New drug discovered which corrects diet-induced obesity: Research

New drug for diet-induced obesity

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Lab Laboratory Research Testing
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Last Updated on January 5, 2024 by The Health Master

Scientists have discovered a new pharmacological approach to prevent mitochondria from fragmenting excessively in the brain and white adipose tissue—a process called mitochondrial fission that drives diet-induced obesity.

“SH-BC-893 corrects diet-induced obesity by preventing the excessive mitochondrial fission that results from increased ceramide levels in the tissues of animals consuming a high-fat diet. Fragmentation of the mitochondrial network leads to reductions in mitochondrial membrane potential, increased ROS [reactive oxygen species], and ER [endoplasmic reticular] stress.

SH-BC-893 prevents these mitochondrial changes that sabotage leptin function, an adipokine that regulates appetite,” said Aimee Edinger, PhD, professor and chancellor’s fellow, developmental and cell biology, at University of California, Irvine (UCI), and senior author on the study.

Earlier mouse genetic studies showed white adipose tissue releases too much leptin when mitochondria are fragmented. Hyperleptinemia, where leptin levels increase in blood, leading to feedback regulatory loops that suppress leptin signaling in the brain “similar to how type-2 diabetics have elevated insulin levels but reduced insulin signaling,” while mitochondrial fission in the brain reduces the response to even normal levels of leptin. Mouse studies have also shown maintaining mitochondrial networks in a fused state can overcome high fat diet-induced obesity.

Laboratory test chemical
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“We show that within four hours of oral administration, SH-BC-893 improves mitochondrial morphology and/or function in white adipose tissue and the brain, restoring normal leptin signaling and reducing food intake to a level that produces weight loss,” said Edinger. The new sphingolipid drug reshapes mitochondria in multiple tissues simultaneously, even though mice continue on the high-fat diet.

These findings of the study are published in the journal EMBO Molecular Medicine, in an article titled, “Drug-like sphingolipid SH-BC-893 opposes ceramide-induced mitochondrial fission and corrects diet-induced obesity.”

Fats abundant in a Western diet trigger metabolic dysfunction by abnormally increasing mitochondrial fission. Mitochondria, the cell’s “powerhouse,” play a crucial role in a cell’s energy production and stress responses. Too much mitochondrial fission impairs their function, undermining metabolism and increasing toxic by-products associated with insulin resistance.

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Edinger and her team used their patented water-soluble, orally bioavailable, synthetic sphingolipid SH-BC-893 to inhibit endolysosomal trafficking proteins required for mitochondrial fission. The authors conducted in vitro experiments on mouse embryonic fibroblasts and in vivo experiments on a high-fat diet-induced obesity mouse model.

The researchers reported that SH-BC-893 corrects mitochondrial dysfunction in the liver, brain, and white adipose tissue of mice consuming a Western diet. This normalizes circulating levels of leptin and adiponectin, leading to weight loss, improved glucose handling, and reversal of fatty liver disease despite continued access to high-fat food.

“Imbalances in the hormones leptin and adiponectin that accompany obesity create an uphill battle for people trying to lose weight. Having too much leptin can increase appetite while too little adiponectin activity is linked to many metabolic diseases. How or why is not really clear, but the state of the mitochondria may be an important link between these hormones and obesity,” said Elizabeth Selwan, PhD, a former graduate student researcher in UCI’s department of developmental and cell biology and co-lead author of the study. Selwan and Vaishali Jayashankar, PhD, are co-first authors on the study.

Nearly 30% of the world’s population is obese, resulting in a staggering social and economic burden. Consuming calorie dense, high-fat foods combined with environmental and genetic factors lead to excessive fat synthesis and metabolic dysfunction. The “eat less and move more” recommendation, while adequate for some, does not resolve obesity in individuals in whom a combination of physiological, mental, and environmental factors prevents a negative energy balance.

Surgery may be an option in extreme cases, but there is a need for medical therapies that could complement dietary and lifestyle changes to help people lose weight and maintain normal metabolisms long-term.

Mice given SH-BC-893 exhibit normal behavior. The study showed they run the same distance as mice treated with the placebo, suggesting the compound is not toxic. Edinger said, “If the compound is safe and efficacious in humans, it would offer a novel approach to treating obesity that could be combined with other therapies and lifestyle interventions. Many metabolic diseases linked to obesity appear to have their roots in mitochondrial disfunction, and it is possible that SH-BC-893 could also be used to treat comorbidities such as cardiovascular disease and NAFLD/NASH.”

Edinger has founded a company with co-author Stephen Hanessian, PhD, that is developing the compound for clinical application.

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