summary: Researchers have developed a new molecule that restricts magnesium transport in mitochondria. The drug prevents weight gain and liver damage in mice fed a high-sugar Western diet from birth. After exposure to this molecule, overweight mice began to lose weight.
sauce: UT Health San Antonio
Researchers at the University of Texas at San Antonio Health Science Center (UT Health San Antonio) have developed a small-molecule drug that prevents weight gain and adverse liver changes in mice fed a high-sugar, high-fat Western diet for life. Did.
“When you give mice this drug for a short period of time, they start losing weight. They all slim down,” says Dr. Madesh Mniswamy, a professor of medicine at the Joe R. and Teresa Lozano Long School of Medicine at the Center for Health Sciences. says.
The findings by collaborators, also at the University of Pennsylvania and Cornell University, were published in the high-impact journal on February 27. cell report. Muniswamy, director of the Center for Mitochondrial Medicine at UT Health San Antonio, is a senior author.
4th most common element
The research team first discovered the drug by investigating how magnesium affects metabolism, the production and consumption of energy in cells. Fuel the process.
Magnesium is the fourth most abundant element in the body after calcium, potassium and sodium and plays many important roles in health, including regulation of blood sugar and blood pressure and bone formation. But researchers have found that too much magnesium slows down energy production in the mitochondria, the cell’s powerhouses.
“It just hits the brakes and slows down,” says co-lead author Travis R. Madaris, a PhD student in the Muniswamy lab at UT Health San Antonio.
Deletion of MRS2, a gene that facilitates magnesium transport into mitochondria, made sugar and fat metabolism more efficient at the power plant.
Rodent liver and adipose (fat) tissue showed no evidence of complications associated with fatty liver disease, poor diet, obesity, and type 2 diabetes.
small molecule drug
The drug, which researchers call CPACC, accomplishes the same thing. Limits the transfer of magnesium to power plants. In the experiment, the result was again lean, healthy mice. UT Health San Antonio has applied for a patent on this drug.
Mice served as a model system for long-term dietary stress caused by high-calorie, high-fat, and high-fat Western diets. Common consequences of this stress are obesity, type 2 diabetes, and cardiovascular complications.
“Lowering mitochondrial magnesium mitigated the negative effects of long-term dietary stress,” said co-lead author Dr. Manigandan Venkatesan, a postdoctoral fellow in the Muniswamy Lab.
Dr. Joseph A. Baur of the University of Pennsylvania and Dr. Justin J. Wilson of Cornell University are also collaborators. “We came up with a small molecule and Justin synthesized it,” Madaris said.
significant meaning
“These findings are the result of several years of research,” said Muniswamy. “A drug that can reduce the risk of cardiometabolic diseases such as heart attack and stroke and reduce the incidence of liver cancer secondary to fatty liver will have a major impact. ”
Funders of this project include the National Institutes of Health, the US Department of Defense, and the San Antonio Partnership for Precision Therapeutics.
About this obesity and pharmacology research news
author: Will Sansom
sauce: UT Health San Antonio
contact: Will Sansom – UT Health San Antonio
image: image is public domain
Original research: open access.
“Limiting Mrs2-dependent mitochondrial Mg2+ uptake induces metabolic programming with prolonged dietary stressBy Travis R. Madaris et al. cell report
overview
Limiting Mrs2-dependent mitochondrial Mg2+ uptake induces metabolic programming with prolonged dietary stress
highlight
- Mitochondrial Mg2+ Channel Mrs2 Rheostat MCU Ca2+ Signals that maintain bioenergetic circuits
- DNL precursors and cellular Mg2+ A citrate chelator suppresses HIF1α signaling and oxidative metabolism
- decrease metersmagnesium2+ Reduces obesity and metabolic syndrome caused by long-term dietary stress
- The Mrs2 channel blocker CPACC reduces lipid accumulation and promotes browning and weight loss
summary
Most abundant cellular divalent cation, Mg2+ (mM) and Ca2+ (nM-μM), which antagonistically regulate divergent metabolic pathways with affinity preferences of several orders of magnitude, but the physiological significance of this competition remains elusive.
Genetic depletion of mitochondrial Mg in mice on a Western diet2+ channel Mrs2 It prevents weight gain, increases mitochondrial activity, reduces fat accumulation in the liver, and causes significant browning of white fat. de novo Lipogenesis.
Since citrate is endogenous Mg2+ chelating agents, which may represent an adaptive response to the lack of recognized cations.
Transcriptional profiling of liver and white fat revealed higher expression of genes involved in glycolysis, β-oxidation, thermogenesis and HIF-1α targets. Mrs2−/− Mice further enhanced under Western diet-related metabolic stress.therefore lower metersmagnesium2+ It promotes metabolism and suppresses diet-induced obesity and metabolic syndrome.
