Obesity is a complex condition resulting from a combination of genetics, dietary environment, behavior, and other factors.
For thousands of years, getting enough food to survive and thrive was difficult. Now, for most people, what was difficult is as easy as opening the refrigerator.
Gene regulates food intake
A study published in the journal Advance Science on July 17 found that a gene called SH2B1 plays an important role in regulating food intake.
SH2b1 mutations in humans are associated with obesity, type 2 diabetes, and metabolic syndrome-related fatty liver disease, formerly known as nonalcoholic fatty liver disease.
“This gene controls food intake and energy expenditure,” says Liangyu Rui, PhD, of the Department of Molecular and Integrative Physiology and the Elizabeth Weiser Caswell Diabetes Institute at the University of Michigan Medical School. “Obesity is a result of two opposing axes: If you eat too much, you gain fat, and if you expend too little energy, you accumulate fat.”
A study by Roy and his team pinpointed where this gene acts in the brain, an area called the lateral limbic hypothalamus, which is involved in regulating blood pressure and fluid balance.
In addition, the team discovered that neurons expressing the SH2B1 gene create a circuit that communicates with neurons in an area known as the dorsal limbic nucleus in the brainstem.
This region is involved in energy homeostasis, body weight maintenance, and emotionally motivated behavior. Stimulation of this circuit suppresses appetite in mice, while conversely, silencing SH2B1-expressing neurons in the lateral limbic hypothalamus leads to obesity.
The team also discovered the molecular mechanism behind how SH2B1 helps maintain weight; in part by enhancing BDNF/TRKB signaling, which promotes brain growth during development and maintains brain health in the mature brain. When these signals are disrupted, obesity and metabolic disease develop.
The role of inflammation
One theory Roy suggests is that the inflammation associated with weight gain could indirectly negatively affect this pathway, weakening the signals to stop eating.
Moreover, no side effects have been identified so far for SH2B enhancement, unlike currently popular drugs such as Ozempic or Mounjaro that activate GLP-1 agonists.
“If we can find a way to enhance SH2B activity, there is great promise for treating obesity and related diseases,” Roy says.