Nrg4 and Gpr120 signalling in brown fat

Abstract

Brown adipose tissue (BAT) dissipates energy, whereas white adipose tissue (WAT) is an energy storage site. The worldwide increase in obesity and its associated metabolic complications represents a growing challenge for health care systems. With the recent demonstration of significant deposits of adult human BAT, and that WAT is dynamic and can gain BAT characteristics, there is therefore a possibility for manipulative control of energy homeostasis via the induction of specific genes to enhance BAT levels. Nrg4 and Gpr120 are two genes we identified to be highly expressed in BAT and regulated in a temperature-dependent manner. Nrg4 is a member of the Neuregulin family that activates the ErbB-4 (HER4) tyrosine kinase receptor. Nrg4 was secreted from brown adipocytes and promoted neurite outgrowth, a function that may improve BAT thermogenesis by enhancing sympathetic innervation. Gpr120 is a member of the superfamily of G protein-coupled receptors that is activated by long chain fatty acids. Although Gpr120 is known to mediate anti-inflammatory and insulin-sensitizing effects in humans and mice, its role in BAT is unknown. In order to identify the signalling pathways and downstream functions activated by this receptor in brown adipocytes, distinct known and novel Gpr120 ligands, GW9508, TUG891 and TUG1096, were employed. These ligands increased expression of genes associated with glucose and fatty acid metabolism and reduced inflammatory gene markers. All of these effects were reversed in Gpr120 knockout cells. However, the levels of gene expression varied considerably with each ligand. Although Gpr120 is a known Gαq/11-coupled receptor in other cell systems, these distinct ligands exhibited various degrees of bias towards Gαq/11 and distinct signalling pathways. These findings could provide insight into the requirements for Gpr120 function in BAT, the exploitation of which could generate ligands for therapeutic benefit and represents a promising opportunity to develop safer and more efficacious drugs.