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PI3Kα inhibition reduces obesity in mice
Elena Lopez-Guadamillas1, Maribel Muñoz-Martin1, Sonia Martinez2
1Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid E28029, Spain.
Abstract:
Partial inhibition of PI3K is one of the best-validated and evolutionary conserved manipulations to extend longevity. The best known health beneficial effects of reduced PI3K are related to metabolism and include increased energy expenditure, reduced nutrient storage, and protection from obesity. We have previously shown that a dual chemical inhibitor of the alpha and delta PI3K isoforms (CNIO-PI3Ki) reduces obesity in mice and monkeys, without evident toxic effects after long-term treatment. Here, we dissect the role of the alpha and delta PI3K isoforms by making use of selective inhibitors against PI3Kα (BYL-719 also known as alpelisib) or PI3Kδ (GS-9820 also known as acalisib). Treatment of mice with the above mentioned inhibitors indicated that BYL-719 increases energy expenditure in normal mice and efficiently reduces body weight in obese (ob/ob) mice, whereas these effects were not observed with GS-9820. Of note, the dose of BYL-719 required to reduce obesity was 10x higher than the equivalent dose of CNIO-PI3Ki, which could suggest that simultaneous inhibition of PI3K alpha and delta is more beneficial than single inhibition of the alpha isoform. In summary, we conclude that inhibition of PI3Kα is sufficient to increase energy expenditure and reduce obesity, and suggest that concomitant PI3Kα inhibition could play an auxiliary role.
Insights
Partial inhibition of phosphoinositide 3-kinase (PI3K) extends longevity. Selective PI3K-alpha inhibition increases energy expenditure and reduces obesity, suggesting a key role in metabolic health.
Area of Science:
- Longevity research
- Metabolic regulation
- Pharmacology
Background:
- Partial inhibition of PI3K is a conserved longevity-extending strategy.
- PI3K inhibition improves metabolism, increasing energy expenditure and reducing obesity.
- A dual PI3K inhibitor (CNIO-PI3Ki) previously reduced obesity in mice and monkeys without toxicity.
Purpose of the Study:
- To dissect the roles of PI3K-alpha and PI3K-delta isoforms in metabolic regulation.
- To evaluate the effects of selective PI3K-alpha and PI3K-delta inhibitors on energy expenditure and body weight.
- To compare the efficacy of single-isoform inhibition versus dual inhibition.
Main Methods:
- Utilized selective inhibitors: BYL-719 (PI3K-alpha) and GS-9820 (PI3K-delta).
- Treated normal and obese (ob/ob) mice with the selective inhibitors.
- Assessed changes in energy expenditure and body weight.
Main Results:
- PI3K-alpha inhibition (BYL-719) increased energy expenditure in normal mice and reduced body weight in obese mice.
- PI3K-delta inhibition (GS-9820) did not produce these metabolic effects.
- Higher doses of BYL-719 were needed compared to the dual inhibitor, suggesting PI3K-delta may play an auxiliary role.
Conclusions:
- PI3K-alpha inhibition is sufficient to increase energy expenditure and reduce obesity.
- Concomitant PI3K-alpha and PI3K-delta inhibition may be more beneficial than PI3K-alpha inhibition alone.
- Targeting PI3K-alpha offers a potential therapeutic strategy for obesity and metabolic disorders.
