Desnutrin, an Adipocyte Gene Encoding a Novel Patatin Domain-containing Protein, Is Induced by Fasting and Glucocorticoids

Abstract

We have used rat cDNA microarrays to identify adipocyte-specific genes that could play an important role in adipocyte differentiation or function. Here, we report the cloning and identification of a 2.0-kb mRNA coding for a putative protein that we have designated as desnutrin. The novel gene is expressed predominantly in adipose tissue, and its expression is induced early during 3T3-L1 adipocyte differentiation. Desnutrin mRNA levels were regulated by the nutritional status of animals, being transiently induced during fasting. In vitro desnutrin gene expression was up-regulated by dexamethasone in a dose-dependent manner but not by cAMP, suggesting that glucocorticoids could mediate the increase in desnutrin mRNA levels observed during fasting. Desnutrin mRNA codes for a 486-amino acid putative protein containing a patatin-like domain, characteristic of many plant acyl hydrolases belonging to the patatin family. Confocal microscopy of enhanced green fluorescent protein-tagged desnutrin protein-transfected cells showed that the fusion protein localized in the cytoplasm. Moreover, cells overexpressing desnutrin by transfection showed an increase in triglyceride hydrolysis. Interestingly, we also found that the desnutrin gene expression level was lower in ob/ob and db/db obese mouse models. Overall, our data suggest that the newly identified desnutrin gene codes for an adipocyte protein that may function as a lipase and play a role in the adaptive response to a low energy state, such as fasting, by providing fatty acids to other tissues for oxidation. In addition, decreased expression of desnutrin in obesity models suggests its possible contribution to the pathophysiology of obesity.Triglycerides serve as the most efficient form of energy storage in times of caloric excess in many organisms. During periods of energy demand, triglycerides can be rapidly mobilized by the hydrolytic action of lipases, releasing free fatty acids that are oxidized to meet the energy requirement of the organism.

Human adipose triglyceride lipase (PNPLA2) is not regulated by obesity and exhibits low in vitro triglyceride hydrolase activity

“…This corresponds with previous findings of an increased lipolytic effect of catecholamines in visceral fat cells of obese subjects [19]. Altogether, these findings not only suggest that nutritional status has a divergent influence on expression levels of the two lipases, but also indicate putative species differences, given the demonstration of induced Atgl expression after fasting and glucocorticoid administration in mice [8]. As the present study material consists of a limited number of male subjects, it remains to be established whether a subject's sex influences the expression levels of HSL and ATGL.…”

“…However, HSL knock-out mice have residual lipolytic activity [4,5], which may be attributed to an additional lipase with high affinity for triglycerides [6,7]. Accordingly, a novel adipocyte-specific lipase termed adipose triglyceride lipase (ATGL, now known as patatin-like phospholipase domain containing 2 [PNPLA2]), the product of Pnpla2, and alternatively designated iPLA 2 ζ or desnutrin, was recently identified using different strategies [8][9][10]. The murine ATGL-protein consists of 486 amino acids, whereas the corresponding human form is a 506-amino acid protein.…”

Metabolic action of peroxisome proliferator-activated receptor γ agonism in rats with exogenous hypercorticosteronemia

“…39 The present findings strongly suggest that ATGL constitutes an additional level of modulation of lipolysis by GC, given that the enzyme has very recently been established as a major determinant of lipolytic rates in adipose tissue. [46][47][48] Whether additivity of HiCORT and RSG is exerted via a common or distinct pathways and whether these are direct or indirect remain to be established. Thirdly, RSG exerted its expected stimulatory effect on the expression levels of fatty acid esterification (DGAT1), recycling (GyK, PEPCK), and oxidation genes (mCPT1, ACO), 11,42,44 whereas those genes were unaffected by high CORT.…”

PPARγ agonism increases rat adipose tissue lipolysis, expression of glyceride lipases, and the response of lipolysis to hormonal control

“…Recent studies showing that adipocytes from HSL knockout mice retain a marked basal and adrenergically stimulated lipolysis and accumulate diglycerides after stimulation of lipolysis demonstrated that HSL is not the sole lipase involved in triglyceride catabolism [9][10][11]. Three independent groups have discovered a protein-alternatively termed adipose triglyceride lipase (ATGL) [12], desnutrin [13] or calcium-independent phospholipase A 2 /lipase ζ (iPLA 2 ζ) [14]-that fulfils all the predicted characteristics of this new lipase: a preference for the hydrolysis of the first triglyceride ester bond, drastically reduced lipolysis following antibody or antisense ATGL inhibition, and enhanced basal and isoproterenol-stimulated lipolysis following ATGL overexpression [15]. ATGL therefore plays a particularly important role in the control of basal lipolysis, but also appears to participate in the lipolytic response to adrenergic stimulation [16].…”