Variation in the Adiponutrin Gene Influences Its Expression and Associates With Obesity

Abstract

Adiponutrin is one of three recently identified adipocyte lipases. Surprisingly, these proteins also retain transacylase activity, a hitherto unknown pathway of triacylglycerol synthesis in the adipocytes. This may enable them to participate in both anabolic and catabolic processes. The adiponutrin gene (ADPN) is downregulated by fasting and upregulated by refeeding, suggesting a role in lipogenesis. Experiments in human adipocytes confirmed that the gene is upregulated in response to insulin in a glucose-dependent fashion. Obese subjects had increased levels of subcutaneous and visceral abdominal adipose tissue ADPN mRNA. Visceral ADPN mRNA expression was correlated to measures of insulin sensitivity (fasting insulin and homeostasis model assessment). We also studied genetic variation in ADPN and its relation to obesity, lipolysis, and mRNA expression. Two ADPN polymorphisms showed association with obesity. Carriers of the obesity-associated variants showed a lesser increase in the levels of adipose tissue ADPN mRNA and an increased basal lipolysis. Our results suggest that obese subjects that are insulin resistant and/or carriers of the obesity-associated ADPN alleles fail to upregulate the gene and that upregulation of adiponutrin may be an appropriate response to orchestrate energy excess. Diabetes 55: 826 -833, 2006 O besity is a growing health problem associated with development of type 2 diabetes and coronary heart disease. Obesity results from interaction between genetic, environmental, and psychosocial factors. Collectively, these factors alter the balance between energy intake and expenditure (1-3). Energy is stored as triacylglycerol in adipose tissue found at subcutaneous or visceral abdominal sites. The release of energy is governed by several circulating factors, including insulin, cortisol, growth hormone, and cathecholamines, ultimately by regulating the rate of lipolysis (4). Hormone-sensitive lipase (HSL), an adipocyte triacyland diacylglycerol lipase, is believed to be the rate-limiting enzyme in the lipolytic process. However, recent findings have identified three different proteins that seem to complement HSL, particularly concerning triacylglycerol hydrolysis under nonstimulated conditions (4 -8). Surprisingly, these proteins also exhibit transacylase activity (6). This may enable them to participate in both lipolysis and lipogenesis, in the latter case defining a previously unknown pathway of triglyceride synthesis in adipocytes.The expression of one of these proteins, a membraneassociated protein called adiponutrin, is increased during adipogenesis and strongly influenced by nutritional status (5). In both rodents and humans in vivo and in mice preadipocyte cell lines in vitro, fasting results in very low or undetectable adiponutrin mRNA levels, whereas refeeding, particularly with a carbohydrate-rich diet, increases expression (5,9 -13). This indicates that adiponutrin may promote adipocyte energy storage or recycling and plays an anabolic lipogenic rather than catabolic lipolytic rol...

Obesity and polymorphisms in genes regulating human adipose tissue

“…95,96 Obese subjects have been reported to have either increased or unchanged levels of abdominal adipose tissue ADPN mRNA levels. 95,97 Two ADPN intronic polymorphisms are associated with obesity. 97 Carriers of the obesity-associated variants display a lower increase in levels of adipose tissue ADPN mRNA and increased basal lipolysis compared to non-carriers.…”

“…95,97 Two ADPN intronic polymorphisms are associated with obesity. 97 Carriers of the obesity-associated variants display a lower increase in levels of adipose tissue ADPN mRNA and increased basal lipolysis compared to non-carriers. 97 Perilipin (PLIN) is a phosphoprotein that coats the surface of intracellular lipid droplets in adipocytes and protects them against hydrolysis.…”

Diet-induced obesity affects expression of adiponutrin/PNPLA3 and adipose triglyceride lipase, two members of the same family

“…Adiponutrin mRNA levels were determined in fed, fasted and re-fed animals, as both stimuli (fasting/re-feeding) produce important acute changes in adiponutrin expression. 2,[8][9][10] ATGL levels were only determined in fed and fasted animals because fasting is the most important stimulus affecting the expression of the ATGL gene, 7,18,19 while 3 or 12 h refeeding after fasting does not produce any change in the ATGL mRNA levels attained during fasting. 36,37 Total RNA was extracted using Tripure reagent (Roche, Barcelona, Spain) according to the instructions provided by the supplier.…”

“…[21][22][23] Adiponutrin and ATGL mRNA expression has been described to be altered in adipose tissue of animal models of genetic obesity, 2,7,10 and it has been demonstrated that two human adiponutrin polymorphisms are associated with obesity. 9,24 In addition, our group has reported that adiponutrin nutritional regulation is impaired in obese Zucker rats 10 and that fasting upregulation of ATGL in white adipose tissue is impaired in old rats, which could be related to the weight gain that occurs with aging. 19 However, the studies relating adiponutrin and ATGL expression with obesity have been carried out mainly using genetic models of obesity.…”

“…Its expression sharply decreases in adipose tissue after fasting and is strongly upregulated by feeding [2][3][4][5] through the mediation of insulin and glucose release. 2,[8][9][10] In vitro suppression or overexpression of adiponutrin in adipocytes, as well as its global targeted deletion in mice, does not affect triacylglycerol content or energy homeostasis. 8,11,12 Thus, although it can have lipolytic/ lipogenic capacity, the function of this protein remains unclear.…”