Signalling pathways underlying metabolic adaptation of adipocytes to nutrient limitation

Finding new molecular pathways and strategies modulating lipolysis in adipocytes is an attractive goal of the current research. In adipose tissue reduced blood vessel density occurring during aging, is related to hypoxia state, cell death and inflammation. Here it has been demonstrated that adipocytes of poorly vascularized enlarged visceral adipose tissue (i.e. adipose tissue of old mice) suffer from limited nutrient delivery. It has been showed that in adipocytes transcription factor FoxO1 is up-regulated by nutrient restriction (NR) via a ROS-dependent pathway involving the activation of mitochondrial proline oxidase (POX). Activated FoxO1 exerts the transcriptional control of lipid catabolism via the induction of lysosomal acid lipase (Lipa) and Adipose Triglyceride Lipase (ATGL). Liberated fatty acids (FAs) participate in signal transduction promoting the expression of genes related to mitochondrial oxidative metabolism (peroxisome proliferator-activated receptor-α, peroxisome proliferator-activated receptorγ coactivator-1α), thus setting a metabolic switch towards fat utilization. Furthermore, an increased autophagy and co-localization of lipid droplets (LDs) with lysosomes was observed implying lipophagy in NR-mediated LDs degradation. Interestingly, it has been found that metformin treatment, a biguanide drug commonly used to cure type-2 diabetes, recapitulates the metabolic adaptation to NR in adipose tissue. Actually, it is able to elicit FoxO1dependent ATGL and Lipa induction as well as LDs degradation through lipophagy. A crucial role of AMP-dependent protein kinase (AMPK) in sustaining FAs oxidation and up-regulating lipid oxidative genes in adipocytes has been also documented. In particular, it has been demonstrated that, besides promoting lipid signalling, FAs released by ATGL and Lipa are directed towards AMPK-mediated mitochondrial oxidation, thus maintaining energetic homeostasis, preventing adipocyte death and adipose tissue inflammation. In conclusion, our data show that cytoplasmic and lysosomalmediated lipid catabolism are activated by NR in adipocytes and give further support to the use of metformin as a NR mimetic to combat age-related diseases associated with altered lipid metabolism.