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

doi:10.1016/j.celrep.2023.112488

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

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

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.

Original language	English (US)
Article number	112488
Journal	Cell Reports
Volume	42
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2023.112488
State	Published - May 30 2023

Keywords

ACC1
CP: Metabolism
FASN
UCP1
acetyl-CoA
adipose tissue
browning
fatty acids
lipogenesis
malonyl-CoA
thermogenesis

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2023.112488

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Guilherme, A., Rowland, L. A., Wetoska, N., Tsagkaraki, E., Santos, K. B., Bedard, A. H., Henriques, F., Kelly, M., Munroe, S., Pedersen, D. J., Ilkayeva, O. R., Koves, T. R., Tauer, L., Pan, M., Han, X., Kim, J. K., Newgard, C. B., Muoio, D. M., & Czech, M. P. (2023). Acetyl-CoA carboxylase 1 is a suppressor of the adipocyte thermogenic program. Cell Reports, 42(5), Article 112488. https://doi.org/10.1016/j.celrep.2023.112488

Guilherme, A, Rowland, LA, Wetoska, N, Tsagkaraki, E, Santos, KB, Bedard, AH, Henriques, F, Kelly, M, Munroe, S, Pedersen, DJ, Ilkayeva, OR, Koves, TR, Tauer, L, Pan, M, Han, X, Kim, JK, Newgard, CB, Muoio, DM & Czech, MP 2023, 'Acetyl-CoA carboxylase 1 is a suppressor of the adipocyte thermogenic program', Cell Reports, vol. 42, no. 5, 112488. https://doi.org/10.1016/j.celrep.2023.112488

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title = "Acetyl-CoA carboxylase 1 is a suppressor of the adipocyte thermogenic program",

abstract = "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.",

keywords = "ACC1, CP: Metabolism, FASN, UCP1, acetyl-CoA, adipose tissue, browning, fatty acids, lipogenesis, malonyl-CoA, thermogenesis",

author = "Adilson Guilherme and Rowland, {Leslie A.} and Nicole Wetoska and Emmanouela Tsagkaraki and Santos, {Kaltinaitis B.} and Bedard, {Alexander H.} and Felipe Henriques and Mark Kelly and Sean Munroe and Pedersen, {David J.} and Ilkayeva, {Olga R.} and Koves, {Timothy R.} and Lauren Tauer and Meixia Pan and Xianlin Han and Kim, {Jason K.} and Newgard, {Christopher B.} and Muoio, {Deborah M.} and Czech, {Michael P.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = may,

day = "30",

doi = "10.1016/j.celrep.2023.112488",

language = "English (US)",

volume = "42",

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T1 - Acetyl-CoA carboxylase 1 is a suppressor of the adipocyte thermogenic program

AU - Guilherme, Adilson

AU - Rowland, Leslie A.

AU - Wetoska, Nicole

AU - Tsagkaraki, Emmanouela

AU - Santos, Kaltinaitis B.

AU - Bedard, Alexander H.

AU - Henriques, Felipe

AU - Kelly, Mark

AU - Munroe, Sean

AU - Pedersen, David J.

AU - Ilkayeva, Olga R.

AU - Koves, Timothy R.

AU - Tauer, Lauren

AU - Pan, Meixia

AU - Han, Xianlin

AU - Kim, Jason K.

AU - Newgard, Christopher B.

AU - Muoio, Deborah M.

AU - Czech, Michael P.

PY - 2023/5/30

Y1 - 2023/5/30

N2 - 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.

AB - 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.

KW - ACC1

KW - CP: Metabolism

KW - FASN

KW - UCP1

KW - acetyl-CoA

KW - adipose tissue

KW - browning

KW - fatty acids

KW - lipogenesis

KW - malonyl-CoA

KW - thermogenesis

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DO - 10.1016/j.celrep.2023.112488

M3 - Article

C2 - 37163372

AN - SCOPUS:85158065697

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 5

M1 - 112488

ER -

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

Abstract

Keywords

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