The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis.
Brown fat activates uncoupled respiration in response to cold temperature and contributes to systemic metabolic homeostasis. To date, the metabolic action of brown fat has been primarily attributed to its role in fuel oxidation and uncoupling protein 1 (UCP1)-mediated thermogenesis. Whether brown fat engages other tissues through secreted factors remains largely unexplored. Here we show that neuregulin 4 (Nrg4), a member of the epidermal growth factor (EGF) family of extracellular ligands, is highly expressed in adipose tissues, enriched in brown fat and markedly increased during brown adipocyte differentiation. Adipose tissue Nrg4 expression was reduced in rodent and human obesity. Gain- and loss-of-function studies in mice demonstrated that Nrg4 protects against diet-induced insulin resistance and hepatic steatosis through attenuating hepatic lipogenic signaling. Mechanistically, Nrg4 activates ErbB3 and ErbB4 signaling in hepatocytes and negatively regulates de novo lipogenesis mediated by LXR and SREBP1c in a cell-autonomous manner. These results establish Nrg4 as a brown fat-enriched endocrine factor with therapeutic potential for the treatment of obesity-associated disorders, including type 2 diabetes and nonalcoholic fatty liver disease (NAFLD).
Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
Guo-Xiao
GX
Wang
Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
Xu-Yun
XY
Zhao
Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
Zhuo-Xian
ZX
Meng
Department of Medicine, University of Leipzig, Leipzig, Germany.
Matthias
M
Kern
Department of Surgery, University of Leipzig, Leipzig, Germany.
Arne
A
Dietrich
Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
Zhimin
Z
Chen
Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
Zoharit
Z
Cozacov
Department of Internal Medicine, Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Dequan
D
Zhou
Department of Internal Medicine, Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Adewole L
AL
Okunade
Department of Biochemistry and Molecular Biology, Soochow University Medical College, Suzhou 215123, China.
Xiong
X
Su
Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
Siming
S
Li
Department of Medicine, University of Leipzig, Leipzig, Germany.
Matthias
M
Blüher
Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
Jiandie D
JD
Lin
D041721:3T3-L1 Cells; D052437:Adipocytes, Brown / Q000378:metabolism; D050156:Adipogenesis; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007333:Insulin Resistance; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D051379:Mice; D020880:Neuregulins / Q000235:genetics* / Q000378:metabolism; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics*; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D066247:Receptor, ErbB-4 / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism
D000071518:Liver X Receptors; D020880:Neuregulins; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; C467747:neuregulin-4; C581292:ERBB3 protein, human; C587689:ERBB4 protein, human; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4