Proline oxidase–adipose triglyceride lipase pathway restrains adipose cell death and tissue inflammation

Abstract

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...

Inhibition of Age-Related Cytokines Production by ATGL: A Mechanism Linked to the Anti-Inflammatory Effect of Resveratrol

“…As reported in Figure 3(a), ATGL lacking cells [ATGL(−)] displayed impaired PPAR α expression and higher expression of TNF α and IL-6 than controls, in line with what we observed in C 2 C 12 myotubes (Figure 2(b)) and previously revealed on primary adipocytes and mouse embryonic fibroblasts [5]. However, contrary to what we observed in 21-day-old adipocytes, RSV was unable to revert the induction of TNF α and IL-6 in ATGL(−) adipocytes; but rather it unexpectedly further upregulated their mRNA expression, indicating an enhancement of NF κ B activity (Figure 3(a)).…”

“…Therefore, on the basis of these data we can postulate that the failure of ATGL-mediated stress response observed in 24-month-old and 21-day-old adipocytes triggers the production of proinflammatory cytokines. In agreement with this idea, higher levels of inflammatory markers were observed upon ATGL downregulation in vitro and in vAT of ATGL KO mice [5]. The modulatory action of ATGL on tissue inflammation has been reported recently also in cardiac muscle [15].…”

Adipose Tissue and FoxO1: Bridging Physiology and Mechanisms

“…As concerns the activation of FoxO1 in starved adipocytes, the mitochondrial ROS were identified as the triggering molecules. More specifically, activation of the proline oxidase/dehydrogenase (POX/PRODH), a mitochondrial inner-membrane enzyme that starts proline catabolism, contributes to generate ROS under nutrient shortage [89]. In support of the relevance of ROS signaling in FoxO1 nuclear translocation in adipocytes and lipolysis activation were the results with the antioxidant N-acetylcysteine, which abrogated both phenomena [27,90].…”

Structure, Function and Metabolism of Hepatic and Adipose Tissue Lipid Droplets: Implications in Alcoholic Liver Disease

“…ATGL activity is normally inhibited by insulin [154] and it has been suggested that insulin resistance that develops with chronic ethanol abuse could mechanistically be related to increased WAT lipolysis [152]. Further ethanol-induced oxidative stress [155, 156] can also induce ATGL expression in a FoxO1-dependent manner [157]. …”