PI3Kα inhibition reduces obesity in mice.
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.
Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid E28029, Spain.
Elena
E
Lopez-Guadamillas
Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid E28029, Spain.
Maribel
M
Muñoz-Martin
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Madrid E28029, Spain.
Sonia
S
Martinez
Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Madrid E28029, Spain.
Joaquin
J
Pastor
Bioactive Products and Metabolic Syndrome Group, Madrid Institute of Advanced Studies (IMDEA) in Food, CEI UAM+CSIC, Madrid E28049, Spain.
Pablo J
PJ
Fernandez-Marcos
Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid E28029, Spain.
Manuel
M
Serrano
D000818:Animals; D001835:Body Weight / Q000187:drug effects*; D004734:Energy Metabolism / Q000187:drug effects*; D008297:Male; D051379:Mice; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; C585539:Alpelisib
PI3K; diabetes; energy expenditure; metabolism; obesity