On April 5, scientists at the University of Texas Health Science Center at San Antonio reported that inhibiting a liver enzyme in obese mice showed promising results, including in Decreased appetite and weight loss after 12 weeks of treatment. This study points to a potential new way of intervening in metabolic diseases.
In a breakthrough discovery, scientists from the University of Texas Health Science Center at San Antonio (UT Health San Antonio) report , inhibition of liver enzymes in obese mice reduces appetite in rodents, increases energy expenditure in adipose tissue and leads to weight loss.
The findings, published in the journal Cell Metabolism, provide a potential ideal drug target for treating metabolic problems such as obesity and diabetes, the authors say .
“We first needed to discover the mechanism, and now that we have it, we can develop drugs to improve metabolic syndrome,” says senior author Masahiro Morita said Ph.D., an assistant professor of molecular medicine at the Sam and Ambassope Institute for Longevity and Aging at the University of Texas Health San Antonio.
First author Sakie Katsumura said: “We have an enzyme inhibitor, and we wanted to increase its effect more specifically.” Dr. Sakie Katsumura is a postdoctoral researcher in Morita’s lab.
This liver enzyme, called CNOT6L deadenylase, turns off messenger ribonucleic acid (mRNA), which normally Genetic instructions are passed from the nucleus to where in the cell the two liver proteins are made.
One of these proteins is growth differentiation factor 15 (GDF15), which sends signals to two areas in the back of the brain to control food intake. The other is fibroblast growth factor 21 (FGF21), which signals brown and white adipose tissue to increase energy expenditure. CNOT6L deadenylase hinders the coding of GDF15 and FGF21 mRNAs, thereby reducing these benefits.
The researchers’ first CNOT6L inhibitor, iD1, stabilized GDF15 and FGF21 mRNA in the liver of obese mice and increased blood levels of levels of these two proteins. After 12 weeks, the treated rodents ate 40 percent less food and lost 30 percent of their body weight. Energy expenditure in adipose tissue increased by about 15%. Liver fat was reduced by 30%.
Mice treated with iD1 showed improved insulin sensitivity and lower blood sugar levels.
“Targeting mRNA is a fairly novel concept in the treatment of metabolic diseases,” said co-author Nicolas Musi, MD, PhD Professor of Medicine at UT Health San Antonio and Director of the Sam and Ann Barshop Institute. “This is a new platform for thinking about how to treat these diseases.”
In Texas and the United States, obesity, type 2 diabetes , fatty liver and related metabolic diseases have become an epidemic.
More than 37 million Americans have diabetes, according to the Centers for Disease Control and Prevention (CDC). Type 2 diabetes accounts for at least 90% of all cases. In Texas, approximately 2.7 million people have been diagnosed with diabetes, and another 600,000 have diabetes without knowing it. Another 7 million people in Texas have prediabetes.
Data from the Centers for Disease Control and Prevention (CDC) show that the prevalence of obesity in the United States exceeds 40% and is rising. Obesity-related diseases include heart disease, stroke, type 2 diabetes and some cancers.
“These are very serious problems and any intervention that can treat them, including medication, is necessary,” said Dr. Musi . “By describing this mechanism and proof of concept, Drs Morita and Katsumura made the groundbreaking discovery that a drug targeting this pathway can improve all these parameters, including glucose levels, glucose tolerance and high-fat diets and fat Liver-induced insulin resistance.”
Dr. Katsumura reiterated that their next step is to refine this mechanism and find out what might be more targeted , more effective new drugs.
This is a complete, sweeping schema change.
References
Deadenylase-dependent mRNA decay of GDF15 and FGF21 orchestrates food intake and energy expenditure
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