Aly; 2Universita Telematica di Roma San Raffaele, By means of di Val Cannuta
Aly; 2Universita Telematica di Roma San Raffaele, By means of di Val Cannuta, Rome 00166, Italy and 3IRCCS San Raffaele, Biochemistry of Ageing, By means of di Val Cannuta, Rome 00166, Italy Corresponding author: K Aquilano, Division of Biology, University of Rome Tor Vergata, By way of della Ricerca Scientifica, Rome 00133, Italy. Tel: 39 06 7259 4312, 39 06 7259 4311; E-mail: katia.aquilanouniroma2.it or MR Ciriolo, Division of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, Rome, 00133, Italy. Tel: 39 06 7259 4369; 39 06 7259 4311; E-mail: ciriolobio.uniroma2.it Keywords and phrases: aging; ATGL; lipid metabolism; adipose tissue; autophagy Abbreviations: ATGL, adipose triglyceride lipase; Lipa, lysosomal acid lipase; FoxO1, forkhead homeobox sort protein O1; EGFP, enhanced green fluorescent protein; TG, triglycerides; FFAs, absolutely free fatty acids; NR, nutrient restriction; Metf, metformin; AT, adipose tissue; ORO, Oil Red-O; LDs, lipid dropletsReceived 29.7.13; revised 11.9.13; accepted 13.9.13; Edited by G MelinoNR and metformin induce lipophagy in adipocytes D Lettieri Barbato et aldifferentiation.15 Accordingly, enhanced autophagy in AT has been linked with obesity and type-2 diabetes in mice and humans.16,17 Additional recently, autophagy has been implicated in LDs degradation in fat cells both under basal and hormonestimulated lipolysis,18 thus implicating it in FFAs release from AT and possibly fat mass reduce. It can be now clearly evident that an imbalance between the hydrolysis and synthesis of TG is involved in excessive fat pad accumulation and essential for the improvement of age-related metabolic issues. For this reason, the manipulation of lipid metabolism at pharmacological level represents an desirable tactic to extend life and healthspan. Amongst the emerging antiaging drugs, metformin (Metf) is integrated.191 It is actually presently utilized as an oral antidiabetic specifically in overweight and obese subjects.22 In addition to the well-recognized hypoglycemizing action, because of its capability to enhance peripheral glucose uptake, Metf has been found to induce autophagy.23,24 Metf was shown to lead to a mild energetic drop as a result mimicking a NR-related state.19,25 Notwithstanding, the precise mechanisms behind the geroprotective effect of Metf are not nonetheless clearly established, specifically those related to regulation of lipid metabolism in AT. Despite adipocytes are deemed the key cells capable to accumulate lipids within the form of TG, scarce evidence exists with regards to the function of autophagy in regulation of TG breakdown. In this function, we’ve got investigated the role of FoxO1 in IL-12 Molecular Weight modulating lysosomal lipid CYP1 web catabolism throughout NR in adipocytes and tested the possible use of Metf as a pro-lypolytic drug by way of the induction of FoxO1-mediated lipophagy in AT.Benefits FoxO1 modulates Lipa expression upon nutrient restriction and Metf treatment in adipocytes. The nutrientsensing FoxO1 transcription factor regulates ATGL expression promoting lipid catabolism in adipose cells.9 Interestingly, it has been recently reported that the FoxO1 homolog (dFOXO) induces lysosomal acid lipase (Lipa) in D. melanogaster participating in lipid catabolism for the duration of fasting.26 Around the basis of this proof, we asked regardless of whether NR could induce Lipa expression in mammalian adipocytes and FoxO1 could mediate this occasion. In 3T3-L1 murine adipocytes, we observed a progressive enhance of FoxO1 protein level during NR (Figure 1a), which was accompanied by a time-dependent induction of Lipa and ATG.
