Metabolic Regulation of Hsp60/Hsp10 Chaperone Complex Impacts on Hypothalamic Lipid Metabolism

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The pancreas-derived hormone insulin and the fat-secreted hormone leptin are key metabolic hormones. Receptors for both hormones are expressed throughout the brain and control metabolism and cognitive function via central activation of their pathways. Both hormones exhibit not only similar physiological function, such as regulating food intake, they also crossactivate their signaling pathways on a molecular level. Insulin and leptin resistance are hallmarks of metabolic disorders. Thus, research over the last decade has been focused on understanding the occurrence and consequences of central insulin and leptin resistance. This led to the discovery of the influence of unfolded protein response of the endoplasmatic reticulum (UPRer) on metabolism. This stress response aims to restore cellular homeostasis by stopping protein translation, upregulating chaperones to cope with the burden of misfolded proteins and increasing the degradation of misfolded proteins. A reduction of ER chaperones improves insulin and leptin signaling, whereas overactivation of this pathway induces central insulin and leptin resistance. Thus, increased expression of ER chaperones in diabetic conditions has been observed in a variety of tissues.In addition to UPRer, there is also an UPR of the mitochondria (UPRmt). This stress response is a mitochondria-to-nuclear signal transduction pathway inducing mitochondrial protective genes including mitochondrial proteases and chaperones, such as Hsp60 and Hsp10, to re-establish protein homeostasis within the mitochondria. The effect of UPRmt on metabolism is poorly understood. Mitochondrial dysfunction has been associated with an increased production of reactive oxygen species (ROS) and insulin resistance, yet the effect of mitochondrial chaperones, especially Hsp60, on insulin signaling was demonstrated just recently. The metabolic regulation of the UPRmt and its effect on hypothalamic leptin signaling is unknown. Although oxidative stress induces insulin resistance, antioxidants failed in reversing insulin resistance in clinics. One hypothesis is that just reducing oxidative stress is not sufficient enough to restore insulin signaling, as other features of mitochondrial function have to be restored. Mitochondria are also crucial for fatty acid metabolism, where folding of key enzymes such as MCAD is catalyzed by Hsp60 and Hsp10. Thus, it is proposed that an altered UPRmt will affect hypothalamic fatty acid metabolism and insulin sensitivity, as fatty acid metabolites such as acylcarnitines can induce insulin resistance.This proposal aims to investigate, a) the metabolic regulation of the mitochondrial UPR in the brain, b) the effect of mitochondrial chaperones on leptin signaling and c) the consequence of a dysregulated UPRmt on hypothalamic fatty acid metabolism and central insulin sensitivity.