High-Fat Diet Induces Leptin Resistance in Leptin-Deficient Mice

C. E. Koch, C. Lowe, D. Pretz, J. Steger, L. M. Williams, A. Tups

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

The occurrence of type II diabetes is highly correlated with obesity, but the mechanisms linking the two conditions are incompletely understood. Leptin is a potent insulin sensitizer and in leptin deficient, insulin insensitive, Lep(ob/ob) mice leptin improves glucose tolerance, indicating that leptin resistance may link obesity to insulin insensitivity. Leptin resistance occurs in response to a high fat diet (HFD) and both hyperleptinemia and inflammation have been proposed as causative mechanisms. Scrutinizing the role of hyperleptinemia in this process, central hyperleptinemia in Lep(ob/ob) mice was induced by chronic (intracerebroventricular) ICV infusion of leptin (4.2μg/day) over 10 days. This treatment led to a dramatic decline in body weight and food intake as well as improvement in glucose tolerance. Transfer to HFD for 4 days markedly arrested the beneficial effects of leptin on these parameters. Since Lep(ob/ob) mice are exquisitely sensitive to leptin the possibility that leptin could reverse HFD-induced glucose intolerance in these animals was investigated. HFD led to increased body weight and glucose intolerance compared to a low fat diet (LFD). Older and heavier Lep(ob/ob) mice were used as body weight matched controls. Mice in each group received either intraperitoneal leptin (ip 1.25 mg/kg) or vehicle and glucose tolerance, food intake and the number of phospho-STAT3 immunoreactive cells in the arcuate nucleus (ARC) and ventromedial hypothalamus (VMH) were analysed. Leptin improved glucose tolerance (p = 0. 019) and reduced food intake in Lep(ob/ob) mice on LFD (P ≤ 0.001), but was ineffective in mice on HFD. Furthermore when leptin was administered centrally the glucose tolerance of Lep(ob/ob) mice on HFD was significantly impaired (p = 0.007). While leptin induced the number of phospho-STAT3 immunoreactive cells in the ARC and VMH of Lep(ob/ob) mice on LFD, HFD was associated with elevated phospho-STAT3 immunoreactivity in vehicle treated Lep(ob/ob) mice that was unaffected by leptin treatment suggesting central leptin resistance. Negating central inflammation by co-administering a c-Jun n-terminal kinase (JNK) inhibitor reinstated the glucose lowering effects of leptin. These findings demonstrate that Lep(ob/ob) mice develop leptin resistance on a HFD independent of hyperleptinemia and indicate that the JNK inflammatory pathway plays a key role in the induction of diet-induced glucose intolerance. This article is protected by copyright. All rights reserved.
Original languageEnglish
Pages (from-to)58-67
Number of pages10
JournalJournal of Neuroendocrinology
Volume26
Issue number2
Early online date19 Feb 2014
DOIs
Publication statusPublished - Feb 2014

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High Fat Diet
Leptin
Glucose
Fat-Restricted Diet
Glucose Intolerance
Arcuate Nucleus of Hypothalamus
Eating
Body Weight
Insulin
Phosphotransferases
Obesity
Intraventricular Infusions
Inflammation
Type 2 Diabetes Mellitus

Keywords

  • energy and glucose homeostasis
  • hypothalamus
  • inflammation
  • JNK pathway

Cite this

High-Fat Diet Induces Leptin Resistance in Leptin-Deficient Mice. / Koch, C. E. ; Lowe, C.; Pretz, D.; Steger, J.; Williams, L. M.; Tups, A.

In: Journal of Neuroendocrinology, Vol. 26, No. 2, 02.2014, p. 58-67.

Research output: Contribution to journalArticle

Koch, C. E. ; Lowe, C. ; Pretz, D. ; Steger, J. ; Williams, L. M. ; Tups, A. / High-Fat Diet Induces Leptin Resistance in Leptin-Deficient Mice. In: Journal of Neuroendocrinology. 2014 ; Vol. 26, No. 2. pp. 58-67.
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