The mitochondrial chaperones heat shock protein 10 (HSP10) and 60 enable proper protein folding and thereby facilitate mitochondrial function. Previously, we demonstrated a reduction of hypothalamic Hsp60 gene expression in type 2 diabetic mice and patients which caused mitochondrial dysfunction and central insulin resistance. Mitochondrial HSP10 is also reduced in brains of db/db mice. However, the effects of reduced HSP10 expression in brain on metabolism and insulin sensitivity are unknown. Thus, we generated a shRNA-mediated knockdown (KD) of Hsp10 in the hypothalamic murine cell line Clu183 and investigated cellular stress responses, mitochondrial function and insulin signaling. 50% KD of HSP10 in vitro causes impaired mitochondrial dynamics and reduced mitochondrial count, but increases mitochondria-endoplasmatic reticulum (ER) contact sites. These cells exhibit reduced mitochondrial respiration and mild oxidative stress represented by a 35% decrease of protein amount of SOD2 along with about 20% decreased protein amounts of subunits of the electron transport chain complexes IV and II. Notably, HSP10 KD induces ER stress shown by the increased gene expression of Chop and increased phosphorylation of IRE1(S724). Most importantly, KD of HSP10 induces acute insulin resistance shown by reduced phosphorylation of IRS-1(Y612) and AKT/PKB(S473) after 5 min of 10 nM insulin stimulation. Preliminary data of a lentiviral-mediated KD approach of Hsp10 in the mediobasal hypothalamus in C57BL/6N mice revealed an unexpected 11% reduction in liver weight partly due to reduced hepatic glycogen content compared to control mice. Consistently, hepatic gene expression of Pepck, which is suppressed by insulin, was increased in Hsp10 KD mice by 60%.

In conclusion, we identified an unexpected role of Hsp10 in regulating hypothalamic mitochondrial function, insulin sensitivity and liver function. Thus, hypothalamic Hsp10 may present a novel regulator of the brain-liver crosstalk.


K. Wardelmann: None. J. Castro: None. M. Rath: None. J. Weiß: None. A. Schuermann: None. A. Kleinridders: None.

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