Researchers from the University of Michigan have identified where a gene called SH2B1 is acting inside the paraventricular hypothalamus (PVH), which 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," explained Dr Liangyou Rui, Department of Molecular & Integrative Physiology and the Elizabeth Weiser Caswell Diabetes Institute at the U-M Medical School.
A study by Rui and team has identified the gene is acting inside the paraventricular hypothalamus (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 behaviour. 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 signalling, which during development promotes brain growth and in a mature brain, maintains brain health. When this signalling 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 species, from the fruit fly to humans," said Rui. "It functions as sort of a universal currency, not only enhancing cell signalling, but the hormones leptin and insulin, which help regulate appetite and metabolism."
Furthermore, there have so far been no identified side effects to enhancing SH2B protein, unlike currently popular drugs, such as Ozempic or Mounjaro, that activate GLP-1 receptors.
"If we can find a way to enhance SH2B activity, there is huge promise for treating obesity and its related diseases,” he added.
The findings were reported in the paper, ‘SH2B1 Defends Against Energy Imbalance, Obesity, and Metabolic Disease via a Paraventricular Hypothalamus→Dorsal Raphe Nucleus Neurocircuit’, published in the journal Advanced Science.
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