Abstract 1426: Decrease Basal Metabolism and Energy Expenditure and Increase Obesity in Mice with Targeted Deletion of ROCK2
Background: The peroxisome proliferators-activated receptors (PPARs) and transcriptional coactivator PGC-1α (PPAR-coactivator-1) are key regulators of basal metabolism, energy expenditure, and obesity. Activation of PPARs occurs through binding to PPAR ligands, but the regulation of PGC-1α remains largely unknown. Here we show that the Rho-associated coiled-coil kinase (ROCK)-2, a key modulator of the actin cytoskeleton, regulates basal metabolism and energy expenditure through phosphorylation and stabilization of PGC-1α
Methods and Results: To determine the role of ROCKs in regulating basal metabolism, energy expenditure, and obesity, we developed mutant mice with targeted deletion of ROCK1 and ROCK2. Homozygous deletion of ROCKs leads to embryonic and perinatal lethality. However, heterozygous deletion of ROCK1 and ROCK2 leads to 50% reduction of ROCK1 and ROCK2 protein, respectively, without compensatory changes in the other ROCK isoform. At 4 weeks of age, body weights were similar between WT, ROCK1+/− and ROCK2+/− mice. However, beginning at 17 weeks of age on a regular chow diet, ROCK2+/− mice exhibited increase body weight compared to that of WT or ROCK1+/− mice, despite comparable food intake. At 20 weeks of age, ROCK2+/− mice developed insulin resistance and have 25% higher body weight than WT or ROCK1+/− mice. Obesity in ROCK2+/− mice was confirmed by DEXA scan showing higher body fat content (33% compared to 17% for WT and ROCK1+/− mice). Furthermore, ROCK2+/− mice have impaired adaptive thermogenesis and showed a 43% decrease in whole-body oxygen consumption compared to WT and ROCK1+/− mice. Analysis of brown adipose tissues and skeletal muscles in ROCK2+/− mice showed lack of upregulation of PGC-1α in response to cold exposure or exercise. Indeed, ROCK2 associates and phosphorylates PGC-1α, leading to increase PGC-1α protein stability.
Conclusions: These findings indicate that loss of ROCK2 leads to reduced basal metabolism, cold intolerance, decreased energy expenditure, and increased obesity through downregulation of PGC-1α. These results suggest that factors or conditions that increase ROCK2 activity in adipose tissues and skeletal muscle may have therapeutic benefits in preventing diet-induced obesity.