PT  - JOURNAL ARTICLE
AU  - Nelson E. Bruno
AU  - Jerome C. Nwachukwu
AU  - Sathish Srinivasan
AU  - Richard Hawkins
AU  - David Sturgill
AU  - Gordon L. Hager
AU  - Stephen Hurst
AU  - Shey-Shing Sheu
AU  - Michael D. Conkright
AU  - Kendall W. Nettles
TI  - Activation of the Crtc2/Creb1 transcriptional network in skeletal muscle enhances weight loss during intermittent fasting
AID  - 10.1101/2020.06.27.175323
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.27.175323
4099  - http://biorxiv.org/content/early/2020/06/28/2020.06.27.175323.short
4100  - http://biorxiv.org/content/early/2020/06/28/2020.06.27.175323.full
AB  - Exercise is a behavior modification indispensable for long-term weight loss. Exercise activates the Creb-Regulated Transcriptional Coactivator (Crtc) family of transcriptional coregulators to drive Creb1-mediated anabolic transcriptional programs in skeletal muscle. Here, we show that induced overexpression of a skeletal muscle specific Crtc2 transgene in aged mice leads to greater weight loss during alternate day fasting, and selective loss of fat rather than lean mass. Transcriptional profiling revealed that fasting and weight loss downregulated most of the mitochondrial electron transport genes and other regulators of mitochondrial function that were substantially reversed in the Crtc2 mice, which maintained higher energy expenditure during fasting. The Crtc2 mice displayed greater mitochondrial activity, metabolic flux capacity for both carbohydrates and fats, improved glucose tolerance and insulin sensitivity, and increased oxidative capacity before the fast, suggesting muscle-intrinsic mechanisms in support of improved weight loss. This work reveals that Crtc2/Creb1-mediated signaling coordinates metabolic adaptations in skeletal muscle that explain how Crtc2/Creb contribute to the effects of exercise on metabolism and weight loss.Competing Interest StatementThe authors have declared no competing interest.