Elsevier

Molecular Metabolism

Volume 6, Issue 8, August 2017, Pages 863-872
Molecular Metabolism

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

https://doi.org/10.1016/j.molmet.2017.03.016Get rights and content
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open access

Highlights

  • Nrg4 is a target of pro-inflammatory and anti-inflammatory signaling in adipocytes.

  • Transgenic expression of Nrg4 increased energy expenditure and glucose metabolism.

  • Nrg4 stimulates hepatic fatty acid oxidation and ketogenesis during starvation.

  • Nrg4 promotes a beneficial adipokine profile during obesity.

Abstract

Objective

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

Adipose tissue
Brown fat
Nrg4
Adipokine
NAFLD
Diabetes

Abbreviations

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

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