CLPP deficiency protects against metabolic syndrome but hinders adaptive thermogenesis

Abstract

Mitochondria are fundamental for cellular metabolism as they are both a source and a target of nutrient intermediates originating from converging metabolic pathways, and their role in the regulation of systemic metabolism is increasingly recognized.Thus, maintenance of mitochondrial homeostasis is indispensable for a functional energy metabolism of the whole organism.Here, we report that loss of the mitochondrial matrix protease CLPP results in a lean phenotype with improved glucose homeostasis.Wholebody CLPP-deficient mice are protected from diet-induced obesity and insulin resistance, which was not present in mouse models with either liver-or muscle-specific depletion of CLPP.However, CLPP ablation also leads to a decline in brown adipocytes function leaving mice unable to cope with a cold-induced stress due to non-functional adaptive thermogenesis.These results demonstrate a critical role for CLPP in different metabolic stress conditions such as high-fat diet feeding and cold exposure providing tools to understand pathologies with deregulated Clpp expression and novel insights into therapeutic approaches against metabolic dysfunctions linked to mitochondrial diseases.