Metabolic syndrome increases the risk of 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 metabolismresearchers from University Hospitals (UH), the Harrington Discovery Institute at UH, and Case Western Reserve University continued 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 raises blood sugar by acting on the hypothalamus and liver,” explained Atul Chopra, MD, PhD, lead study author, researcher at the Harrington Discovery Institute. and associate director of the Oxford-Harrington Rare Disease Center, assistant medical geneticist at UH, and associate professor of medicine, genetics, and genomics at Case Western Reserve School of Medicine. “People who have low levels of asprosin in their blood don’t feel hungry like others and have lower glucose and insulin levels.”
Asprosin stimulates appetite by activating key “hungry” neurons in the brain, called AgRP neurons. Asprosin works by attaching a protein to the surface of the neuron called a ‘receptor’. To better understand how receptors work, one could use a key and lock analogy, where a hormone is a key and its receptor is the lock.
“Using a sophisticated technique called mass spectrometry, we identified the protein tyrosine phosphatase receptor? (Ptprd) as an asprosin receptor,” said Ila Mishra, PhD, study first author 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 the mice immune to the appetite-stimulating effect of asprosin. In other words, Ptprd is required for the stimulation of appetite mediated by asprosin. This finding is central to our finding. A receptor is required for a hormone to function, and in the case of asprosin’s ability to control appetite and body weight, this receiver is Ptprd.”
The identity of the receptor that allows asprosin to activate AgRP neurons and stimulate appetite was previously a mystery, and this lack of knowledge has been a barrier to fully understanding how this hormone works.
Since the discovery of asprosin, numerous studies have shown that blood levels of asprosin are elevated in patients with metabolic syndrome, leading to weight gain and high blood sugar. The research team also found that reducing blood levels of asprosin resulted in protection against metabolic syndrome by suppressing appetite and blood sugar.
“The identification of Ptprd as an asprosin receptor has provided us with the opportunity to develop a novel treatment for metabolic syndrome,” Dr. Chopra said.
“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 sugar in obese mice by sequestering plasma asprosin. metabolic.”
“Furthermore, we believe that asprosin performs many other functions besides stimulating appetite,” Dr. Mishra added. “Identifying these new functions is the next step in our research.”
The team also plans to study the intracellular mechanisms involved in asprosin-Ptprd signaling, and simultaneously develop the Ptprd receptor trap for potential use in patients with metabolic syndrome.