SRC-1 gene variants related to human obesity

Maintaining a healthy weight is not an easy task. A better understanding of how the body controls appetite could help tip the balance on the healthy side. Contributing to the achievement of this goal, a team led by researchers from Baylor College of Medicine and the University of Cambridge Nature Communications that the SRC-1 gene affects the control of body weight by regulating the function of neurons in the hypothalamus – the center of the brain's appetite.

Mice lacking the SRC-1 gene eat more and become obese. SRC-1 also appears to be involved in regulating the weight of the human body. Researchers have identified 15 severely obese CRS-1 genetic variants in severely obese children. When the mice were genetically modified to express one of these variants, the animals ate more and gained weight.

"The protein called steroid coactivator-1 (SRC-1) is known to participate in the regulation of body weight, but its precise role is not clear," said Dr. Yong Xu, co-corresponding author, professor Associate of Pediatrics and Molecular and Cell Biology and Researcher at the USDA / ARS Children's Nutrition Research Center of Baylor College of Medicine and Texas Children's Hospital. "We have here explored the role of SRC-1 in the hypothalamus, an area of ​​the brain that regulates appetite."

The researchers found that SRC-1 is highly expressed in the mouse hypothalamus, particularly in neurons that express the Pomc gene. Pomc neurons are known to regulate appetite and body weight.

Other experiments have shown that SRC-1 is involved in the regulation of Pomc gene expression 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.

Researchers also investigated whether SRC-1 would also play a role in regulating human body weight.

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

Working together, Xu, Sadaf Farooqi and their colleagues found that many of the SRC-1 variants in obese children produced dysfunctional proteins that disrupted the normal functioning of SRC-1. On the other hand, SRC-1 variants in healthy individuals did not disrupt the function of SRC-1.

In addition, mice genetically engineered to express one of the SRC-1 human genetic variants found in obese children ate more and gained weight. This is the first report indicating that SRC-1 plays a role in the hypothalamus in the context of body weight control.

"By providing evidence linking basic and genetic animal studies with human genetic data, we have demonstrated that SRC-1 is an important body weight regulator," said Xu.

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Yongjie Yang, Agatha A. van der Klaauw, Liangru Zhu, Tessa M. Cacciottolo, Yanlin He and Lukas K.J. also contributed to this work. Stadler, Chunmei Wang, Pingwen Xu, Kenji Saito, Antentor Hinton Jr, Xiaofeng Yan, Julia M. Keogh, Elana Henning, Matthew C. Banton, Elena G. Bochukova, Audrey E. Hendricks, Katherine L. Lawler, Vanisha Mistry, Lan Liao, Jianming Xu, Stephen O. Rahilly, Qingchun Tong, UK10K consortium, Inês Barroso and Bert W. O. Malley. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine; Metabolic Research Laboratories of the University of Cambridge; Wellcome Trust-Institute of Metabolic Sciences, CRM University of Science and Technology Huazhong, China; Wellcome Sanger Institute, Cambridge; University of Colorado – Denver and Health Sciences Center of the University of Texas at Houston.

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