Skeletal muscle PGC-1α modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice

Ketone bodies (KBs) are crucial energy substrates during states of low carbohydrate availability. However, an aberrant regulation of KB homeostasis can lead to complications such as diabetic ketoacidosis. Exercise and diabetes affect systemic KB homeostasis, but the regulation of KB metabolism is still enigmatic. In our study in mice with either knockout or overexpression of the peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1 alpha in skeletal muscle, PGC-1 alpha regulated ketolytic gene transcription in muscle. Furthermore, KB homeostasis of these mice was investigated during withholding of food, exercise, and ketogenic diet feeding, and after streptozotocin injection. In response to these ketogenic stimuli, modulation of PGC-1 alpha levels in muscle affected systemic KB homeostasis. Moreover, the data demonstrate that skeletal muscle PGC-1 alpha is necessary for the enhanced ketolytic capacity in response to exercise training and overexpression of PGC-1 alpha in muscle enhances systemic ketolytic capacity and is sufficient to ameliorate diabetic hyperketonemia in mice. In cultured myotubes, the transcription factor estrogen-related receptor-a was a partner of PGC-1 alpha In the regulation of ketolytic gene transcription. These results demonstrate a central role of skeletal muscle PGC-1 alpha in the transcriptional regulation of systemic ketolytic capacity.-Svensson, K., Albert, V., Cardel, B., Salatino, S., Handschin, C. Skeletal muscle PGC-1 alpha modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice. www.fasebj.org