Less than two years ago, researchers led by Dr. Atul Chopra, a medical geneticist at Baylor College of Medicine, discovered a new hormone called asprosin, that regulates blood-glucose levels. New studies on the hormone have now revealed that asprosin also acts on the brain, stimulating the hunger center in the hypothalamus to control appetite and body weight. This opens an intriguing possibility for developing novel treatments for overweight people, a population for whom no effective medical therapies currently exist.

The study appeared in the journal Nature Medicine.

“We discovered asprosin when studying individuals affected by a rare medical condition called neonatal progeroid syndrome,” said Chopra, corresponding author, Caroline Wiess Law Scholar and assistant professor of molecular and human genetics and molecular and cellular biology at Baylor College of Medicine. “We found that patients with neonatal progeroid syndrome have a mutation in the FBN1 gene that causes them to lack a small piece of the fibrillin-1 protein. In individuals without the FBN1mutation, this small piece, which we named asprosin, is cut and released into the circulation from the end of the protein.”

One of the cardinal features that defines neonatal progeroid syndrome is extreme thinness or very low body weight. To understand the cause of this issue, Chopra and his colleagues assessed the food intake pattern and metabolic rate of the patients.

“We evaluated the patients’ energy balance in a chamber called an indirect calorimeter,” said Chopra, who also is a member of the Dan L Duncan Comprehensive Cancer Center at Baylor. “This allowed us to measure how much food they ate relative to the number of calories they burned every day. This test gave us a clear answer. Compared with individuals with normal weight, neonatal progeroid syndrome patients have abnormally low appetite. Because these patients have low blood asprosin levels due to their mutations, we wondered whether asprosin was in fact necessary to maintain normal appetite in people.”

To investigate how the mutation affected the patients’ appetite, the researchers genetically engineered mice to carry the same genetic mutation the patients have. The result was mice that mimicked the human condition; they had low blood asprosin levels, low appetite and were very thin.

“In this mouse model we were able to reverse the low appetite simply by administering asprosin to the mice,” Chopra said.

To understand how asprosin controls appetite, the researchers turned to colleagues at the USDA/ARS Children's Nutrition Research Center who specialize in studying brain circuits that control appetite.

“In collaboration with Dr. Yong Xu’s laboratory, we found that in the brain asprosin interacts with neurons in the appetite center of the hypothalamus,” Chopra said. “There are two types of neurons involved in appetite control. One type, the AgRP neurons, stimulates appetite while the other type, POMC neurons, suppresses it. Asprosin works on both types of neurons in an opposite manner; it activates appetite-stimulating AgRP neurons and it deactivates appetite-suppressing POMC neurons.”

“The effects of asprosin on AgRP and POMC neurons appear to be quite unique, as we did not find asprosin changing the firing activities of other appetite-regulating neurons,” said Xu, associate professor of pediatrics and nutrition and of molecular and cellular biology at Baylor and a corresponding author of this work.

The resulting effect of these two asprosin actions in the brain is an increase in appetite, a phenomenon that is deficient in individuals and mice with neonatal progeroid syndrome.

“Although we know some intracellular signals, for example cAMP, are required to mediate asprosin’s appetite-stimulating effects on AgRP neurons, the receptors for the hormone remain to be identified,” Xu said. “This is our current focus.”