Nuevas funciones del supresor de tumores PTEN en metabolismo y envejecimiento

Resumen

Decreased signalling of insulin and Igf1 increases longevity across animal evolution, including mammals. The effects of insulin/Igf1 on aging are intracellularly mediated by the PI3K/Akt/Foxo pathway in worms and flies. Here, we have extended this paradigm to mammals by directly attenuating PI3K signalling in mice through moderate overexpression of the tumour suppressor Pten under its own transcriptional regulatory elements. Ptentg mice have lower levels of PI3K signalling, are protected from cancer, and present a significant extension of lifespan that is independent of their lower cancer incidence. Interestingly, Ptentg mice show an elevated rate of energy expenditure, which is accompanied by decreased adiposity and protection from highfat diet-induced liver damage. Accounting for the elevated energy expenditure, we found that brown and white adipose tissues from Ptentg mice express high levels of the uncoupling protein Ucp1 and its transcriptional activator Pgc1¿, and the relative uptake of glucose by brown adipose tissue (BAT) is constitutively increased. Also, the BAT of Ptentg mice contains lower levels of phosphorylated Akt, which is a negative regulator of both Pgc1¿ and its critical partner Foxo1. In support of this, a synthetic PI3K inhibitor elevates the expression of Pgc1¿ and Ucp1 in vitro differentiated brown adipocytes, as well as, in the BAT of adult mice. Finally, Ptentg fibroblasts programmed in vitro with Prdm16 and C/Ebpß, master factors for brown adipocyte differentiation, formed ectopic subcutaneous brown adipose pads more efficiently than similarly programmed non transgenic fibroblasts, altogether indicating that the effects of Pten on brown adipocytes are cell autonomous. These observations extend to mammals the evolutionary conserved modulation of organism survival by the PI3K pathway and uncover a role of Pten in promoting energy expenditure by brown adipocytes, thus decreasing the caloric input to the rest of the organism and its associated damage. . In an attempt to translate these results to a pathological setting, we have tested the ability of synthetic PI3K inhibitors (PI3Kis) to decrease adiposity in obese mice. Importantly, diet-induced obese mice treated for two weeks with (PI3Kis) showed the appearance of brown adipocytes within the white adipose tissue, a significant decrease in adiposity, reduction of liver steatosis, and, finally, a significant decrease in body weight. These results provide proof of concept for the therapeutic treatment of obesity with PI3Kis.