Project Summary Cell metabolism plays a central role in cancer biology including cell proliferation, invasion/metastasis, and drug resistance. In addition to cancer, dysregulated cellular metabolism has been shown to be associated with obesity and the development of many chronic illnesses. According to the World Health Organization >2.1 billion adults are estimated to be overweight or obese globally, and accumulating, consistent, evidence suggests that higher amounts of body fat are associated with increased risks of a number of cancers. Previously, we discovered an essential role of histone deacetylase 11 (HDAC11) in metabolism homeostasis. More recently, our studies revealed a novel enzymatic activity of HDAC11, removing long-chain fatty acyl groups, that is >10,000-fold higher than the presumed deacetylation activity. Further, our recent preliminary studies show: 1) HDAC11 KO promotes the expression of UCP1 and boosts the thermogenic capacity of brown adipose tissue; 2) Lack of HDAC11 elevates the level of plasma adiponectin, a key messenger involved in communicating between adipose tissue and other organs, and suppresses metabolic derangements, leading to type 2 diabetes, obesity, and non- alcoholic fatty liver disease; 3) HDAC11 deficiency not only results in the accumulation of diacylglycerol (DG) and metabolites, but also attenuates the triacylglycerol (TAG) level in the liver, indicating dysfunction of diglyceride acyltransferase 2 (DGAT2). In this diversity supplement application, the Supplement Candidate will rigorously test the hypothesis that the novel defatty-acylation activity of HDAC11 is critical for its impact on HFD-driven metabolic reprogramming. The Candidate will focus on elucidating major HDAC11 KO-driven events in key lipid metabolism tissues by performing the following studies: 1) investigate the role of HDAC11 as a regulator of thermogenesis through the UCP1 pathway in BAT and examine whether HDAC11 altered Cdc42-fatty-acylation plays a crucial role in cAMP/PKA mediated UCP1 expression; 2) examine the effect of HDAC11 on adiponectin function in white adipose tissue and investigate the impact of HDAC11 on adiponectin conserved lysine-modification and multimerization; 3) explore HDAC11 KO-induced suppression of TAG synthesis through affecting DGAT function in liver tissue and investigate the role of BASP1 in DGAT regulation. The proposed experiments in this supplement are distinct from, yet highly relevant to, the proposed work in the parent grant. The supplemental project will contribute to, expands and extends, our understandings of HDAC11 in cancer. Ultimately, it may lead to new approaches for the treatment of obesity-related cancer diseases.