Central acting Hsp10 regulates mitochondrial function, insulin sensitivity and impacts liver metabolism

Mitochondria are critical for hypothalamic function and regulators of metabolism. Hypothalamic mitochondrial dysfunction with decreased mitochondrial chaperone expression is present in type 2 diabetes (T2D). Mitochondrial health is sensed and adjusted by the mitochondrial unfolded protein response / mitochondrial stress response (MSR). Recently, we demonstrated that dysregulated MSR with reduced chaperone expression in the hypothalamus is an early event in obesity development due to insufficient insulin signaling. While insulin activates this response and improves metabolism, the metabolic impact of one of its members, the mitochondrial chaperone heat shock protein 10 (Hsp10), is unknown. Therefore, we investigated the role of chaperone Hsp10 by introducing a lentiviral-mediated Hsp10 knockdown (KD) in the hypothalamic cell line CLU-183 as well as in the arcuate nucleus (ARC) of C57BL / 6N male mice. We analyzed mitochondrial function and insulin signaling in vitro and in vivo utilizing qPCR, Western Blot, XF24 Analyzer, immunohistochemistry and microscopy techniques. We show that Hsp10 expression is reduced in T2 D mice brains and is regulated by leptin. Hsp10 KD in hypothalamic cells induced mitochondrial dysfunction with altered fatty acid metabolism and increased mitochondria-specific oxidative stress resulting in neuronal insulin resistance. Strikingly, reduction of Hsp10 in the ARC of C57BL / 6N mice caused – next to inducing insulin resistance in this brain region - acute liver insulin resistance with increased hepatic gluconeogenic gene expression and features of low-grade inflammation. Conclusively, Hsp10 is pivotal for mitochondrial function and insulin sensitivity in the hypothalamus. Furthermore, it presents a novel regulator of brain-liver crosstalk modulating hepatic gluconeogenesis and insulin sensitivity.

Interessenskonflikt

The authors declare no conflict of interest.

Publication History

Article published online:
06 May 2021