Gene Variants Linked to Human Obesity Discovered

SRC-1 gene was found to affect body weight control by regulating the function of neurons in the hypothalamus - the appetite center of the brain, said a team led by researchers at Baylor College of Medicine and the University of Cambridge reports in //the journal Nature Communications. Maintaining a healthy body weight is no simple matter. A better understanding of how the body regulates appetite could help tip the scale toward the healthy side.

Mice lacking the SRC-1 gene eat more and become obese. SRC-1 also seems to be involved in regulating human body weight. The researchers identified in severely obese children 15 rare SRC-1 genetic variants that disrupt its function. When mice were genetically engineered to express one of these variants, the animals ate more and gained weight.

"The protein called steroid receptor coactivator-1 (SRC-1) is known to participate in the regulation of body weight, but its precise role is not clear," said co-corresponding author Dr. Yong Xu, associate professor of pediatrics and of molecular and cellular biology and a researcher at the USDA/ARS Children's Nutrition Research Center at Baylor College of Medicine and Texas Children's Hospital. "Here we explored the role of SRC-1 in the hypothalamus, a brain area that regulates appetite."

The researchers discovered that SRC-1 is highly expressed in the hypothalamus of mice, specifically in neurons that express the Pomc gene. Pomc neurons are known to regulate appetite and body weight.

Further experiments showed that SRC-1 is involved in regulating the expression of Pomc gene in these cells. When Xu and his colleagues deleted the SRC-1 gene in Pomc neurons, the cells expressed less Pomc and the mice ate more and became obese.

"We had identified a group of severely obese children carrying rare genetic variants in the SRC-1 gene," said co-corresponding author Dr. I. Sadaf Farooqi, professor of metabolism and medicine in the Department of Clinical Biochemistry at the University of Cambridge and Wellcome Trust Principal Research Fellow.

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Working together, Xu, Sadaf Farooqi and their colleagues found that many of the SRC-1 variants in the obese children produced dysfunctional proteins that disrupted the normal function of SRC-1. On the other hand, SRC-1 variants in healthy individuals did not disrupt SRC-1 function. Furthermore, mice genetically engineered to express one of the human SRC-1 genetic variants found in obese children ate more and gained weight. This is the first report of SRC-1 playing a role in the hypothalamus in the context of body weight control.

Source-Eurekalert