Targeting Fat Cells With Sphingosine Kinase 2 Inhibitors Shows Promise Against Obesity in Mouse Studies

Scientists at Virginia Commonwealth University’s Massey Comprehensive Cancer Center report that an enzyme called sphingosine kinase 2, when blocked specifically in fat cells, produced meaningful metabolic improvements in mouse models of diet-induced obesity. In the study, published in Science Advances on 21 August 2026, the team found that targeting SPHK2 within adipocytes led to significant reductions in body weight, improved glucose tolerance, improved insulin sensitivity, and reduced lipid accumulation in the liver. The researchers propose that this cell-specific approach could eventually complement existing obesity therapies and, by easing the metabolic state that links excess body fat to malignancy, help lower the risk of obesity-associated cancers.

The motivation for the work stems partly from the limits of current treatment. GLP-1 receptor agonists are well established to help reduce body weight, but as Christopher Green, Ph.D., study co-author and a member of the Cancer Biology research program at Massey, noted, they do not work for everyone, and weight often returns once the medication is stopped. “So, there is a need to develop additional therapies, and we think that targeting adipocytes with sphingosine kinase 2 inhibitors could be a new strategy to treat people with obesity and affect their susceptibility to developing cancer,” Green said. The urgency of that search is underlined by national data: from August 2021 to 2023, the prevalence of obesity among adults in the United States exceeded 40 percent, a level associated with a wide range of downstream health complications.

The biological rationale connecting obesity to cancer is well documented. Fat tissue produces excess estrogen, and elevated estrogen levels have been associated with increased risks of breast, endometrial, ovarian and some other cancers. People with obesity often show increased blood levels of insulin and insulin-like growth factor-1, both of which have been associated with higher risks of colorectal, thyroid, breast, prostate, ovarian and endometrial cancers. Chronic inflammation, common in obesity, promotes tumor growth, while adipocytes secrete hormones called adipokines that can influence cell growth. Beyond cancer incidence, obesity can also worsen aspects of survivorship, including quality of life, cancer recurrence, cancer progression, prognosis and the risk of second primary cancers.

SPHK2 is an enzyme that creates sphingosine 1-phosphate, a bioactive signaling molecule with both intracellular and extracellular roles. The lipid has been shown to be involved in many types of cancer, particularly liver cancer, and in inflammation. Notably, in various models SPHK2 has been found to either promote or slow tumor growth depending on the type of tissue involved, which makes its adipocyte-specific role an important focus. In previous studies, Green and his research team had observed that whole-body deletion of SPHK2 protected male mice from Western diet-induced obesity, reduced fat accumulation across multiple adipose depots, and reduced liver cancer in those animals. In the new work, the team narrowed the target: rather than deleting the enzyme throughout the body, they targeted SPHK2 specifically in adipocytes in these mouse models. The result was a significant reduction in body weight along with improved glucose tolerance, improved insulin sensitivity and reduced lipid accumulation in the liver. These initial results led the researchers to believe that directing sphingosine kinase 2 inhibitors at fat cells could become a new strategy to reduce the risk of cancers that stem from obesity, although the findings so far are from animal models and further study is required before any clinical application.

Several obstacles stand between the current results and potential therapies. The inhibitors currently on the market have off-target effects, meaning they act on molecules other than SPHK2, so the team is hopeful that more specific inhibitors will be developed that solely target SPHK2. Green also emphasized the value of precision in delivery. “Additionally, future therapeutic strategies designed to more precisely target specific fat depots will be immensely beneficial,” he said. “By localizing treatment, these strategies can reduce obesity and its comorbidities-including cancer-while minimizing unwanted side effects.” The study, titled “Sphingosine kinase 2 regulates adipocyte browning and whole-body metabolism,” was led by first author Ryan D. R. Brown, with Massey research members Katarzyna Tyc, Ph.D., Christopher Green, Ph.D., and Sara Spiegel, Ph.D., and VCU collaborators Cynthia Weigel, Ph.D., Yadu Vijayan, Ph.D., and Christiane Carter. The work was funded by the National Institutes of Health and the VCU Accelerate Fund. Moving forward, the team plans to continue exploring the role of SPHK2 in obesity and cancer. If subsequent research confirms that adipocyte-restricted SPHK2 inhibition can be achieved safely and selectively, the approach could address a persistent gap in obesity care: patients who do not respond to GLP-1-based therapies and those who regain weight after discontinuing them. For now, the study establishes that manipulating sphingolipid signaling inside fat cells is sufficient to drive systemic metabolic improvements in mice, a result that reframes adipocytes not merely as passive storage depots but as active, druggable regulators of whole-body metabolism and, potentially, of cancer susceptibility.

Subject of Research: Sphingosine kinase 2 inhibition in adipocytes as a potential strategy against obesity and obesity-linked cancer risk

Article Title: Researchers discover new strategy to target obesity and reduce the risk of cancer

Article References: Researchers discover new strategy to target obesity and reduce the risk of cancer. Original publication (Bibliographic details unavailable.)

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Keywords: obesity, sphingosine kinase 2, adipocytes, cancer risk, metabolism, VCU Massey Comprehensive Cancer Center, Science Advances, mouse models, GLP-1, sphingosine 1-phosphate, glucose tolerance, insulin sensitivity