Maintaining a healthy weight can be quite a challenge for many people. The global prevalence of obesity has risen rapidly in recent decades, affecting more than two billion people, making it one of the largest causes of poor health worldwide. Moreover, after people reach middle age, many people will inevitably gain weight. Obesity-related diseases, including heart disease, stroke, type 2 diabetes and certain types of cancer, are a significant cause of preventable premature death.
One way the body regulates weight is by using leptin, which is produced by fat tissue. The more adipose tissue in the body, the more leptin is produced. Leptin travels to the brain and “tells” specific neurons how much fat is stored in the body, and a lot of leptin means there is a lot of fat stored. In response, the brain triggers behaviors that suppress appetite and increase energy expenditure, leading to loss of fat tissue and weight loss. When all is well, a leptin-mediated feedback loop between fat tissue and the brain results in sustained healthy body weight.
Leptin’s ability to prevent excessive weight gain by suppressing appetite and concomitantly increasing energy expenditure makes it a promising treatment for obesity. Unfortunately, in most cases of diet-induced obesity, leptin supplementation strategies tend to be ineffective, in part due to the development of leptin resistance in the body, a state in which circulating leptin levels remain high, but it does not suppress food intake and weight gain.
On January 2, 2023, Xu Yong’s team from Baylor College of Medicine and Liu Feng’s team from the Second Xiangya Hospital of Central South University published a research paper entitled: Hypothalamic Grb10 enhances leptin signaling and promotes weight loss in the Nature Metabolism.
Through the study of mouse models, the study found that Grb10 protein can promote the activity of leptin in the brain, which laid the foundation for the development of new methods for obesity treatment based on Grb10.
To find strategies to help people achieve and maintain a healthy weight, the research team investigated how leptin activity is regulated, and they identified the Grb10 protein as a novel regulator of leptin activity.
The study found that the Grb10 protein can promote the activity of leptin. It differs from the previously discovered leptin regulators in that it acts in a different way. Grb10 directly binds to the leptin receptor on neurons to form a complex. This combination enhances leptin signaling, helping to reduce food intake and increase energy expenditure. Other leptin regulatory factors do not directly bind to the leptin receptor, but bind to other molecules downstream of it.
After eliminating Grb10 in leptin-responsive neurons in the brains of mice, the mice either ate more or expended less energy, leading to weight gain. Increasing Grb10, on the other hand, had beneficial effects, leading the mice to reduce food intake, increase energy expenditure and lose body weight.
Professor Yong Xu, corresponding author of the paper, said these findings suggest that boosting Grb10 activity may provide a way to increase leptin signaling, which could aid in weight loss. This finding supports further research into the possibility of developing Grb10-based treatments for obesity.
Going forward, the research team expressed interest in further studying the mechanism of action of Grb10 in the brain. Leptin also regulates mood and other emotional states, and does Grb10 regulate mood by interacting with leptin receptors? This is a direction worthy of further exploration.