Neuregulin 4: A “Hotline” Between Brown Fat and Liver

Abstract

The discovery that functional brown adipose tissue (BAT) in adult humans is inversely related to body fat mass and may reflect metabolic health has stimulated adipose tissue research to explore activation of BAT as a potential target for antiobesity treatments. In addition to the capacity of BAT to increase energy expenditure and glucose and lipid uptake, BAT secretes factors that may contribute to the regulation of whole‐body metabolism. Among signals released from BAT, neuregulin 4 (NRG4) has been recently identified as an endocrine factor that may link the activation of BAT to protection against diet‐induced obesity, insulin resistance, and hepatic steatosis. NRG4 was shown to directly reduce lipogenesis in hepatocytes, and it could indirectly activate BAT via sympathetic neurons or via inducing brown adipocyte–like signatures in white adipocytes in a paracrine manner. However, the potential relevance of NRG4 as a diagnostic tool or target for the treatment of obesity‐related diseases remains to be explored.

Adipose Tissue-Liver Cross Talk in the Control of Whole-Body Metabolism: Implications in Nonalcoholic Fatty Liver Disease

“…Although most adipokine factors are predominantly produced by white AT, neuregulin 4 (Nrg4), is produced predominantly by BAT or beige adipocytes (147,148). Regulated by BMP8b ( 149), it has a direct effect on AT, inducing AT angiogenesis, reducing AT hypoxia (150) and modulating the AT adipokine profile towards a more healthy pattern (151).…”

The Effect of Omega-3 Fatty Acid Supplementation on Serum Adipocytokines, Lipid Profile and Biochemical Markers of Inflammation in Recreational Runners

“…NRG-4 reduces gluconeogenesis and lipogenesis, and increases fatty acid oxidation [ 43 , 88 ]. A recent study showed that brown adipose tissue-derived NRG-4 may also promote the growth of neurites in adipose tissue, increasing sympathetic innervation, stimulating brown adipose tissue activity and browning of white adipose tissue [ 46 , 51 ]. In our study, serum levels of NRG-4 increased in response to ω-3 PUFA diet.…”

“…Furthermore, NRG-4 levels positively correlated with ω-3 index, while as expected, lower AA/EPO ratio was associated with greater NRG-4 secretion. These findings indicate a possible role of NRG4 in the white adipose tissue browning, as well as possible increased lipid metabolism [ 46 , 47 , 51 ]. The benefits of NRG4 in response to ω-3 PUFA diet should be treated with caution, however, as no analyses of NRG-4 effect on brown adipocyte tissue thermogenesis were performed in this study.…”

“…Neuregulin-4 (NRG-4), a member of the neuregulin family (NRG1–NRG4), has recently been introduced as a novel adipocytokine with beneficial metabolic effect [ 43 , 44 , 45 , 46 ]. NRG-4 produces signals through the receptor tyrosine—protein kinases/human epidermal growth factor receptors (ErB/HER) and exerts pleiotropic effects that ultimately regulate energy metabolism and insulin sensitivity, as well as protects against oxidative stress [ 47 ].…”

Single Cell RNA Profiling Reveals Adipocyte to Macrophage Signaling Sufficient to Enhance Thermogenesis

“…beiging. Previous work has shown uniquely high levels of Neuregulin 4 (Nrg4) secreted from brown and beige adipocytes compared to other cell types [44][45][46][47] , and it has been suggested that Nrg4 may enhance sympathetic nerve-induced beiging [47][48][49] . Based on this concept, coupled with the above data suggesting divergent pathways for promoting iWAT thermogenesis, we hypothesized that Nrg4 may be required for optimal iWAT beiging in response to cold exposure but not in iAdFASNKO mice.…”