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

Xiaosong Li, Xhiping Wu, Raul Camacho, Gary J. Schwartz, Derek LeRoith

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26 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere17058
JournalPLoS One
Volume6
Issue number2
DOIs
StatePublished - 2011

Fingerprint

Intraventricular Infusions
Leptin
leptin
homeostasis
Homeostasis
Glucose
liver
glucose
Liver
mice
insulin resistance
Insulin Resistance
Insulin
Muscle
skeletal muscle
food intake
Skeletal Muscle
Eating
glucose tolerance
Triglycerides

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Intracerebroventricular leptin infusion improves glucose homeostasis in lean type 2 diabetic MKR mice via hepatic vagal and non-vagal mechanisms. / Li, Xiaosong; Wu, Xhiping; Camacho, Raul; Schwartz, Gary J.; LeRoith, Derek.

In: PLoS One, Vol. 6, No. 2, e17058, 2011.

Research output: Contribution to journalArticle

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