Browning of white adipose tissue is increasingly recognized as a potential new therapeutic target for the treatment of obesity and diabetes. The mechanisms that govern this process remain incompletely understood, in particular how the process is linked to intracellular metabolic cues. We have now uncovered a novel molecular pathway that regulates browning of white fat, and which integrates two of the most important intracellular metabolic sensors: mTOR and AMPK. At the heart of this pathway lies Folliculin (FLCN), a protein mutated in the hamartomatous Birt-Hogg-Dube syndrome. FLCN interacts directly with, and transduces signals, to and from both the mTOR and AMPK pathways. The absence of FLCN in adipose tissue leads to marked browning of white fat, and dramatic potentiation of thermogenesis. We thus hypothesize that FLCN in white adipose tissue is a key nexus that integrates metabolic cues to coordinate the browning of white fat. We propose experiments to: 1) Delineate the molecular mechanisms by which FLCN, mTOR, and AMPK regulate browning in fat. 2) Use genetic epistatic experiments in intact mice to definitively test the role of this novel axis in browning of fat in vivo. 3) Test if inhibition of adipocyte FLCN improves metabolic homeostasis and can protect from obesity and diabetes in both diet-induced and genetic murine models.
Obesity and diabetes are leading causes of morbidity and mortality worldwide, and are on the rise. The conversion of fat from energy storing (?white?) to energy dissipating (?brown?) is a newly discovered and exciting potential approach to combating obesity and diabetes, but how fat tissue accomplishes this conversion remains poorly understood. We have uncovered here a novel mechanism that regulates this process, and we propose experiments to understand the process in molecular and physiological detail, in order to determine if targeting this pathway may have therapeutic potential.
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