Treatment with opaganib suppressed weight gain in male mice fed a high-fat diet.
Opaganib administration resulted in improved glucose tolerance in high-fat diet-fed mice at multiple time points.
The drug reduced hemoglobin A1c levels and fat deposition in the inguinal region of obese mice.
Equivalent effects were observed in both male and female mice treated with opaganib.
Opaganib and semaglutide showed similar efficacy in promoting weight loss and improving glucose tolerance.
Opaganib either used alone or after semaglutide treatment prevented weight rebound in obese mice.
Simplified
INTRODUCTION: has been implicated in many diseases including cancer, pathologic inflammation, viral infection, neurologic pathologies and metabolic pathologies, including obesity and diabetes. We have previously shown that opaganib (aka ABC294640) inhibits three key enzymes in the sphingolipid metabolism pathway: sphingosine kinase-2, dihydroceramide desaturase and glucosylceramide synthase. We and others have demonstrated anticancer, anti-inflammatory and antiviral activities of opaganib in multiple experimental models. Furthermore, opaganib has been studied in clinical trials with patients having cancer or severe Covid-19. In the present studies, the effects of opaganib in the well-established model of High-Fat Diet (HFD)-induced obesity have been studied.
METHODS: Male or female C57BL/6 mice were fed Control Diet (CD) or HFD and treated with vehicle or opaganib by oral gavage once daily, 5 days per week. Body weights were monitored and glucose tolerance was measured periodically for up to 16 weeks. In some experiments, obese HFD-fed mice were treated with vehicle, opaganib alone, semaglutide alone or opaganib plus semaglutide.
RESULTS: Treatment with opaganib markedly suppressed weight gain in male mice fed the HFD but not in mice given the CD. Compared with mice given CD, mice on the HFD demonstrated poor glucose tolerance at 8, 12 and 16 weeks, consistent with the progression of obesity. Importantly, opaganib treatment of the HFD-fed mice abolished this developing glucose intolerance at all times of measurement. Opaganib treatment also reduced the elevation of hemoglobin A1c and the deposition of inguinal fat in HFD-fed mice. Similar results were obtained with female mice, indicating equivalent efficacy of opaganib in both sexes. Additionally, opaganib and semaglutide were equally effective in promoting body weight loss and improving glucose tolerance in obese mice. Opaganib administered either concurrently with semaglutide or as a single drug following cessation of semaglutide treatment eliminated weight rebound.
CONCLUSION: Overall, the data indicate that opaganib effectively suppresses the loss of metabolic control in mice on HFD, suggesting that opaganib may be useful alone or in combination with existing therapies for weight management and improve conditions associated with obesity and diabetes.
Key numbers
73%
Weight Gain Suppression
Percentage decrease in weight gain compared to control.
100%
Improvement
Percentage of glucose intolerance abolished at all measurement times.
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Lynn W. Maines, Staci N. Keller, Ryan A. Smith and Charles D. Smith are employees and own stock in Apogee Biotechnology Corporation. Apogee Biotechnology Corporation owns patent rights to opaganib, and the value of these rights may be affected by the research reported in the enclosed paper. The authors declare no other commercial or financial relationships that could be construed as a potential conflict of interest for this work.
PubMed
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