[Abstract unavailable

Finding new molecular pathways and strategies modulating lipolysis in adipocytes is an attractive goal of the current research. Indeed, it is becoming clear that several human age-related pathologies are caused by adipose tissue expansion and altered lipid metabolism. In the present work, we show that transcription factor forkhead homeobox type protein O1 (FoxO1) is upregulated by nutrient restriction (NR) in adipocytes and exerts the transcriptional control of lipid catabolism via the induction of lysosomal acid lipase (Lipa). An increased autophagy and colocalization of lipid droplets (LDs) with lysosomes was observed implying lipophagy in Lipa-mediated LDs degradation. Interestingly, we found that metformin (Metf), a biguanide drug commonly used to treat type-2 diabetes, exerts effects comparable to that of NR. Actually, it was able to elicit FoxO1-dependent Lipa induction as well as LDs degradation through lipophagy. Moreover, we demonstrate that, during NR or Metf treatment, free fatty acids released by Lipa are directed toward AMP-activated protein kinase-mediated mitochondrial oxidation, thus maintaining energetic homeostasis in adipocytes. In conclusion, our data show that lysosomal-mediated lipid catabolism is activated by NR in adipocytes and give further support to the use of Metf as a NR mimetic to combat age-related diseases associated with altered lipid metabolism.

The nutrient-sensing lipolytic enzyme adipose triglyceride lipase (ATGL) has a key role in adipose tissue function, and alterations in its activity have been implicated in many age-related metabolic disorders. In adipose tissue reduced blood vessel density is related to hypoxia state, cell death and inflammation. Here we demonstrate that adipocytes of poorly vascularized enlarged visceral adipose tissue (i.e. adipose tissue of old mice) suffer from limited nutrient delivery. In particular, nutrient starvation elicits increased activity of mitochondrial proline oxidase/dehydrogenase (POX/PRODH) that is causal in triggering a ROS-dependent induction of ATGL. We demonstrate that ATGL promotes the expression of genes related to mitochondrial oxidative metabolism (peroxisome proliferator-activated receptor-a, peroxisome proliferator-activated receptor-c coactivator-1a), thus setting a metabolic switch towards fat utilization that supplies energy to starved adipocytes and prevents cell death, as well as adipose tissue inflammation. Taken together, these results identify ATGL as a stress resistance mediator in adipocytes, restraining visceral adipose tissue dysfunction typical of age-related metabolic disorders. A growing body of evidence emerges on the molecular mechanisms that determine how ageing impacts fat tissue function and how this, in turn, leads to age-related disorders.1,2 During ageing while the subcutaneous fat progressively decrease, visceral adipose tissue (AT) bed expands and resident adipocytes become relatively hypoxic because of the inability of the vasculature to keep pace with AT remodelling.2-9 Suppression of vascularization generally results in enhanced tissue metabolic perturbations such as apoptosis and inflammation, as a consequence of hypoxia and reduced nutrient delivery. 10-15Adipose triglyceride lipase (ATGL) is a nutrient-sensing lipolytic enzyme expressed in most tissues of the body with highest mRNA levels and enzyme activity found in white and brown AT. 16 The important role of ATGL in lipolysis became evident from observations in ATGL knockout (KO) mice, which accumulate triglycerides (TGs) in essentially all organs.16 ATGL selectively performs the rate-limiting initial step in TG hydrolysis releasing the first fatty acid (FA) from the glycerol backbone and produces diacylglycerol (DAG). DAG is promptly hydrolyzed by hormone-sensitive lipase (HSL) to generate monoacylglycerol and a second FA. Monoacylglycerol lipase (MGL) then hydrolyzes monoacylglycerol, thus producing glycerol and a third FA. The FAs generated by white AT can enter the circulation and be taken up by other tissue for b-oxidation and subsequent ATP generation. Alterations in ATGL activity have been found in many age-related metabolic disorders including insulin resistance states. 17,18 Recently, ATGL-mediated fat catabolism has been involved in the activation of peroxisome proliferator-activated receptor-a (PPARa)/peroxisome proliferator-activated receptor-g coactivator-1a (PGC-1a) network, sustaining a more efficient...

Neuronal nitric oxide synthase (nNOS) and peroxisome proliferator activated receptor c co-activator 1a (PGC-1a) are two fundamental factors involved in the regulation of skeletal muscle cell metabolism. nNOS exists as several alternatively spliced variants, each having a specific pattern of subcellular localisation. Nitric oxide (NO) functions as a second messenger in signal transduction pathways that lead to the expression of metabolic genes involved in oxidative metabolism, vasodilatation and skeletal muscle contraction. PGC1a is a transcriptional coactivator and represents a master regulator of mitochondrial biogenesis by promoting the transcription of mitochondrial genes. PGC-1a can be induced during physical exercise, and it plays a key role in coordinating the oxidation of intracellular fatty acids with mitochondrial remodelling. Several lines of evidence demonstrate that NO could act as a key regulator of PGC-1a expression; however, the link between nNOS and PGC-1a in skeletal muscle remains only poorly understood. In this Commentary, we review important metabolic pathways that are governed by nNOS and PGC-1a, and aim to highlight how they might intersect and cooperatively regulate skeletal muscle mitochondrial and lipid energetic metabolism and contraction.

Non-enzymatic antioxidant capacity (NEAC) represents a sensitive biomarker measuring the in vivo antioxidant potential of vegetable foods. To evaluate the effectiveness of plant-derived foods and beverages on the plasma non-enzymatic antioxidant system, we analysed all literature published upto May 2010. Data were extracted by two authors independently, and the effect size was summarised using standardised mean differences by a random-effects model. For the analysis, eighty-eight studies were included, reporting a total number of 122 interventions and involving 2890 subjects. There was overall evidence of the effectiveness of fruit, vegetables, dietary patterns based on plant foods, red wine and tea in increasing plasma NEAC. No changes were found for chocolate and fruit juices. We observed an overall effect size three times higher in subjects with risk factors when compared with healthy subjects. Total radical-trapping antioxidant parameter, oxygen radical absorbance capacity and ferric-reducing antioxidant power methods showed a similar increase in plasma NEAC following dietary supplementation, whereas Trolox equivalent antioxidant capacity did not respond to dietary supplementation. Data from the present meta-analysis show that plant-derived foods represent an effective strategy to enhance an endogenous antioxidant network in humans. This is particularly evident in the presence of oxidative stress-related risk factors.Key words: Plant foods: Antioxidant capacity: Oxidative stress: Human nutrition: Flavonoids A large body of epidemiological evidence strongly suggests a primary role for plant-based dietary patterns in reducing the risk of diseases (1) . However, the identification of the molecules involved in the protective effect of vegetable food and their mechanism of action is far from being understood (2) . Phytochemicals contained in the plant kingdom are hypothesised to reduce free radical-related cellular damage, potentiating redox defence of the body and contributing to reduction of the risk of developing oxidative stress-related diseases (3) . On the basis of the so-called 'antioxidant hypothesis', long-term clinical trials have been developed to investigate the effect of supplementation with natural antioxidants to reduce the development of oxidative stress-related diseases. However, clinical trials have produced extremely contrasting results, highlighting the difficulties in mimicking the healthy effect of plant-derived foods through the usage of natural supplements (4,5) . Moreover, a negative effect in increasing mortality rates of overall mortality and cancer has been observed in specific meta-analyses, raising strong concerns about the use of galenic antioxidants for disease prevention (5,6)