San Antonio Express-News (Sunday)
Restraining A Liver Enzyme Could Help Us Trim Down, Reduce Appetite
Novel approach identified to tackle metabolic diseases
In a breakthrough discovery, scientists from The University of Texas Health Science Center at San Antonio, also called UT Health San Antonio, noted weight loss and decreased appetite in obese mice treated with a novel investigational therapy. The therapy slows liver enzyme activity, which leads to appetite control in the brain, increased energy expenditure in fat cells and — as a result — weight loss.
This finding, published in Cell Metabolism, provides a potentially desirable 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 UT Health San Antonio’s Sam and Ann Barshop Institute for Longevity and Aging Studies.
“We now 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.
The issue being addressed
The liver enzyme, called CNOT6L deadenylase, turns off messenger ribonucleic acids (mRNAs) that ordinarily 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 other, fibroblast growth factor 21 (FGF21), sends signals to brown and white adipose tissues to increase energy expenditure. CNOT6L deadenylase impedes mRNA code-carrying for both GDF15 and FGF21, which reduces these benefits.
The researchers’ first-in-class CNOT6L inhibitor, dubbed iD1, stabilized liver GDF15 and FGF21 mRNAs in obese mice, increasing levels of the two proteins in the blood. After 12 weeks, treated rodents ate less food and exhibited 30% reduced body weight. Energy expenditures in the adipose tissues increased by about 15%. Liver fat decreased 30%.
And, importantly, mice treated with iD1 showed improved insulin sensitivity and lower blood glucose levels.
A timely and needed idea
“In the treatment of metabolic disease, targeting mRNA is a fairly novel concept,” said coauthor Nicolas Musi, MD, professor of medicine at UT Health San Antonio and director of the Sam and Ann Barshop Institute. “It is a new platform for thinking about how to treat this group of diseases.”
In Texas and the U.S., obesity, type 2 diabetes, fatty liver disease and related metabolic disorders are at epidemic proportions.
According to the U.S. Centers for Disease Control and Prevention (CDC), 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. Obesityrelated diseases include heart attack, stroke, type 2 diabetes and some cancers.
“These are very serious problems, and any intervention, including drugs, that can treat them is necessary,” Dr. Musi said. “Dr. Morita and Dr. Katsumura have made a groundbreaking discovery by delineating this mechanism and the proof
of concept that a drug that targets this pathway improves all these parameters including glucose levels, glucose tolerance and insulin resistance caused by a high-fat diet and fatty liver.”
“A drug that improves glucose levels, glucose tolerance and insulin resistance caused by a high-fat diet and fatty liver would be comprehensive, thorough and paradigm-changing.” —
Their next step, Dr. Katsumura reiterated, is to refine this mechanism and identify new drugs that may be more specific and more potent.
The researchers are in the UT Health San Antonio’s Sam and Ann Barshop Institute for Longevity and Aging Studies.
Nicolas Musi, MD, Director,
Barshop Institute, UT Health San Antonio
Learn more about how UT Health San Antonio makes lives better at EverythingItTakes.org.
About UT Health San Antonio
UT Health San Antonio is the largest research university in South Texas with an annual research portfolio of approximately $350 million. It is the region’s only academic health institution, and its Joe R. and Teresa Lozano Long
School of Medicine is listed among U.S. News & World Report’s best medical schools, ranking in the top 30% in the U.S. for research. The institution’s strategic investment in research of metabolic diseases (such as obesity and diabetes) is a direct response to the heavy burden of these conditions on South Texas families. Its faculty members are likewise committed to conquering adult and childhood cancer, brain diseases, heart attack, stroke and many other health dilemmas that rob people of life and productivity.
Research led by UT Health San Antonio faculty has yielded new therapies for COVID-19, new treatments for chronic leukemia and post-traumatic stress disorder, and advancements in detecting and treating many other diseases. UT Health San Antonio, designated a HispanicServing Institution by the U.S. Department of Education, continues in its 50-year mission to teach, discover and heal in service of the public good across South Texas.
About UT Health San Antonio’s Sam and Ann Barshop Institute for Longevity and Aging Studies
The Barshop Institute, named for legendary San Antonio businessman Sam Barshop and his wife, Ann, is one of the world’s premier institutes dedicated to the study of age-related diseases. The Barshop Institute is the only aging-intensive research institute in the country to have four peer-reviewed designations: two National Institute on Aging (NIA)-funded centers (Nathan Shock and Claude D. Pepper centers), a testing site of the NIA-sponsored Interventions Testing Program, and a U.S. Department of Veterans Affairs Geriatric Research, Education and Clinical Center.