Abstract 2268: Altered Basal Metabolism and Increased Obesity in Mice With Targeted Deletion of Rho-associated Coiled-coil Forming Kinase (ROCK)-2
Background: The Rho-associated coiled-coil forming kinases (ROCKs) are important regulators of cell shape, motility, and contraction through their effects on the actin cytoskeleton. Recent studies suggest that ROCKs may play an important role in insulin signaling and adipogenesis. However, the precise signaling mechanism by which ROCKs regulate energy metabolism and obesity is not known.
Methods and Results: To determine the role of ROCKs in obesity, we generated mutant mice with global targeted deletion of ROCK1 and ROCK2, and adipocyte-specific targeted deletion of ROCK2. Here we show that ROCK2 is a critical regulator of basal metabolism, energy expenditure, and obesity. Despite comparable food intake, mice with hemizygous deletion of ROCK2 (ROCK2+/−) develop insulin resistance, have 25% higher body weight, and 2 times more body fat than wild-type or ROCK1+/− mice. Similar findings were observed in mutant mice with adipocyte-specific deletion of ROCK2. Furthermore, ROCK2+/− mice exhibited circadian rhythm disturbances, impaired adaptive thermogenesis, and 43% reduction in whole-body oxygen consumption; features which are similar to mice with homozygous deletion of peroxisome proliferators-activated receptor γ co-activator (PGC)-1α. Indeed, ROCK2, but not ROCK1, phosphorylates PGC-1α in skeletal muscle and adipose tissue, and phosphorylation of PGC-1α is required for PGC-1α induction in response to physiological stimuli (cold exposure and exercise). Furthermore, phosphorylation of PGC-1α by ROCK2 mediates mitochondrial biogenesis and increased energy metabolism.
Conclusions: These findings indicate a novel non-contractile function of ROCK2 as a critical regulator of obesity through its effects on PGC-1α and energy metabolism. These results suggest that therapeutic strategies that enhance ROCK2-PGC-1α signaling in skeletal muscle and adipose tissue may have clinical benefits in preventing diet-induced obesity.