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 1

HSP60 reduction is associated with central insulin resistance.

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HSP60 reduction is associated with central insulin resistance. (A) Weste...
(A) Western blot analysis of phosphorylated AKT and ERK of dissected arcuate nuclei of control and db/db mice. Experiment was repeated twice with a total of six for each genotype. See Supplemental Figure 1 for densitometric analysis. (B) Western blot and (C) densitometric analysis of phosphorylated IRS1 Ser307 and JNK in hypothalami of db/+ and db/db mice (n = 3 for each). (D) Basal respiration and (E) respiratory capacity measurements, displayed as AUC, of isolated mitochondria dissected from hypothalami of db/+ and db/db mice (n = 3 for each). (F) Gene expression (n = 6 each) and (G) Western blot analysis of HSP60 in dissected hypothalami from db/+ mice and db/db mice (n = 3 each). (H) Densitometric analysis of HSP60 relative to β-actin and VDAC from db/+ and db/db mice (n = 3 each). (I) Gene expression (n = 6 each) and (J) Western blot analysis of HSP60 in dissected hypothalami of ob/+ mice and ob/ob mice (n = 3 each). (K) Densitometric analysis of HSP60 relative to β-actin of ob/+ and ob/ob mice. (L) Western blot and densitometric analysis of HSP60 and (M) phosphorylated IRS1 Ser307 in hypothalami of mice fed a normal chow diet (NCD) or a high-fat diet (HFD) (n = 4–5 each). (N) Gene expression analysis of HSP60 in dissected human brain samples of controls (n = 3) and patients with diabetes mellitus (DM) (n = 4). Displayed values are the means ± SEM. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.