CLEVELAND—Metabolic syndrome increases a person’s risk for diabetes, heart disease, and stroke, and includes conditions such as obesity, high blood pressure and high blood sugar. In a recent mouse-model study, published in Cell Metabolism, researchers at University Hospitals (UH), Harrington Discovery Institute at UH, and Case Western Reserve University have furthered their progress to develop a drug to treat metabolic syndrome by identifying a receptor that controls appetite and body weight.
“In 2016, our lab discovered a hormone called asprosin, which stimulates appetite and increases blood glucose levels by acting on the hypothalamus and the liver,” explained Atul Chopra, MD, PhD, senior author on the study, Investigator at the Harrington Discovery Institute and Associate Director of the Oxford-Harrington Rare Disease Center, Attending Medical Geneticist at UH, and Associate Professor of Medicine, and Genetics and Genomics at Case Western Reserve School of Medicine. “Individuals that have low blood asprosin levels don’t feel hunger like others do and have lower glucose and insulin levels.”
Asprosin stimulates appetite by activating key “hunger” neurons of the brain, called AgRP neurons. Asprosin works by binding a protein on the neuron surface called a “receptor.” To better understand how receptors work, one might use a key and lock analogy, where a hormone is a key, and its receptor is the lock.
“By using a sophisticated technique called mass spectrometry, we identified protein tyrosine phosphatase receptor δ (Ptprd) as the receptor for asprosin,” said Ila Mishra, PhD, first author on the study and research associate at Harrington Discovery Institute and Case Western Reserve School of Medicine. “Genetic deletion of Ptprd in mice reduced appetite and body weight, rendering mice unresponsive to asprosin’s appetite stimulating effect. In other words, Ptprd is necessary for asprosin-mediated appetite stimulation. This result is the crux of our discovery. A receptor is necessary for a hormone to work, and in the case of asprosin’s ability to control appetite and body weight, that receptor is Ptprd.”
The identity of the receptor that allows asprosin to activate AgRP neurons and stimulate appetite was previously a mystery, and this gap in knowledge was a barrier to fully understanding how this hormone works.
Since the discovery of asprosin, many studies have shown that blood asprosin levels are elevated in patients with metabolic syndrome, leading to weight gain and high blood sugar. The research team has also seen that reduced blood asprosin levels lead to protection from metabolic syndrome by suppressing appetite and blood sugar.
“The identification of Ptprd as an asprosin receptor provided us an opportunity to develop a new therapeutic against metabolic syndrome,” said Dr. Chopra.
“We used the discovery of the asprosin-receptor to develop a new drug called a receptor trap,” explained Dr. Mishra. “This new drug suppressed appetite, body weight and blood glucose levels in obese mice by sequestering plasma asprosin. From a clinical standpoint, it means that this discovery could potentially yield a brand-new drug against metabolic syndrome.”
“Further, we believe that asprosin performs many more functions in addition to appetite stimulation,” added Dr. Mishra. “Identifying these new functions is the next step in our research.”
The team also plans to study intracellular mechanisms involved in asprosin-Ptprd signaling, and simultaneously develop the Ptprd receptor trap for potential use in patients with metabolic syndrome.
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Mishra, I. et al. “Protein tyrosine phosphatase receptor δ serves as the orexigenic asprosin receptor.” Cell Metabolism. DOI: 10.1016/j.cmet.
About University Hospitals / Cleveland, Ohio
Founded in 1866, University Hospitals serves the needs of patients through an integrated network of 23 hospitals (including 5 joint ventures), more than 50 health centers and outpatient facilities, and over 200 physician offices in 16 counties throughout northern Ohio. The system’s flagship quaternary care, academic medical center, University Hospitals Cleveland Medical Center, is affiliated with Case Western Reserve University School of Medicine, Northeast Ohio Medical University, Oxford University and the Technion Israel Institute of Technology. The main campus also includes the UH Rainbow Babies & Children's Hospital, ranked among the top children’s hospitals in the nation; UH MacDonald Women's Hospital, Ohio's only hospital for women; and UH Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center. UH is home to some of the most prestigious clinical and research programs in the nation, with more than 3,000 active clinical trials and research studies underway. UH Cleveland Medical Center is perennially among the highest performers in national ranking surveys, including “America’s Best Hospitals” from U.S. News & World Report. UH is also home to 19 Clinical Care Delivery and Research Institutes. UH is one of the largest employers in Northeast Ohio with more than 30,000 employees. Follow UH on LinkedIn, Facebook and Twitter. For more information, visit UHhospitals.org.
About Harrington Discovery Institute at University Hospitals
The Harrington Discovery Institute at University Hospitals in Cleveland, OH – part of The Harrington Project for Discovery & Development – aims to advance medicine and society by enabling our nation’s most inventive scientists to turn their discoveries into medicines that improve human health. The institute was created in 2012 with a $50 million founding gift from the Harrington family and instantiates the commitment they share with University Hospitals to a Vision for a ‘Better World’. For more information, visit: HarringtonDiscovery.org.
About Case Western Reserve University
Case Western Reserve University is one of the country's leading private research institutions. Located in Cleveland, we offer a unique combination of forward-thinking educational opportunities in an inspiring cultural setting. Our leading-edge faculty engage in teaching and research in a collaborative, hands-on environment. Our nationally recognized programs include arts and sciences, dental medicine, engineering, law, management, medicine, nursing and social work. About 5,800 undergraduate and 6,300 graduate students comprise our student body. Visit case.edu to see how Case Western Reserve thinks beyond the possible