This microscopic image shows the development of hypothalamic tissue in a mouse. Red marks POMC neuron precursors, blue marks protein expression of the transcription factor Otp, and green marks future adult AgRP neurons. This image captures the developmental transition in which a subset of POMC precursors begins to express Otp as they acquire the identity of adult AgRP neurons. Researchers at UT Southwestern found that this switch can affect susceptibility to obesity.
DALLAS – February 16, 2026 – Researchers at UT Southwestern Medical Center have discovered that a key developmental process in the brain’s hypothalamus can influence an individual’s susceptibility to obesity.
Their preclinical results are neuronshowed that a transcription factor called Otp acts as a molecular “switch” that directs immature hypothalamic neurons toward either anorexigenic or orexigenic fates, their final identity as specialized cells. The researchers found that disrupting this switch altered feeding behavior and protected mice from diet-induced obesity.
Dr. Chen Liu is an associate professor of internal medicine and neuroscience and a research associate at the Peter O’Donnell Jr. Brain Institute at UT Southwestern. He is also a principal investigator at UTSW’s Center for Hypothalamic Research.
“These findings show that early developmental decisions in the hypothalamus have long-term effects on energy balance,” said the lead author. Dr. Chen Liu,Associate Professor Internal medicine and neuroscience and the investigator Peter O’Donnell Jr. Brain Institute at UT Southwestern. “By unraveling this fate-altering program, we can begin to understand how the brain establishes lifelong metabolic set points.”
The hypothalamic melanocortin system, composed of proopiomelanocortin (POMC) neurons that promote satiety (the feeling of fullness after a meal) and agouti-related peptide (AgRP) neurons that cause hunger, is essential for maintaining energy balance. Although these neurons are well studied in adults, how they arise early in development remains unclear.
Using state-of-the-art single-nucleus multiohm sequencing methods, Dr. Liu and his colleagues Liu laboratory mapped the entire landscape of neurons derived from POMC-expressing progenitor (parent) cells in the adult mouse hypothalamus. The researchers found that less than one-third of progenitor neurons continue to express POMC into adulthood. Instead, POMC precursors diversify into many neuronal subtypes, including a significant fraction of adult AgRP neurons.
This study identified Otp as a key regulator that directs POMC-derived neurons toward AgRP identity. When Otp was selectively deleted in POMC-expressing progenitor cells, these cells failed to acquire the AgRP hunger-inducing fate and instead retained the identity of an alternative POMC satiety-promoting neuron. As a result, adult mice lacking this developmental switch had a reduced urge to consume high-fat food and were resistant to diet-induced obesity. Notably, this protective effect was stronger in women, due in part to enhanced estrogen receptor (ERα) signaling in specific POMC-derived subpopulations.
“From an evolutionary perspective, the POMC→AgRP fate switch likely served as an adaptive mechanism,” said Dr. Liu, principal investigator at UTSW. Hypothalamus Research Center. “In an environment of fluctuating food availability, animals needed a quick and reliable way to increase food intake when high-calorie food became available. By generating a population of highly responsive ‘starvation’ neurons, this developmental switch enabled overeating, helping animals build energy reserves and survive periods of deprivation.”
However, today’s world is full of high-calorie foods. more easily The availability of this once beneficial mechanism could further increase vulnerability to obesity, Dr. Liu said. The researchers’ findings demonstrate that disabling this switch early in development prevents the brain from overreacting to high-fat diets, ultimately reducing the risk of obesity. He said this contrast highlights a broader theme in modern metabolic diseases: biological programs tailored for survival in our ancestors can become maladaptive in modern environments.
Dr. Liu said he and his colleagues will next investigate whether external factors, such as maternal overnutrition or undernutrition, influence this genetic fate-switching program, thereby influencing subsequent metabolic health.
Other UTSW researchers who contributed to this study are co-lead authors Baijie Xu, Ph.D., a postdoctoral fellow in the Liu lab, and Li Li, Ph.D., a former lecturer in internal medicine, a former postdoctoral fellow in the Liu lab, and currently an assistant professor of animal physiology at the University of Wyoming. Swati, MSc, Research Scientist and Lab Manager in Liu Lab. Rong Wan, MSc, Researcher in Liu Lab. Amanda Almeida, MBA, Director of Ambulatory Analysis. Dr. Stephen Weiler, Lecturer in Internal Medicine and member of the Hypothalamic Research Center.
This research was supported by grants from the National Institutes of Health (R01DK114036, DK130892, and DK136592). He received a Postdoctoral Fellowship (23POST1019715) and a Career Development Award (24CDA1257999) from the American Heart Association. and UTSW metabolic phenotype coresupported by UTSW Nutrition and Obesity Research Center (NORC) grant (P30DK127984).
About UT Southwestern Medical Center
UT Southwestern is one of the nation’s leading academic medical centers, combining pioneering biomedical research with outstanding clinical care and education. The institution’s faculty have received six Nobel Prizes, including 24 members of the National Academy of Sciences, 25 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Fellows. Our more than 3,300 full-time faculty members are responsible for groundbreaking medical advances and are committed to rapidly translating science-driven research into new clinical treatments. UT Southwestern’s physicians in more than 80 specialties treat more than 143,000 hospitalized patients, respond to more than 470,000 emergency room cases, and oversee nearly 5.3 million outpatient visits annually.