Consuming a high-fat diet can lead to obesity and metabolic disorders such as diabetes and fatty liver. Palmitate, a fat abundant in a Western diet, triggers metabolic dysfunction by causing excessive mitochondrial fission within cells. Mitochondria play a crucial role in a cell's energy production, but also coordinate cell stress responses. Too much mitochondrial fission impairs their function, undermining metabolism and increasing toxic by-products associated with insulin resistance in some tissue types.

"Elegant genetic studies in mice show that maintaining mitochondrial networks in a fused state can overcome high fat diet-induced obesity. Our study uses a small molecule to re-shape mitochondria in multiple tissues simultaneously, reversing obesity and correcting metabolic disease even though mice continue to consume the unhealthy diet," said senior author Aimee Edinger, UCI Chancellor's Fellow and professor of developmental & cell biology.

In their new study, Professor Edinger and her team utilized their patented water-soluble, orally bioavailable, synthetic sphingolipid SH-BC-893 to inhibit endolysosomal trafficking proteins required for mitochondrial fission. The study was conducted using in vitro experiments and a high-fat diet-induced obesity mouse model. The researchers observed that SH-BC-893 prevented mitochondrial dysfunction in the liver, brain, and white adipose tissue of mice consuming a Western diet. As a result, circulating levels of critical metabolic hormones, leptin and adiponectin, were normalized 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, a former graduate student researcher in UCI's Department of Developmental and Cell Biology and co-lead author of the study.

The study's findings suggest that SH-BC-893 could be a promising therapy for managing diet-induced obesity. The authors found the drug to be safe and effective in the mouse model and plan on further investigating the compound for possible use in human patients.

"This compound works through a novel mode of action -- if it is safe and effective in humans, it would offer a new weight loss strategy that could also be combined with other treatments," said Professor Edinger.

Researchers who contributed to this work were: Vaishali Jayashankar, Amandine Verlande, Maggie Goodson, Kazumi Eckenstein, Giedre Milinkeviciute, Brianna Hoover, Angela Fleischman, Karina Cramer and Selma Masri from the University of California, Irvine; Sarah Hancock and Nigel Turner from the University of New South Wales; and Bin Chen and Stephen Hanessian from the Université de Montréal.

The study was supported by the University of California, Irvine, the National Institutes of Health, UCI Beall Applied Innovation, the National Health and Medical Research Council of Australia, the Concern Foundation for Cancer Research, the V Foundation for Cancer Research, and the U.S. Department of Education.

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Materials provided by University of California - Irvine. Note: Content may be edited for style and length.

Journal Reference:

1. Vaishali Jayashankar, Elizabeth Selwan, Sarah E Hancock, Amandine Verlande, Maggie O Goodson, Kazumi H Eckenstein, Giedre Milinkeviciute, Brianna M Hoover, Bin Chen, Angela G Fleischman, Karina S Cramer, Stephen Hanessian, Selma Masri, Nigel Turner, Aimee L Edinger. Drug‐like sphingolipid SH‐BC‐893 opposes ceramide‐induced mitochondrial fission and corrects diet‐induced obesity. EMBO Molecular Medicine, 2021; 13 (8) DOI: 10.15252/emmm.202013086