Mighty Mitochondria: How Correcting Imbalances in Our Cells’ Energy Powerhouses Supports Weight Management and Metabolism in Mice

With rates tripling over the past four decades, almost three-quarters of adults in the United States are now classified as overweight or obese. As one of society’s most considerable public health problems, having an unhealthy body weight accounts for 4 million premature deaths globally each year — not to mention the immense socioeconomic burden that comes along with it.

Because many of the current weight loss medications on the market either cause significant side effects or have low efficacy, doctors and patients alike hope to identify new therapies that lead to meaningful and safe weight reduction. Now, researchers out of UC Irvine find that one solution may lie with our cells’ energy powerhouses — the mitochondria. Published in the journal EMBO Molecular Medicine, Jayashankar and colleagues show in a series of elegant experiments how a small compound brings about changes to the network of these cellular battery packs, and with it, improving body weight and reducing metabolic abnormalities in obese mice.

The Dynamics of Our Cells’ Dynamos

Mitochondria are highly dynamic organelles (essentially, a “little organ” inside a cell); they change shape and size in response to key processes known as fission and fusion. Both are essential aspects of mitochondrial dynamics but perform different duties. 

Fusion helps to reduce cellular stress by fusing mitochondrial parts to create healthy, whole mitochondria. Conversely, fission breaks apart mitochondria to create new organelles, which can help remove damaged mitochondria and facilitate programmed cell death, known as apoptosis. However, excessive fission occurs in response to bodily stress, leading to mitochondrial fragmentation — fragments of mitochondria that aren’t fully functional. Excessive fragmentation increases the production of harmful compounds called reactive oxygen species and is linked to poor metabolic function and unhealthy weights. 

With this in mind, Jayashankar and colleagues patented a small molecule designed to inhibit mitochondrial fission, which occurs more often in response to the unhealthy, high-fat diets that are increasingly common in the United States and worldwide.   

Novel Compound Corrects Mitochondrial Dynamics

This novel compound, SH-BC-893, is a synthetic sphingolipid (a type of fat that provides structural support to cell membranes) that inhibits several pathways essential for mitochondrial fission. As described by senior author Aimee Edinger, UCI Chancellor's Fellow and professor of developmental & cell biology, "Our study uses a small molecule to re-shape mitochondria in multiple tissues simultaneously, reversing [unhealthy weights] and correcting [metabolism] even though mice continue to consume the unhealthy diet."

To start, Jayashankar and colleagues looked at mitochondrial health in a cell-based experiment. Mouse cells exposed to high amounts of fats experienced severe rates of mitochondrial fission. After adding SH-BC-893, mitochondrial fragments were reduced, indicating that this compound disrupts the excess fission. Fragmented mitochondria generate more reactive oxygen species (ROS) and cellular stress that disrupts metabolism and weight management; the cells that received SH-BC-893 were protected from these disruptions.

Fighting Fission and Mastering Metabolism

Next, the research team tested the effects of SH-BC-893 in mice who were fed a high-fat diet designed to induce unhealthy weights and compromised metabolic function. In young male obese mice who were on this unhealthy diet for most of their lives, a single treatment of SH-BC-893 normalized the dynamics and morphology — shapes, sizes, and structures — of mitochondria in the brain, liver, and fat tissue.

Another driver of unhealthy weights is an imbalance between the hormones leptin and adiponectin — higher amounts of leptin and lower adiponectin are linked to weight gain, increased food intake, and dysfunctional metabolisms. In the obese mice, a single dose of SH-BC-893 normalized these hormones, boosting adiponectin and reducing leptin. This decline in leptin triggered a reduction in overall food intake, which stood strong for 18 hours and didn’t lead to the mice overcompensating with increased consumption the next day. 

Regulating leptin signaling is thought to be a vital component of maintaining a healthy weight. As Elizabeth Selwan, co-lead author and former graduate student researcher in UCI's Department of Developmental and Cell Biology, describes, "Imbalances in the hormones leptin and adiponectin...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 [unhealthy weight]."

The research team then split obese mice into three groups — a lower dose of SH-BC-893, a higher dose of SH-BC-893, and a placebo. After four weeks of these treatments, the placebo group continued to gain weight while both of the groups who received three doses of SH-BC-893 per week experienced significant weight loss, despite remaining on a high-fat diet. Although the higher dose group did show more weight loss, the lower dose was sufficient and clinically meaningful for weight loss. 

Lastly, they looked at how this compound affected weight when supplemented with aerobic exercise, finding that this combination augmented the beneficial effects and produced even more significant weight gain than either treatment alone. 

Tipping the Scales 

The outcomes of this study are extremely encouraging for the millions of people struggling with their weight. However, it remains uncertain if these results would translate to humans, as this research was only done with young male mice. But, as imbalances in mitochondrial fission have been well-documented to cause poor metabolic health, this safe and well-tolerated compound could likely benefit obese humans. 

As Edinger concludes of this proof-of-concept study, "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.”

References: 

Vaishali Jayashankar, Elizabeth Selwan, Sarah E Hancock, et al. Drug‐like sphingolipid SH‐BC‐893 opposes ceramide‐induced mitochondrial fission. EMBO Molecular Medicine, 2021; 13 (8) DOI: 10.15252/emmm.202013086