OBESITY GENE IMPACT ON THE BRAIN

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OBESITY GENE IMPACT ON THE BRAIN

The discovery could lead to new treatments for metabolic diseases with fewer side effects.

    

Obesity is a complicated condition caused by a combination of genetics, the food environment, behavior, and other factors.

For millennia, getting enough food to survive and thrive was difficult. For most people, it's now as easy as opening a refrigerator.

A gene called SH2B1 has been shown to play an essential 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 by Rui and the team identifies where this gene acts inside the brain, an area called the paraventricular hypothalamus, or PVH, which regulates 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 affects energy balance, body weight maintenance, and emotion-motivated behavior.

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, partly by enhancing BDNF/TrkB signaling, which promotes brain growth during development and maintains brain health in a mature brain. When this signaling goes awry, obesity and metabolic disease develop.

One theory, Rui notes, is that the inflammation associated with weight gain can negatively indirectly affect this pathway, 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 a universal currency, enhancing cell signaling and leptin and insulin hormones, which help regulate appetite and metabolism.

Furthermore, there have been no identified side effects to enhancing SH2B protein, unlike currently popular drugs, such as Ozempic or Mounjaro, that activate glp-1 receptors.

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


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