Research identifies the SH2B1 gene’s critical role in obesity through its impact on brain function and energy regulation, offering promising therapeutic potential for obesity management without the side effects of current drugs like Ozempic.
This breakthrough may pave the way for innovative treatments for metabolic diseases that have reduced side effects.
Obesity is a complex condition influenced by genetics, the food environment, behavior, and other factors. Historically, securing enough food to survive was challenging, but today, for most people, it’s as simple as opening a refrigerator.
A gene called SH2B1 has been shown to play an important role in regulating food intake. SH2B1 mutations in people are associated with obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease, formerly known as non-alcoholic fatty liver disease.
“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,” said Liangyou Rui, Ph.D., Department of Molecular & Integrative Physiology and the Elizabeth Weiser Caswell Diabetes Institute at the U-M Medical School.
A study conducted by Rui and the team identifies where this gene is acting inside the brain, an area called the paraventricular hypothalamus, or PVH, which is involved in regulating blood pressure and fluid balance.
Additionally, the team discovered that neurons that express SH2B1 create a circuit, talking to neurons downstream in an area known as the dorsal raphe nucleus, located in the brainstem. This area is implicated in energy balance and body weight maintenance and emotion-motivated behavior.
Impact of SH2B1 on Weight Management
Stimulating this circuit suppresses appetite in mice. Conversely, silencing the SH2B1-expressing neurons in the PVH leads to obesity. The team also uncovered the molecular mechanism behind how SH2B1 helps maintain weight, in part by enhancing BDNF/TrkB signaling, which during development promotes brain growth and in a mature brain, maintains brain health. When this signaling goes awry, obesity and metabolic disease develop.
One theory, Rui notes, is that the inflammation associated with weight gain can negatively affect this pathway in an indirect way, weakening the signals to stop eating.
“We know that SH2B1 action is important, as it is highly conserved across DOI: 10.1002/advs.202400437
Additional authors include Yuan Li, Min-Hyun Kim, Lin Jiang, Lorelei Baron, Latrice D. Faulkner, David P. Olson, Xingyu Li, Noam Gannot, Peng Li. The research was funded by the
Discussion about this post