Editors' ChoiceMetabolism

BAT Signal to the Liver

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Sci. Signal.  23 Dec 2014:
Vol. 7, Issue 357, pp. ec355
DOI: 10.1126/scisignal.aaa5346

Genetic analysis suggests that brown adipose tissue (BAT) can increase systemic energy metabolism not only by dissipating energy in the form of heat, but also through endocrine effects. Wang et al. identified neuregulin 4 (NRG4), an epidermal growth factor–like domain–containing ligand that binds to ErbB receptors, as a factor secreted by BAT that acted on hepatocytes. Nrg4 expression was detected in white adipose tissue (WAT) and was enriched in brown adipocytes. Nrg4 expression was increased during differentiation of brown preadipocytes and by stimuli that increase the activity of brown fat (such as norephinephrine treatment of differentiated brown adipocytes or acute cold exposure in mice). When expressed in HEK293 cells, NRG4 was cleaved and released into the medium. Binding assays indicated that recombinant NRG4 bound to ErbB3 and ErbB4 receptors in liver. When fed a high-fat diet, mice lacking Nrg4 had greater plasma triacylglyceride concentrations, lower glucose tolerance and insulin sensitivity, and greater hepatic lipid accumulation than wild-type mice. The livers of Nrg4-deficient mice showed higher expression of genes encoding enzymes required for de novo lipogenesis and lower expression of genes involved in fatty acid β-oxidation than those of wild-type mice. In mouse hepatocytes expressing ErbB4, recombinant Nrg4 treatment increased the tyrosine phosphorylation of ErbB3 (which can be phosphorylated in a ligand-dependent manner when heterodimerized with ErbB4) and of the transcription factor STAT5, and inhibited the drug-induced activation of the liver X receptor (LXR), a nuclear hormone receptor that responds to nutritional cues. Luciferase assays performed in Hepa1 hepatoma cells suggested that STAT5 transrepressed LXR, which activates the transcription factor SREBP1c, which in turn activates genes that encode lipogenic enzymes. Nrg4 expression was reduced in the WAT of mice fed a high-fat diet or ob/ob and db/db mice, which are genetic models of obesity, the BAT of ob/ob and db/db mice, and the WAT of individuals with decreased glucose tolerance or type 2 diabetes. When fed a high-fat diet, mice overexpressing Nrg4 in adipose tissue had decreased hepatic steatosis, plasma triacylglyceride concentrations, glucose and insulin concentrations, mRNA and protein abundance of SREBP1c, and mRNA expression of lipogenic enzyme-encoding genes than wild-type mice. These results suggest that NRG4 could be developed as a treatment for metabolic disorders.

G.-X. Wang, X.-Y. Zhao, Z.-X. Meng, M. Kern, A. Dietrich, Z. Chen, Z. Cozacov, D. Zhou, A. L Okunade, X. Su, S. Li, M. Blüher, J. D. Lin, The brown fat–enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. Nat. Med. 20, 1436–1443 (2014). [PubMed]