Endocrine Abstracts

Partial inhibition of PI3K is one of the best-validated and evolutionary conserved manipulations to extend longevity. PI3K is a master regulator of anabolism and the best validated beneficial effects of reduced PI3K are related to metabolism and include increased energy expenditure, reduced nutrient storage, and protection from obesity. We have found that a dual chemical inhibitor of the α and δ PI3K isoforms (CNIO-PI3Ki) reduces obesity in mice and monkeys, without evident toxic effects after long-term treatment. Similar effects have been observed with the pan-PI3K inhibitor GDC-0941.The doses used only achieved a mild inhibition of PI3K activity and therfore did not result in significant hyperglycemic peaks. More recently, we have found that the selective PI3Kα inhibitor BYL-719 (also known as alpelisib) also has anti-obesity activity. This is in contrast to the selective PI3Kδ inhibitor GS-9820 (also known as acalisib), which had no effect. However, the dose of BYL-719 required to reduce obesity was 10-times higher than the equivalent dose of CNIO-PI3Ki, which could suggest that simultaneous inhibition of PI3K α and δ is more effective than single inhibition of the α isoform. In summary, we conclude that inhibition of PI3Kα is sufficient to reduce anabolism, increase energy expenditure and reduce obesity, and suggest that concomitant PI3Kδ inhibition could play an auxiliary role.