Neuregulin 4 as a novel adipokine in energy metabolism

Abstract

Adipose tissue has been shown to play a key role in energy metabolism and it has been shown to regulate metabolic homeostasis through the secretion of adipokines. Neuregulin 4 (Nrg4), a novel adipokine secreted mainly by brown adipose tissue (BAT), has recently been characterized as having an important effect on the regulation of energy homeostasis and glucolipid metabolism. Nrg4 can modulate BAT-related thermogenesis by increasing sympathetic innervation of adipose tissue and therefore has potential metabolic benefits. Nrg4 improves metabolic dysregulation in various metabolic diseases such as insulin resistance, obesity, non-alcoholic fatty liver disease, and diabetes through several mechanisms such as anti-inflammation, autophagy regulation, pro-angiogenesis, and lipid metabolism normalization. However, inconsistent findings are found regarding the effects of Nrg4 on metabolic diseases in clinical settings, and this heterogeneity needs to be further clarified by future studies. The potential metabolic protective effect of Nrg4 suggests that it may be a promising endocrine therapeutic target.

Paternal preconceptional supplementation of n‐3 polyunsaturated fatty acids alleviates offspring nonalcoholic fatty liver disease in high‐fat diet‐induced obese mice

“…Interestingly, in the current study, paternal n-3 PUFA supplementation lessened the BAT whitening either in the F1 or F2 offspring fed the HFD, with upregulated expression of Ucp1 and Nrg4 in the negatively regulates de novo lipogenesis mediated by LXR/SREBP1c in a cell-autonomous manner, and thus improving metabolic dysregulation and protecting against diet-induced obesity, insulin resistance, and hepatic steatosis (Liu et al, 2023;Guo et, al., 2017;Wang et al, 2014). In consistency, herein, the expression of Ucp1 or Nrg4 in the BAT was closely correlated to the expression of hepatic Erbb3, and genes associated with fat metabolism, inflammation, and fibrosis.…”

“…Recently, research evidence supports a thermogenesis‐independent role of BAT in physiology development and metabolic diseases, particularly through its release of secreted factors or metabolites, such as Nrg4 and succinate (Mills et al., 2021; Starling, 2021; Wang et al., 2015). Nrg4 activates hepatic Erbb3/Erbb4 signaling and negatively regulates de novo lipogenesis mediated by LXR/SREBP1c in a cell‐autonomous manner, and thus improving metabolic dysregulation and protecting against diet‐induced obesity, insulin resistance, and hepatic steatosis (Liu et al., 2023; Guo et, al., 2017; Wang et al., 2014). In consistency, herein, the expression of Ucp1 or Nrg4 in the BAT was closely correlated to the expression of hepatic Erbb3, and genes associated with fat metabolism, inflammation, and fibrosis.…”

Brown Adipose Tissue, Batokines, and Bioactive Compounds in Foods: An Update

“…[ 64 ] Recent findings show that Nrg4 signaling can regulate the development and differentiation of pancreatic islets as well as insulin secretion by beta cells, where obesity, followed by reduced levels of Nrg4, disrupts glucose homeostasis. [ 64,65 ] BAT activation and Nrg4 release are potential targets for preventing and treating the triad: NAFLD, insulin resistance, and diabetes.…”

Early Life Programming of Adipose Tissue Remodeling and Browning Capacity by Micronutrients and Bioactive Compounds as a Potential Anti-Obesity Strategy

“…Mechanisms explaining the EPA stimulation of brown/beige fat include (i) the activation of free fatty acid receptor 4 (FFAR4, also known as GPR120), leading to the upregulated expression of microRNAs (such as miR-30b and miR-378) promoting brown adipogenesis in adipose precursor cells [125], and the secretion of FGF21 by the adipocytes [126]. FGF21 activates brown/beige adipocytes in a paracrine/autocrine manner and also acts centrally to induce SNS activity [127]; (ii) the stimulation of Neuregulin 4 (NRG4) production by preadipocytes [128], a batokine/adipokine linked to brown/beige adipocyte activation [129,130]; and (iii) the activation of transient receptor potential vanilloid 1 (TRPV1) receptor [131]. TRPV1 is present (among other sites) in the gastrointestinal tract, on vagal afferent fibers to the brain, and its interaction with dietary agonists such as EPA may lead to SNS activation and catecholamine release to BAT/WAT [131].…”