Dreaming about munching on fast food menus with donuts, ice creams and large sodas without putting on any weight? It might just be possible!
Mice exposed to a diet high in sugar and fat throughout their lives successfully averted weight gain and safeguarded their livers when treated with a newly developed experimental drug.
Crafted by a team spearheaded by The University of Texas Health Science Center at San Antonio (UT Health San Antonio), this small-molecule drug, identified by its chemical acronym CPACC, functions by restricting the entry of magnesium into the mitochondria. These cellular powerhouses are responsible for generating energy and burning calories.
Mitochondrial irregularities have been linked to various diseases, encompassing obesity, diabetes, and cardiovascular ailments.
The outcomes, detailed in a published paper, are the culmination of extensive research spanning several years, notes Madesh Muniswamy, a molecular biochemist from UT Health San Antonio and the senior author of the study.
Magnesium, among the four principal positively charged ions influencing cellular activities, including calcium, potassium, and sodium, plays a multifaceted role in the body’s functions. Notably, it regulates blood sugar and blood pressure while contributing to sturdy bone formation. However, an excess of magnesium hampers energy production within the mitochondria.
“The process slows down significantly,”Travis Madaris from UT Health San Antonio, one of the co-lead authors of the study.
In their investigation, researchers stumbled upon the new drug while examining the consequences of eliminating a specific gene known as MRS2, responsible for encoding a magnesium transporter protein called Mrs2. This protein functions as a conduit, facilitating the movement of magnesium across the mitochondrial membrane.
Their study compared the effects of a prolonged intake of a Western diet high in fat, sugar, and calories on standard mice versus mice with the MRS2 gene removed.
Deleting MRS2 resulted in leaner, healthier mice demonstrating enhanced sugar and fat processing within their mitochondria, despite starting the Western diet at 14 weeks of age and continuing it for up to a year (a substantial duration in a mouse’s life).
In the regulation of sugar and fat metabolism following meals and fasting, the liver assumes a pivotal role. While a resilient organ, the liver does have its limitations. Notably, the mice without the MRS2 gene exhibited no signs of fatty liver disease in their liver or fat tissues, a condition often associated with an imbalanced diet, obesity, or type 2 diabetes.
“Reducing mitochondrial magnesium levels alleviated the detrimental impacts of prolonged dietary strain,”Manigandan Venkatesan from UT Health San Antonio.
Further experiments administering CPACC yielded similar outcomes to deleting the MRS2 gene. This drug operates by impeding the magnesium channels encoded by the gene, resulting once again in leaner, healthier mice by curtailing the influx of magnesium into the mitochondria.
Naturally, findings in mice may not directly translate to humans, and the study’s authors acknowledge certain limitations. Their approach involves inducing metabolic syndrome in humans through prolonged dietary stress. Introducing short-term dietary stress could offer insights into the primary effects of MRS2 deletion.
Additionally, the researchers point out that using a complete deletion method for MRS2 prevents examining how each tissue impacts metabolic regulation. Given the widespread presence of MRS2, they stress the significance of further exploration into its effects on various organs such as the brain, heart, kidneys, lungs, and skeletal muscles.
The most abundant cellular divalent cations, Mg2+ (mM) and Ca2+ (nM-μM), antagonistically regulate divergent metabolic pathways with several orders of magnitude affinity preference, but the physiological significance of this competition remains elusive. In mice consuming a Western diet, genetic ablation of the mitochondrial Mg2+ channel Mrs2 prevents weight gain, enhances mitochondrial activity, decreases fat accumulation in the liver, and causes prominent browning of white adipose. Mrs2 deficiency restrains citrate efflux from the mitochondria, making it unavailable to support de novo lipogenesis. As citrate is an endogenous Mg2+ chelator, this may represent an adaptive response to a perceived deficit of the cation. Transcriptional profiling of liver and white adipose reveals higher expression of genes involved in glycolysis, β-oxidation, thermogenesis, and HIF-1α-targets, in Mrs2−/− mice that are further enhanced under Western-diet-associated metabolic stress. Thus, lowering mMg2+ promotes metabolism and dampens diet-induced obesity and metabolic syndrome.