Mitochondria are highly adaptable organelles that can facilitate communication between tissues to meet the energetic demands of the organism. However, the mechanisms by which mitochondria can nonautonomously relay stress signals remain poorly under- stood. Here we report that mitochondrial mutations in the young, preprogeroid polymerase gamma mutator (POLG) mouse produce a metabolic state of starvation. As a result, these mice exhibit signs of metabolic imbalance including thermogenic defects in brown adipose tissue (BAT). An unexpected benefit of this adaptive re- sponse is the complete resistance to diet-induced obesity when POLG mice are placed on a high-fat diet (HFD). Paradoxically, HFD further increases oxygen consumption in part by inducing thermo- genesis and mitochondrial biogenesis in BAT along with enhanced expression of fibroblast growth factor 21 (FGF21). Collectively, these findings identify a mechanistic link between FGF21, a long- known marker of mitochondrial disease, and systemic metabolic adaptation in response to mitochondrial stress.

Vector Biolabs made the shFGF21 adenovirus used in this study.

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