ErbB4 deletion predisposes to development of metabolic syndrome in mice

Abstract

ErbB4, a member of the EGF receptor family, plays a variety of roles in physiological and pathological states. Genetic studies have indicated a link between ErbB4 and type 2 diabetes and obesity, but its role in metabolic syndrome (MetS) has not been reported. In the current study we found that mice with ErbB4 deletion developed MetS after 24 wk on a medium-fat diet (MFD), as indicated by development of obesity, dyslipidemia, hepatic steatosis, hyperglycemia, hyperinsulinemia, and insulin resistance, compared with wild-type mice. ErbB4 deletion mice also exhibited increased amounts of subcutaneous and visceral fat, with increased serum leptin levels, compared with wild-type mice, whereas levels of adiponectin were not significantly different. Histologically, severe inflammation, indicated by F4/80 immunostaining and M1 macrophage polarization, was detected in inguinal and epididymal white adipose tissue in ErbB4 deletion mice. ErbB4 expression decreased during 3T3-L1 preadipocyte differentiation. Administration of neuroregulin 4, a specific ligand for ErbB4, to 3T3-L1 adipocytes had no effect on adipogenesis and lipolysis but significantly inhibited lipogenesis, promoted browning, induced GLUT4 redistribution to the cell membrane, and increased glucose uptake. Neuroregulin 4 also significantly increased glucose uptake in adipocytes isolated from wild-type mice, while these effects were significantly decreased in adipocytes isolated from ErbB4 deletion mice. In conclusion, our results indicate that ErbB4 may play an important role in glucose homeostasis and lipogenesis. ErbB4 deficiency-related obesity and adipose tissue inflammation may contribute to the development of MetS.

The brown fat-secreted adipokine neuregulin 4 is decreased in human and murine chronic kidney disease

“…Furthermore, treatment of epididymal adipocytes from WT mice with recombinant NRG4 has increased glucose uptake to levels comparable to insulin treatment, whereas there is no effect of NRG4 in adipocytes isolated from Erbb4 −/− ht + mice (40). It is worth noting that we have shown a beneficial and negative association of the adipokine with markers of insulin resistance, for example, HOMA-IR, in our cohort supporting the rodent data from Zeng et al (40). Based on our data in mice with DKD, there is no similar pattern of renal Erbb4 mRNA expression as compared to Nrg4 expression in adipose tissue depots.…”

“…In more detail, the adipokine exerts its beneficial metabolic effects by binding to the ERBB4 receptor (6). Zeng and coworkers convincingly demonstrate that heart rescued ERBB4 deletion mice (Erbb 4 −/− ht + ) have increased HOMA-IR levels (40). Furthermore, treatment of epididymal adipocytes from WT mice with recombinant NRG4 has increased glucose uptake to levels comparable to insulin treatment, whereas there is no effect of NRG4 in adipocytes isolated from Erbb4 −/− ht + mice (40).…”

Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication

“…NRG4-deficient mice fed a high-fat diet display increased body weight gain, decreased WAT and BAT vessel density, increased WAT inflammation, liver steatosis, and impaired glucose tolerance and insulin sensitivity (201,204,205). While similar effects occur in high-fatchallenged ErbB4-deficient mice, opposite effects can be achieved by adipocyte-or hepatocyte-specific overexpression of NRG4 (201,203,204,212,213). This argues for beneficial effects of NRG4 on metabolic homeostasis.…”

Neuregulin 4 Is a Novel Marker of Beige Adipocyte Precursor Cells in Human Adipose Tissue

“…In human breast cancer cells, NRG1 binding to ERBB4 activates SREBP-2 and led to increased expression of LDL uptake- and cholesterol biosynthesis-related genes (Haskins et al, 2015). A recent study demonstrated that ErbB4 deletion accelerated the development of obesity, dyslipidemia, hepatic steatosis, hyperglycemia, hyperinsulinemia and insulin resistance after 24 week on a medium-fat diet (Zeng et al, 2018). Nrg4, a specific ligand for ErbB4 involved in neurite growth, administration in 3T3-L1 adipocytes inhibited lipogenesis and induced browning and glucose uptake, but did not exert any effects on adipogenesis and lipolysis (Zeng et al, 2018).…”