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Mol Metab. 2017 Jun 21;6(8):863-872. doi: 10.1016/j.molmet.2017.03.016. eCollection 2017 Aug.

Nrg4 promotes fuel oxidation and a healthy adipokine profile to ameliorate diet-induced metabolic disorders.

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Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Program in Molecular Medicine and Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
423 Heritage Medical Research Building, University of Alberta Edmonton, Alberta T6G 2S2, Canada.
Weldon School of Biomedical Engineering and Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA. Electronic address:



Brown and white adipose tissue exerts pleiotropic effects on systemic energy metabolism in part by releasing endocrine factors. Neuregulin 4 (Nrg4) was recently identified as a brown fat-enriched secreted factor that ameliorates diet-induced metabolic disorders, including insulin resistance and hepatic steatosis. However, the physiological mechanisms through which Nrg4 regulates energy balance and glucose and lipid metabolism remain incompletely understood. The aims of the current study were: i) to investigate the regulation of adipose Nrg4 expression during obesity and the physiological signals involved, ii) to elucidate the mechanisms underlying Nrg4 regulation of energy balance and glucose and lipid metabolism, and iii) to explore whether Nrg4 regulates adipose tissue secretome gene expression and adipokine secretion.


We examined the correlation of adipose Nrg4 expression with obesity in a cohort of diet-induced obese mice and investigated the upstream signals that regulate Nrg4 expression. We performed metabolic cage and hyperinsulinemic-euglycemic clamp studies in Nrg4 transgenic mice to dissect the metabolic pathways regulated by Nrg4. We investigated how Nrg4 regulates hepatic lipid metabolism in the fasting state and explored the effects of Nrg4 on adipose tissue gene expression, particularly those encoding secreted factors.


Adipose Nrg4 expression is inversely correlated with adiposity and regulated by pro-inflammatory and anti-inflammatory signaling. Transgenic expression of Nrg4 increases energy expenditure and augments whole body glucose metabolism. Nrg4 protects mice from diet-induced hepatic steatosis in part through activation of hepatic fatty acid oxidation and ketogenesis. Finally, Nrg4 promotes a healthy adipokine profile during obesity.


Nrg4 exerts pleiotropic beneficial effects on energy balance and glucose and lipid metabolism to ameliorate obesity-associated metabolic disorders. Biologic therapeutics based on Nrg4 may improve both type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) in patients.


Adipokine; Adipose tissue; BAT, Brown adipose tissue; BMPs, Bone morphogenetic proteins; Brown fat; CoA, Co-enzyme A; Diabetes; FGF21, Fibroblast growth factor 21; GPR120, G-protein coupled receptor 120; HFD, High-fat diet; IL-6, Interleukin-6; KO, Knockout; NAFLD; NALFD, Non-alcoholic fatty liver disease; Nrg4; Nrg4, Neuregulin 4; TAG, Triglyceride; TNFα, Tumor necrosis factor α; Tg, Transgenic; UCP-1, Uncoupling protein 1; VEGFα, Vascular endothelial growth factor α; WAT, White adipose tissue; WT, Wild type; eWAT, epididymal WAT

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