Brown Fat Hormone Signaling Prevents Obesity by Modulating Liver Lipid Metabolism

A hormone produced by brown adipose tissue has been determined to modulate the activity of liver cells that metabolize sugar into fats and is apparently linked to the development of metabolic disorders such as type II diabetes, nonalcoholic fatty liver disease, and obesity.

Investigators at the University of Michigan (Ann Arbor, USA) worked with genetically engineered mice in which the production of the hormone neuregulin 4 (Nrg4) was either blocked or enhanced. The neuregulins, including NRG4, activate type-1 growth factor receptors to initiating cell-to-cell signaling through tyrosine phosphorylation.

In a paper published in the November 17, 2014, online edition of the journal Nature Medicine, the investigators reported that Nrg4 was highly expressed in adipose tissues, enriched in brown fat, and markedly increased during brown adipocyte differentiation. Adipose tissue Nrg4 expression was reduced in rodent and human obesity. Gain- and loss-of-function studies in genetically engineered mice demonstrated that Nrg4 protected against diet-induced insulin resistance and accumulation of fats in the liver by reducing lipogenic signaling.

Mice genetically engineered to lack the gene for NRG4 became obese and developed symptoms of type II diabetes and fatty liver disease. Animals in which NRG4 levels were genetically elevated were protected from these metabolic disorders when fed a high-calorie, high-fat diet.

Senior author Dr. Jiandie Lin, associate professor of cell and developmental biology at the University of Michigan, said, "In all models of obesity, NRG4 expression is reduced. We think obesity is a state of NRG4 deficiency. Realistically, there are still many challenges to figuring out how it acts in the body and might be used as a drug, but in general, we know that NRG4 is beneficial for body metabolism and are excited about its potential."

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