Increasing liver mRNAs slows appetite and body weight in obese mice

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Researchers from the University of Texas Health Science Center in San Antonio (UT Health San Antonio) reported today that inhibition of a liver enzyme in obese mice decreased rodent appetite, increased energy expenditure in adipose tissue (fat), and resulted in weight loss.

The finding, published in Cell Metabolism, provides a potentially desirable drug target for treating metabolic problems such as obesity and diabetes, the authors said.

“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, Ph.D., assistant professor of molecular medicine at UT Health San Antonio Sam and Ann Barshop Department of Longevity and Aging Studies.

“We have an enzyme inhibitor that we want to make more specific to increase its effects,” said lead author Sakie Katsumura, DDS, Ph.D., postdoc of the Morita Laboratory.

The liver enzyme, called CNOT6L deadenylase, inactivates messenger ribonucleic acids (mRNAs), which normally carry genetic instructions from the nucleus to sites in the cell where two liver proteins are made.

One of the proteins, growth differentiation factor 15 (GDF15), sends signals to two regions of the hindbrain to control food intake. The second, fibroblast growth factor 21 (FGF21), sends signals to brown and white adipose tissue to increase energy expenditure. CNOT6L deadenylase inhibits mRNA code-carrying for both GDF15 and FGF21, reducing these benefits.

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The researchers’ first-class CNOT6L inhibitor, dubbed iD1, stabilized liver GDF15 and FGF21 mRNAs in obese mice, increasing the levels of the two proteins in the blood. After 12 weeks, treated rodents ate 40% less food and showed 30% reduced body weight. Energy consumption in adipose tissue increased by about 15%. Liver fat decreased by 30%.

Mice treated with iD1 showed improved insulin sensitivity and lower blood sugar levels.

“In the treatment of metabolic diseases, targeting mRNA is a fairly new concept,” said co-author Nicolas Musi, MD, professor of medicine at UT Health San Antonio and director of the Sam and Ann Barshop Institute. “It’s a new platform for thinking about how to treat this group of diseases.”

In Texas and the United States, obesity, type 2 diabetes, fatty liver disease, and related metabolic disorders are in epidemic proportions.

According to the US Centers for Disease Control and Prevention (CDC), more than 37 million Americans have diabetes. Type 2 diabetes accounts for at least 90% of cases. In Texas, approximately 2.7 million people have been diagnosed with diabetes, and another 600,000 people in Texas have diabetes but do not know it. Another 7 million people in Texas have pre-diabetes.

The prevalence of obesity in the United States is more than 40% and is increasing, according to the CDC. Obesity-related diseases include heart attacks, strokes, type 2 diabetes and some cancers.

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“These are very serious problems, and any intervention, including medications that can treat them, is necessary,” said Dr. Musi. “Dr. Morita and Dr. Katsumura have made a groundbreaking discovery by defining this mechanism and proof of concept that a drug that targets this pathway improves all of these parameters, including glucose levels, glucose tolerance and insulin resistance caused by a diet with high fat and fatty liver. “

Their next step, Dr. Katsumura, is to refine this mechanism and identify new drugs that may be more specific and more potent.

“I would like to congratulate Dr. Morita and Dr. Katsumura for this amazing work,” said Dr. Musi. “It’s comprehensive, thorough and paradigm shifting.”

A global view of fatty liver and diabetes helps fight other non-communicable diseases and COVID-19 More information: Masahiro Morita, Deadenylase-dependent mRNA degradation of GDF15 and FGF21 orchestrates food intake and energy expenditure, Cell Metabolism (2022). DOI: 10.1016 / j.cmet.2022.03.005. 1550-4131 (22) 00093-6

Provided by the University of Texas Health Science Center in San Antonio

Quote: Increasing liver mRNAs slows appetite, body weight in obese mice (2022, April 5) Retrieved April 6, 2022 from -appetite.html

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