Acetyl-CoA Synthetase Short Chain Family Member-1 (ACSS1) acetylation status is an important regulator of adipose tissue thermogenic function

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Brown adipose tissue (BAT) is a crucial regulator of metabolism specialized in dissipating energy in the form of heat. Cold stimulated BAT uses glucose and free fatty acids for thermogenesis, impacting adiposity, glucose control, and insulin sensitivity. Furthermore, the ability of white adipocytes in white adipose tissue (WAT) to transition into thermogenic or beige adipocytes in response to cold exposure or specific pharmacological activators makes them a promising target for developing therapies to address obesity and other metabolic diseases. Sirtuin 3 (SIRT3), an NAD+- dependent deacetylase found within the mitochondria, controls BAT thermogenesis. Loss of SIRT3 in mice results in compromised BAT lipid metabolism, as well as impaired thermoregulation and mitochondrial respiration in BAT, without affecting UCP1 expression and/or function. Acetyl-CoA Synthetase Short Chain Family Member-1 (ACSS1) is an established SIRT3 deacetylation target that synthetizes acetyl-CoA using acetate that is central for fatty acid oxidation (FAO) and mitochondrial metabolism. To understand the function of ACSS1 acetylation role in BAT and WAT during thermogenesis response, we generated a ubiquitous acetylation mimic knock-in mouse by mutating lysine 635 to glutamine (K635Q), previously shown to alter ACSS1 enzymatic activity, which represents a constitutive ACSS1-K635-Ac rendering a protein with altered functionality. Our studies showed that these mice are intolerant to stimulation with b3 adrenergic receptor agonist CL316243 and died within 24 hours. These mice are not able to maintain body temperature and glucose homeostasis and also displayed dysregulated levels of the major lipid synthesis and oxidation pathways in BAT and inguinal subcutaneous WAT (iWAT). Importantly, the CL316243 intolerant phenotype was not observed in Acss1 knock out mice. This data suggests ACSS1-Ac status is an important regulator of adipose cells/tissue thermogenic function, and therefore is a potential therapeutic target for metabolic diseases. These results open a new roadmap to improve metabolic health through post- translational control of ACSS1. Early Stage Investigator Award, Mays Cancer Center P30CA 054174. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.