Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Program in Molecular Medicine and Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Mol Metab. 2017 Jun 21;6(8):863-872. doi: 10.1016/j.molmet.2017.03.016. eCollection 2017 Aug.
Brown and white adipose tissue exerts pleiotropic effects on systemic energy metabolism in part by releasing endocrine factors. Neuregulin 4 (Nrg4) was recently identified as a brown fat-enriched secreted factor that ameliorates diet-induced metabolic disorders, including insulin resistance and hepatic steatosis. However, the physiological mechanisms through which Nrg4 regulates energy balance and glucose and lipid metabolism remain incompletely understood. The aims of the current study were: i) to investigate the regulation of adipose Nrg4 expression during obesity and the physiological signals involved, ii) to elucidate the mechanisms underlying Nrg4 regulation of energy balance and glucose and lipid metabolism, and iii) to explore whether Nrg4 regulates adipose tissue secretome gene expression and adipokine secretion.
We examined the correlation of adipose Nrg4 expression with obesity in a cohort of diet-induced obese mice and investigated the upstream signals that regulate Nrg4 expression. We performed metabolic cage and hyperinsulinemic-euglycemic clamp studies in Nrg4 transgenic mice to dissect the metabolic pathways regulated by Nrg4. We investigated how Nrg4 regulates hepatic lipid metabolism in the fasting state and explored the effects of Nrg4 on adipose tissue gene expression, particularly those encoding secreted factors.
Adipose Nrg4 expression is inversely correlated with adiposity and regulated by pro-inflammatory and anti-inflammatory signaling. Transgenic expression of Nrg4 increases energy expenditure and augments whole body glucose metabolism. Nrg4 protects mice from diet-induced hepatic steatosis in part through activation of hepatic fatty acid oxidation and ketogenesis. Finally, Nrg4 promotes a healthy adipokine profile during obesity.
Nrg4 exerts pleiotropic beneficial effects on energy balance and glucose and lipid metabolism to ameliorate obesity-associated metabolic disorders. Biologic therapeutics based on Nrg4 may improve both type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) in patients.
棕色和白色脂肪组织通过释放内分泌因子对全身能量代谢发挥多种作用。神经调节蛋白 4（Nrg4）最近被确定为一种富含棕色脂肪的分泌因子，可改善饮食诱导的代谢紊乱，包括胰岛素抵抗和肝脂肪变性。然而，Nrg4 调节能量平衡和葡萄糖及脂质代谢的生理机制仍不完全清楚。本研究的目的是：i）研究肥胖过程中脂肪组织 Nrg4 表达的调节及其涉及的生理信号，ii）阐明 Nrg4 调节能量平衡和葡萄糖及脂质代谢的机制，以及 iii）探索 Nrg4 是否调节脂肪组织分泌组基因表达和脂肪因子分泌。
我们在饮食诱导肥胖小鼠的队列中检查了脂肪 Nrg4 表达与肥胖的相关性，并研究了调节 Nrg4 表达的上游信号。我们在 Nrg4 转基因小鼠中进行代谢笼和高胰岛素-正葡萄糖钳夹研究，以剖析 Nrg4 调节的代谢途径。我们研究了 Nrg4 在禁食状态下如何调节肝脏脂质代谢，并探讨了 Nrg4 对脂肪组织基因表达的影响，特别是那些编码分泌因子的基因。
脂肪 Nrg4 表达与肥胖呈负相关，并受促炎和抗炎信号调节。Nrg4 的转基因表达增加了能量消耗并增强了全身葡萄糖代谢。Nrg4 通过激活肝脏脂肪酸氧化和酮体生成来部分保护小鼠免受饮食诱导的肝脂肪变性。最后，Nrg4 在肥胖期间促进健康的脂肪因子谱。
Nrg4 对能量平衡和葡萄糖及脂质代谢发挥多种有益作用，可改善肥胖相关的代谢紊乱。基于 Nrg4 的生物治疗剂可能改善 2 型糖尿病和非酒精性脂肪性肝病（NAFLD）患者的病情。
