Abstract
Neuregulin 4 (NRG4), an epidermal growth factor-like signaling molecule, plays an important role in cell-to-cell communication during tissue development. Its function to regulate energy metabolism has recently been reported. This current study was designed to assess the preventive and therapeutic effects of NRG4 overexpression on high fat diet (HFD)-induced obesity. Using the hydrodynamic gene transfer method, we demonstrate that Nrg4 gene transfer in mice suppressed the development of diet-induced obesity, but did not affect pre-existing adiposity and body weight in obese mice. Nrg4 gene transfer curbed HFD-induced hepatic steatosis by inhibiting lipogenesis and PPARγ-mediated lipid storage. Concurrently, overexpression of NRG4 reduced chronic inflammation in both preventive and treatment studies, evidenced by lower mRNA levels of macrophage marker genes including F4/80, Cd68, Cd11b, Cd11c, and macrophage chemokine Mcp1, resulting in improved insulin sensitivity. Collectively, these results demonstrate that overexpression of the Nrg4 gene by hydrodynamic gene delivery prevents HFD-induced weight gain and fatty liver, alleviates obesity-induced chronic inflammation and insulin resistance, and supports the health benefits of NRG4 in managing obesity and obesity-associated metabolic disorders.
Highlights
More recent work by Rosell et al showed that Neuregulin 4 (NRG4) is enriched in brown adipose tissue (BAT) and its expression is upregulated in cold-induced beige/brite cells[8]
NRG4 overexpression enhanced the expression of BAT thermogenic genes, including uncoupling protein Ucp[1] (~ 2.2-fold), cell death-inducing DNA fragmentation factor-α-like effector A (Cidea, ~2.4-fold), and the type 2 deiodinase (Dio2, ~2.0-fold) (Fig. 3e), suggesting that Nrg[4] gene transfer influences energy expenditure in BAT
A similar effect of Nrg[4] gene transfer on gene expression was detected in the liver and BAT of mice with NRG4 overexpression (Fig. 8c,d). These results suggest that NRG4 overexpression is capable of inhibiting obesity-related chronic inflammation
Summary
More recent work by Rosell et al showed that NRG4 is enriched in brown adipose tissue (BAT) and its expression is upregulated in cold-induced beige/brite cells[8]. Using NRG4-deficient mice, Wang et al revealed that NRG4 is capable of attenuating hepatic lipogenic signaling and maintaining metabolic homeostasis[9]. The findings from these previous studies indicate that NRG4 may work as a novel adipokine with a possible role in maintaining energy and metabolic homeostasis. We used a gene transfer system to enhance NRG4 expression and investigated its potential to prevent and to provide therapeutic benefits to animals with diet-induced obesity and metabolic disorders. Our results show that an increase of NRG4 expression inhibits diet-induced chronic inflammation, improves insulin resistance, and prevents weight gain in a diet-induced animal model
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