Endogenous Fatty Acid Synthesis Drives Brown Adipose Tissue Involution
Christian Schlein,
Alexander W. Fischer,
Frederike Sass,
Anna Worthmann,
Klaus Tödter,
Michelle Y. Jaeckstein,
Janina Behrens,
Matthew D. Lynes,
Michael A. Kiebish,
Niven R. Narain,
Val Bussberg,
Abena Darkwah,
Naja Zenius Jespersen,
Søren Nielsen,
Camilla Scheele,
Michaela Schweizer,
Ingke Braren,
Alexander Bartelt,
Yu-Hua Tseng,
Joerg Heeren,
Ludger Scheja
Affiliations
Christian Schlein
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Alexander W. Fischer
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Frederike Sass
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Anna Worthmann
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Klaus Tödter
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Michelle Y. Jaeckstein
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Janina Behrens
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Matthew D. Lynes
Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
Michael A. Kiebish
BERG, Framingham, MA, USA
Niven R. Narain
BERG, Framingham, MA, USA
Val Bussberg
BERG, Framingham, MA, USA
Abena Darkwah
BERG, Framingham, MA, USA
Naja Zenius Jespersen
Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Søren Nielsen
Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Camilla Scheele
Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Michaela Schweizer
Core Facility of Electron Microscopy, Center for Molecular Neurobiology ZMNH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Ingke Braren
Vector Facility, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Alexander Bartelt
Department of Molecular Metabolism & Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, 81377 Munich, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany; Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany
Yu-Hua Tseng
Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
Joerg Heeren
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Ludger Scheja
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Corresponding author
Summary: Thermoneutral conditions typical for standard human living environments result in brown adipose tissue (BAT) involution, characterized by decreased mitochondrial mass and increased lipid deposition. Low BAT activity is associated with poor metabolic health, and BAT reactivation may confer therapeutic potential. However, the molecular drivers of this BAT adaptive process in response to thermoneutrality remain enigmatic. Using metabolic and lipidomic approaches, we show that endogenous fatty acid synthesis, regulated by carbohydrate-response element-binding protein (ChREBP), is the central regulator of BAT involution. By transcriptional control of lipogenesis-related enzymes, ChREBP determines the abundance and composition of both storage and membrane lipids known to regulate organelle turnover and function. Notably, ChREBP deficiency and pharmacological inhibition of lipogenesis during thermoneutral adaptation preserved mitochondrial mass and thermogenic capacity of BAT independently of mitochondrial biogenesis. In conclusion, we establish lipogenesis as a potential therapeutic target to prevent loss of BAT thermogenic capacity as seen in adult humans.
