Triterpenoid CDDO-EA Protects from Hyperglycemia, Hyperinsulinemia, and Obesity by Decreasing Energy Intake

Cantu, A. E.; Rasa, C.; Mito, S.; Cantu, D.; Lopez-Alvarenga, J. C.; Rivera-Lopez, L. L.; Rios, I.; Abrego-Gonzalez, A.; Reyna, S. M.

doi:10.1101/2025.02.12.636924

bioRxiv · 10.1101/2025.02.12.636924

Triterpenoid CDDO-EA Protects from Hyperglycemia, Hyperinsulinemia, and Obesity by Decreasing Energy Intake

Cantu, A. E.·Rasa, C.·Mito, S.·Cantu, D.·Lopez-Alvarenga, J. C.·Rivera-Lopez, L. L.·Rios, I.·Abrego-Gonzalez, A.·Reyna, S. M.

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Abstract

Obesity is a significant factor in the development of type 2 diabetes (T2D). Treatment of obesity is pivotal in the prevention and management of T2D, and the development of new pharmacological therapies are studied for improving insulin resistance and glucose intolerance. Oleanolic acid derived triterpenoids, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acids (CDDOs), are studied to elucidate the mechanisms by which they protect against obesity. However, there remain fundamental gaps in knowledge regarding the physiological and molecular mechanisms by which CDDOs protect against obesity. Our recently published studies showed that CDDO-ethyl amide (CDDO-EA) prevents skeletal muscle inflammation by inhibiting activation of nuclear factor kappa B (NF-{kappa}B) signaling. Moreover, CDDO-EA induced translocation of the glucose transporter, GLUT4, in skeletal muscle cells. We hypothesized that CDDO-EA protects from obesity-induced hyperglycemia in mice fed a high fat diet (HFD). Our results show that CDDO-EA protects from HFD-induced obesity but has no effect on body weight in mice fed a low-fat diet (LFD). Our data show that CDDO-EA inhibition of weight gain is associated with reduced caloric intake and glucose and insulin levels in mice fed a HFD. This highlights the potential of CDDO-EA as a therapeutic agent for obesity treatment and the protection against the development of T2D. IMPACT STATEMENTThe significance of our studies is that they define factors affected by CDDOs to maintain energy homeostasis and improve glucose metabolism to protect against obesity-induced insulin resistance. Our work examines metabolic factors affected by CDDO-EA by demonstrating that CDDO-EA protects from weight gain, glucose intolerance, and insulin resistance. Our research adds new knowledge on the anti-obesity and anti-diabetic properties of CDDO-EA by showing that incorporation of CDDO-EA in a high fat diet prevents obesity and an increase in glucose and insulin levels in an animal model of obesity and insulin resistance. Importantly, CDDO-EA incorporated in a low-fat diet does not affect body weight and caloric intake. Given that obesity is the major risk factor in the progression to T2D, our investigation on characterizing the metabolic effects of CDDO-EA on obesity advances and facilitates the use of CDDOs as candidates for the prevention and treatment of T2D.

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Cantu, A. E., Rasa, C., Mito, S., Cantu, D., Lopez-Alvarenga, J. C., Rivera-Lopez, L. L., Rios, I., Abrego-Gonzalez, A., Reyna, S. M.. 2025-02-15. Triterpenoid CDDO-EA Protects from Hyperglycemia, Hyperinsulinemia, and Obesity by Decreasing Energy Intake. https://doi.org/10.1101/2025.02.12.636924

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