Losing weight could come down to your liver

In a breakthrough finding, UT Health San Antonio scientists discovered that inhibiting a liver enzyme in obese mice decreased the rodents’ appetites, increased energy expenditure in fat tissues and resulted in weight loss.

The finding, published in Cell Metabolism, provides a potential drug target to treat metabolic issues such as obesity and diabetes.

“We first needed to discover this mechanism and, now that we have, we can develop drugs to improve metabolic syndrome,” said senior author Masahiro Morita, PhD, assistant professor of molecular medicine in the university’s Sam and Ann Barshop Institute for Longevity and Aging Studies.

“We have an enzyme inhibitor that we want to make more specific to increase its effects,” said first author Sakie Katsumura, DDS, PhD, postdoctoral fellow in the Morita laboratory.

They targeted a liver enzyme called CNOT6L deadenylase. It turns off messenger ribonucleic acids, called mRNAs, that ordinarily carry genetic instructions from the nucleus to sites in the cell where two liver proteins are made. One protein sends signals to the brain to control food intake. The other sends signals to adipose tissues to increase energy expenditure.

The liver enzyme impedes these signals, reducing the benefits. So, the researchers created a first-in-class CNOT6L inhibitor, dubbed iD1, to stabilize the messenger ribonucleic acids in obese mice and increase levels of the two proteins in the blood. After 12 weeks, treated rodents ate less food and showed 30% reduced body weight. Energy expenditures in the adipose tissues increased by 15%. Liver fat decreased 30%.

They also showed improved insulin sensitivity and lower blood glucose levels.

In Texas and the U.S., obesity, Type 2 diabetes, fatty liver disease and related metabolic disorders are at epidemic proportions.

According to the Centers for Disease Control and Prevention, more than 37 million Americans have diabetes. Type 2 diabetes represents at least 90% of the cases. In Texas, approximately 2.7 million people have diagnosed diabetes, and an additional 600,000 people in Texas have diabetes but don’t know it. Another 7 million people in Texas have prediabetes.

Obesity prevalence in the U.S. is more than 40% and is climbing, according to the CDC. Obesity-related diseases include heart attack, stroke, Type 2 diabetes and some cancers.

Next, the researchers will refine the mechanism and identify new drugs that may be more specific and more potent, Katsumura said.