Leptin regulation of Hsp60 impacts hypothalamic insulin signaling
André Kleinridders, … , Peter Bross, C. Ronald Kahn
André Kleinridders, … , Peter Bross, C. Ronald Kahn
Published October 1, 2013
Citation Information: J Clin Invest. 2013;123(11):4667-4680. https://doi.org/10.1172/JCI67615.
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Research Article Metabolism

Leptin regulation of Hsp60 impacts hypothalamic insulin signaling

Abstract

Type 2 diabetes is characterized by insulin resistance and mitochondrial dysfunction in classical target tissues such as muscle, fat, and liver. Using a murine model of type 2 diabetes, we show that there is hypothalamic insulin resistance and mitochondrial dysfunction due to downregulation of the mitochondrial chaperone HSP60. HSP60 reduction in obese, diabetic mice was due to a lack of proper leptin signaling and was restored by leptin treatment. Knockdown of Hsp60 in a mouse hypothalamic cell line mimicked the mitochondrial dysfunction observed in diabetic mice and resulted in increased ROS production and insulin resistance, a phenotype that was reversed with antioxidant treatment. Mice with a heterozygous deletion of Hsp60 exhibited mitochondrial dysfunction and hypothalamic insulin resistance. Targeted acute downregulation of Hsp60 in the hypothalamus also induced insulin resistance, indicating that mitochondrial dysfunction can cause insulin resistance in the hypothalamus. Importantly, type 2 diabetic patients exhibited decreased expression of HSP60 in the brain, indicating that this mechanism is relevant to human disease. These data indicate that leptin plays an important role in mitochondrial function and insulin sensitivity in the hypothalamus by regulating HSP60. Moreover, leptin/insulin crosstalk in the hypothalamus impacts energy homeostasis in obesity and insulin-resistant states.

Authors

André Kleinridders, Hans P.M.M. Lauritzen, Siegfried Ussar, Jane H. Christensen, Marcelo A. Mori, Peter Bross, C. Ronald Kahn

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Figure 3

HSP60 is a leptin-induced mitochondrial chaperone.

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HSP60 is a leptin-induced mitochondrial chaperone. (A) Western blot and ...
(A) Western blot and densitometric analysis of HSP60 in arcuate nuclei of ob/ob mice after saline or leptin treatment. (B) Western blot and (C) densitometric analysis of HSP60 in arcuate nuclei of fasted or refed C57BL/6 mice and serum leptin levels (n = 3 for each group). (D) Gene expression (n = 4 each) and (E) Western blot analysis of HSP60 in SK-N-SH cells after treatment with saline or leptin. This experiment was repeated twice with a total of four for each genotype. (F) Luciferase activity measurement under the control of the human HSP60 promoter after leptin stimulation (n = 4 for each stimulation). (G) ChIP analysis of pSTAT3 after leptin stimulation of the Hsp60 promoter. (H) Western blot analysis of HSP60 in saline- (–) or leptin-treated (+) lysates of SK-N-SH cells transfected with either WT STAT3 or DN STAT3. (I) Gene expression analysis of Hsp60 in arcuate nucleus of control (Ctrl) and leprS1138 mice (s/s) (n = 6 each). Displayed values are the means ± SEM. *P ≤ 0.05; **P ≤ 0.01.