Acetyl-CoA carboxylase 1 is a suppressor of the adipocyte thermogenic program
Adilson Guilherme,
Leslie A. Rowland,
Nicole Wetoska,
Emmanouela Tsagkaraki,
Kaltinaitis B. Santos,
Alexander H. Bedard,
Felipe Henriques,
Mark Kelly,
Sean Munroe,
David J. Pedersen,
Olga R. Ilkayeva,
Timothy R. Koves,
Lauren Tauer,
Meixia Pan,
Xianlin Han,
Jason K. Kim,
Christopher B. Newgard,
Deborah M. Muoio,
Michael P. Czech
Affiliations
Adilson Guilherme
Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Corresponding author
Leslie A. Rowland
Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Nicole Wetoska
Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Emmanouela Tsagkaraki
Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Kaltinaitis B. Santos
Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Alexander H. Bedard
Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Felipe Henriques
Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Mark Kelly
Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Sean Munroe
Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
David J. Pedersen
Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Olga R. Ilkayeva
Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University School of Medicine, Durham, NC 27701, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27705, USA
Timothy R. Koves
Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University School of Medicine, Durham, NC 27701, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27705, USA
Lauren Tauer
Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Meixia Pan
Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Xianlin Han
Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Jason K. Kim
Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Christopher B. Newgard
Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University School of Medicine, Durham, NC 27701, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27705, USA; Departments of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27705, USA
Deborah M. Muoio
Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University School of Medicine, Durham, NC 27701, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27705, USA; Departments of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27705, USA
Michael P. Czech
Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Corresponding author
Summary: 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.
