Study implicates another gene in brain that causes weight gain
Existing drug is possible treatment for obesity caused by genetic mutations, UTSW research suggests
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DALLAS – Jan. 15, 2025 – Mutations in a gene called OTP cause obesity by controlling the output of another gene already targeted by an anti-obesity drug, a study led by UT Southwestern Medical Center researchers shows. The findings, reported in Science Translational Medicine, could lead to new treatments for some types of obesity, a growing health problem that currently affects more than a billion people worldwide.
“Our study uncovers the molecular basis of severe obesity in a group of patients and suggests a potential treatment,” said corresponding author Chen Liu, Ph.D., Associate Professor of Internal Medicine and Neuroscience and a Principal Investigator in the Center for Hypothalamic Research at UT Southwestern. Dr. Liu is also an Investigator with the Peter O’Donnell Jr. Brain Institute.
The drive for humans and other animals to eat – or not eat – is largely controlled by a part of the brain called the hypothalamus, Dr. Liu explained. As part of this complicated mechanism, a protein named melanocortin 4 receptor (MC4R), found on the surface of some hypothalamic neurons, binds to different proteins that either suppress hunger or increase it. Previous studies have shown that mutations that cause the loss of MC4R function lead to severe childhood-onset obesity, and mutations that increase MC4R activity are associated with protection against obesity.
However, Dr. Liu said, surprisingly little is known about how neurons control the amount of MC4R – which in turn affects how much this protein guards against obesity.
To answer this question, Dr. Liu and his colleagues in the Liu Lab tested mice to determine which genes were responsible for producing MC4R in hypothalamic neurons. They soon homed in on OTP, which makes a protein in both mice and humans that appears to bind directly to DNA sequences that control MC4R expression. These factors suggested that OTP might regulate MC4R production.
When the researchers genetically altered mice to turn off OTP, these animals gained significant weight and became obese when switched to a high-fat diet. A closer look revealed that their weight gain was due to increased eating. Further investigation showed that the altered animals produced significantly less MC4R than their littermates, adding evidence that OTP influences how much MC4R the hypothalamic neurons make.
To further confirm OTP’s suspected role, Dr. Liu’s team worked with a group at the University of Cambridge in England that had linked severe obesity in some children to loss-of-function mutations in OTP. After generating mice with the same mutation that one child carried, researchers found that these animals developed early-onset obesity, high cholesterol, fatty liver disease, and Type 2 diabetes – all problems that the child also had. When scientists treated the mice with setmelanotide, a drug used to treat a rare genetic form of obesity caused by deficiencies in MC4R signaling, these health problems gradually reversed.
Together, Dr. Liu said, these results suggest that OTP is one of a handful of genes that scientists have implicated in human obesity. A search in the UK Biobank – a large genetic registry based in the United Kingdom – indicated that several people with mutations in this gene reported problems with obesity. Setmelanotide could be useful in treating obesity in these patients as well, Dr. Liu added.
Other UTSW researchers who contributed to this study are co-first authors Baijie Xu, Ph.D., a postdoctoral researcher in the Liu Lab, and Steven C. Wyler, Ph.D., Instructor of Internal Medicine; Joel K. Elmquist, D.V.M., Ph.D., Professor of Internal Medicine, Pharmacology, and Psychiatry and Director of the Center for Hypothalamic Research; Amanda G. Almeida, M.B.A., Manager of Ambulatory Analytics; Li Li, Ph.D., Instructor of Internal Medicine; and Swati, M.S., and Rong Wan, M.S., research associates.
This study was funded by grants from the National Institutes of Health (NIH) (R01 DK114036, DK130892, DK136592, R01 DK118725, and DK127274), the American Heart Association (23POST1019715 and 24CDA1257999), and the New Zealand Ministry of Business, Innovation and Employment. It also included funding from the UT Southwestern Nutrition Obesity Research Center under the National Institute of Diabetes and Digestive and Kidney Diseases and the NIH (P30-DK127984).
About UT Southwestern Medical Center
UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 24 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.