San Antonio Team Finds Mutation That Could Be Key in Obesity Research

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The Texas Biomedical Research Institute.

Bonnie Arbittier / Rivard Report

A team at San Antonio-based Texas Biomedical Research Institute examined a case of two sisters with low levels of the hunger-suppressing hormone leptin.

A genetic mutation discovered in June by a team at San Antonio-based Texas Biomedical Research Institute could shed light on why hunger can be difficult to suppress, leading to obesity and complications including heart disease and diabetes.

Leptin – known as the hunger-suppressing hormone – is a protein produced by fat cells that, as it circulates throughout the body, makes its way to the brain, signaling a feeling of fullness that suppresses hunger, said Dr. Raul Bastarrachea, staff scientist at Texas Biomed.

His research team examined a case of two sisters living in Colombia who were of normal weight as babies but soon after began gaining weight rapidly. The team found the two women have a recessive genetic disorder due to a mutation in the leptin gene on chromosome 7 causing congenital leptin deficiency.

Raul Bastarrachea

While congenital leptin deficiency is incredibly rare in the United States, with only a few dozen cases reported in medical literature, Bastarrachea said understanding how leptin is received in the brain will help researchers understand and treat obesity better in the general population by looking into how well a person’s brain is responding to leptin. 

“What we found in some extremely overweight people is that there is a ‘misfolding’ protein response that causes leptin to be destroyed before it is able to circulate throughout the blood.” People continue to eat because they never feel full, which causes their extreme obesity, he said.

Bastarrachea uses a manufacturing analogy  to explain leptin misfolding: A living cell acts as a machine, pushing out proteins that can sometimes have deficiencies, imbalances, or “misfolds,” similar to an occasional shoe put together incorrectly during manufacturing.

Even in normal bodies, this misfolding of protein happens occasionally, but the body produces enough correctly formed proteins – just as a shoemaking operation produces enough correctly formed shoes – that the misshapen one is of little consequence.  But when a protein continues to misfold, it’s an indicator that the person is unwell – like an assembly line with a defective machine. 

In 2014, the San Antonio Metropolitan Health District reported that 71 percent of adults in Bexar County were overweight or obese. As rates continue to increase across the state, Texas could be faced with a vastly overweight population – nearly 75 percent – by the year 2040, according to the Department of State Health Services.

Bastarrachea said research into leptin could one day help people struggling with obesity and coexisting conditions such as Alzheimer’s, high blood pressure, and kidney disease. 

“For most overweight people, when you measure leptin in the blood it is [at elevated levels] because the more fat you have the more leptin you have circulating telling your brain” you have the normal amount of fat needed to survive, Bastarrachea said. In the genetic case, though, the Colombian sisters’ leptin levels were so low researchers were unable to detect them using a metabolic testing kit.

“We know the problem isn’t the fat, the problem is with receptors in the brain and how the protein leptin makes its way through the body,” Bastarrachea said. “Knowing this is a very important step in understanding how to create medication that could [impact] leptin receptors in the brain.”

Bastarrachea and his team are now looking into gene therapy to make fat more effective in producing more leptin, or muscles more effective at burning calories to counteract what a person eats. They are also working to get the two Colombian sisters Metreleptin – a very expensive synthetic version of leptin – in hopes of helping them lose weight and lessen the risk for heart disease and diabetes. 

“We are working to understand fully what happens before and after we apply the missing protein [leptin] in the bodies of these ladies,’ Bastarrachea said. “The beauty of learning at this molecular level is that we can find the true origin for obesity cases, which is the only way to treat it effectively and inform treatment for others who suffer from similar problems.”

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