy (LEPTIN + SHAM: 104 ng/dl ±18 vs. LEPTIN ± VAGOTOMY: 109 mg/dl ±13) (Figure 6A). Following ip glucose injection, hepatic branch vagotomized MKR mice showed significantly less of a reduction in blood glucose levels at 15 and 120 min, but their AUC for blood glucose did not differ from that of sham vagotomized mice infused with leptin (Figure 6A,B). Hepatic branch vagotomy alone failed to alter ipGTT in ACSF treated mice relative to sham surgical controls (Figure 6A,B).


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)

Glucose tolerance in leptin-treated MKR mice with or without hepatic vagotomy.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.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0017058-g006: Glucose tolerance in leptin-treated MKR mice with or without hepatic vagotomy.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.
Mentions: Five hr. fasted blood glucose levels were lower in all leptin treated MKR mice compared to ACSF and ACSF pair fed controls, but this leptin-induced reduction was unaffected by hepatic branch vagotomy (LEPTIN + SHAM: 104 ng/dl ±18 vs. LEPTIN ± VAGOTOMY: 109 mg/dl ±13) (Figure 6A). Following ip glucose injection, hepatic branch vagotomized MKR mice showed significantly less of a reduction in blood glucose levels at 15 and 120 min, but their AUC for blood glucose did not differ from that of sham vagotomized mice infused with leptin (Figure 6A,B). Hepatic branch vagotomy alone failed to alter ipGTT in ACSF treated mice relative to sham surgical controls (Figure 6A,B).

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