How an obesity gene influences brain function

Obesity is a complex condition influenced by a multitude of factors, including behavior, diet, and genetics. It has been demonstrated that the gene SH2B1 is crucial for controlling food intake.

Mutations in SH2B1 have been linked to metabolic dysfunction-associated steatotic liver disease (previously known as non-alcoholic fatty liver disease), obesity, and type 2 diabetes in humans.

This gene controls feeding and energy expenditure. Obesity is caused by two opposing axes: If you eat too much, you gain fat. Spend too little energy and fat accumulates.”

Liangyou Rui, Ph.D., Department of Molecular & Integrative Physiology, Elizabeth Weiser Caswell Diabetes Institute, University of Michigan

According to a study by Rui and colleagues, an area of the brain known as the paraventricular hypothalamus, or PVH, which is involved in controlling blood pressure and fluid balance, is where this gene is acting.

Furthermore, the group found that SH2B1-expressing neurons form a circuit and communicate with neurons downstream in the brainstem's dorsal raphe nucleus.

This region is involved in maintaining body weight, balancing energy, and emotion-driven behavior.

Stimulating this circuit suppresses mice's appetite. Conversely, obesity results from the silencing of SH2B1-expressing neurons in the PVH.

The group also discovered the molecular mechanism by which SH2B1 aids in weight maintenance. It does so by augmenting BDNF/TrkB signaling, which stimulates brain growth in a developing brain and preserves brain health in an adult brain. Metabolic disease and obesity arise when this signaling goes wrong.

According to one theory, Rui points out that the pathway may be adversely affected indirectly by the inflammation linked to weight gain, weakening the signals to stop eating.

We know that SH2B1 action is important, as it is highly conserved across species, from the fruit fly to humans. It functions as sort of a universal currency, not only enhancing cell signaling but the hormones leptin and insulin, which help regulate appetite and metabolism.”

Liangyou Rui, Ph.D., Department of Molecular & Integrative Physiology, Elizabeth Weiser Caswell Diabetes Institute, University of Michigan

Also, currently, available drugs that activate glp-1 receptors, like Ozempic or Mounjaro, there have not yet been any documented side effects associated with enhancing SH2B protein. 

If we can find a way to enhance SH2B activity, there is huge promise for treating obesity and its related diseases.”

Liangyou Rui, Ph.D., Department of Molecular & Integrative Physiology, Elizabeth Weiser Caswell Diabetes Institute, University of Michigan