Fawaz Haj, Ph.D.
Associate Professor of Nutrition
UC Davis

“Beige can be slimming; novel insights into the metabolic functions of adipose protein-tyrosine phosphatase 1B and its substrates”

The obesity epidemic, closely associated with increases in type 2 diabetes, cardiovascular disease and many cancers has propelled interest in adipose cells and tissue. There are two major types of adipose tissues in mammals, white and brown. White adipose tissue is the primary site for triglyceride storage and fatty acid release whereas brown adipose cells are specialized to dissipate chemical energy as heat and are associated with improved metabolic phenotypes. We investigated the role of protein-tyrosine phosphatase 1B in adipose metabolic functions using tissue-specific deletion approach. We report that adipose-specific PTP1B deletion reduces body weight and adiposity in male and female mice fed high fat diet. This is due, at least in part, to increased energy expenditure in these mice. In addition, using substrate-trapping and mass spectroscopy approaches we identify pyruvate kinase M2 (PKM2) as a PTP1B substrate in adipocytes. PKM2 tyrosine phosphorylation and activation are regulated nutritionally, decreasing in adipose tissue depots after high-fat feeding. Further, PKM2 phosphorylation correlates with the development of glucose intolerance and insulin resistance in rodents, non-human primates, and humans. Importantly, shRNA-mediated depletion of PKM2 in white preadipocytes promotes the development of a brown fat-like thermogenic program. Reconstitution of knockdown cells with wild type PKM2, but not PKM1, abrogates thermogenic gene induction that is caused by PKM2 deficiency. Notably, transplantation of PKM2-deficient preadipocytes into mice gives rise to ectopic fat pads with morphological and biochemical characteristics of brown adipocytes with enhanced glucose uptake in vivo. Finally, mice treated with the PKM2 inhibitor shikonin exhibit resistance to HFD induced obesity. Collectively, these findings identify PTP1B and PKM2 as novel components of the molecular circuit that contributes to adipocyte plasticity and adaptive thermogenesis, which may have potential therapeutic implications.

Location
1005 GBSF