UC Berkeley

Obesity, defined as abnormal or excessive fat accumulation, has become a global epidemic. Although some obese individuals are metabolically healthy a majority develop several co-morbidities such as type II diabetes, hypercholesterolemia, and cardiovascular disease. Diet and exercise can be effective strategies to lose weight, but many individuals have difficulty making lifestyle changes. Thus, new therapeutic strategies are needed to combat the growing prevalence of obesity. Our lab has focused on understanding the biological function of brown adipose tissue (BAT) and beige adipose tissue (BeAT), which are promising therapeutic tissues to combat obesity and obesity related diseases. Unlike white adipose tissue which serves a purpose of storing energy for later use, BAT and BeAT catabolize fat and glucose, uncoupling the electron transport chain from ATP production, instead generating heat. BAT and BeAT depots are primarily activated by cold exposure via β-adrenergic receptor signaling. Targeting β-adrenergic signaling to activate BAT and BeAT was a promising therapeutic approach, however β-adrenergic receptors are also found in the heart preventing widespread therapeutic use. A deeper biological understanding of BAT and BeAT may lead to new therapeutic targets. Our lab previously uncovered a novel role for actomyosin mediated-tension facilitating thermogenesis in BAT. This novel mechanism became the basis for three projects described within this dissertation. First, we probed the importance of type II myosin activity in BeAT development and thermogenic function; type II myosin 9 (Myh9) was found to regulate UCP1 mRNA expression, mitochondrial function, and lipid metabolism. Second, in collaboration with the company Atomwise we screened novel type II myosin activators in BAT to determine whether pharmacologically activating type II myosins could increase thermogenesis. Third, we sought to understand the function of the mechanosensitive transcriptional paralogs YAP and TAZ in regulating BeAT differentiation.