CLPP deficiency protects against metabolic syndrome but hinders adaptive thermogenesis

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. Whole‐body 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.