Acetyl-CoA carboxylase 1 is a suppressor of the adipocyte thermogenic program

• Published in: Cell reports (Cambridge) 2023-05, Vol.42 (5), p.112488-112488, Article 112488
• Main Authors: Guilherme, Adilson, Rowland, Leslie A., Wetoska, Nicole, Tsagkaraki, Emmanouela, Santos, Kaltinaitis B., Bedard, Alexander H., Henriques, Felipe, Kelly, Mark, Munroe, Sean, Pedersen, David J., Ilkayeva, Olga R., Koves, Timothy R., Tauer, Lauren, Pan, Meixia, Han, Xianlin, Kim, Jason K., Newgard, Christopher B., Muoio, Deborah M., Czech, Michael P.
• Format: Article
• Language: English
• Subjects: ACC1; Acetyl Coenzyme A - metabolism; acetyl-CoA; Acetyl-CoA Carboxylase - metabolism; Adipocytes - metabolism; adipose tissue; Animals; browning; CP: Metabolism; FASN; Fatty Acid Synthases - metabolism; fatty acids; lipogenesis; malonyl-CoA; Mice; Mice, Knockout; Palmitates - metabolism; Thermogenesis; UCP1
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112488

Disruption of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) in mice induces browning in inguinal white adipose tissue (iWAT). However, adipocyte FASN knockout (KO) increases acetyl-coenzyme A (CoA) and malonyl-CoA in addition to depletion of palmitate. We explore which of these metabolite changes triggers adipose browning by generating eight adipose-selective KO mouse models with loss of ATP-citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), ACC2, malonyl-CoA decarboxylase (MCD) or FASN, or dual KOs ACLY/FASN, ACC1/FASN, and ACC2/FASN. Preventing elevation of acetyl-CoA and malonyl-CoA by depletion of adipocyte ACLY or ACC1 in combination with FASN KO does not block the browning of iWAT. Conversely, elevating malonyl-CoA levels in MCD KO mice does not induce browning. Strikingly, adipose ACC1 KO induces a strong iWAT thermogenic response similar to FASN KO while also blocking malonyl-CoA and palmitate synthesis. Thus, ACC1 and FASN are strong suppressors of adipocyte thermogenesis through promoting lipid synthesis rather than modulating the DNL intermediates acetyl-CoA or malonyl-CoA. [Display omitted] •Adipocyte FASN KO blocks lipid synthesis but increases malonyl-CoA and browning•Preventing malonyl-CoA elevation in FASN KO adipocytes does not inhibit browning•Conversely, elevating malonyl-CoA in adipocytes fails to induce browning•Loss of adipocyte FASN or ACC1 promotes browning by inhibiting FA synthesis Guilherme et al. generate several adipose-selective KO mouse models targeting each of the de novo lipogenesis enzymes to investigate their contributions to control of adipocyte thermogenesis. They show that disruption of palmitate synthesis caused by loss of adipocyte ACC1 or FASN upregulates UCP1 independent of alterations in acetyl-CoA or malonyl-CoA.