Adipose Triglyceride Lipase Is Implicated in Fuel- and Non-fuel-stimulated Insulin Secretion

Peyot, Marie‐Line; Guay, Claudiane; Latour, Martin G.; Lamontagne, Julien; Lussier, Roxane; Pineda, Marco; Ruderman, Neil B.; Haemmerle, Guenter; Zechner, Rudolf; Joly, Etienne; Madiraju, S.R. Murthy; Poitout, Vincent; Prentki, Marc

doi:10.1074/jbc.m109.006650

Cited by 75 publications

(90 citation statements)

References 69 publications

(74 reference statements)

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“…However, this view was challenged by the phenotype of ATGL-deficient mice, which showed increased glucose and insulin tolerance despite massive TG accumulation in SM. The severe decline of circulating insulin levels of ATGL-deficient mice is believed to be the consequence of both defective pancreatic insulin secretion and increased tissue insulin sensitivity (36,42). Defective adipose tissue lipolysis in ATGL-deficient mice provoked a decreased availability of FA as oxidative fuel that could favor organ glucose utilization in line with the Randle (34) hypothesis.…”

Section: Discussionmentioning

confidence: 51%

Functional Cardiac Lipolysis in Mice Critically Depends on Comparative Gene Identification-58

Zierler

Jaeger

Pollak

et al. 2013

Journal of Biological Chemistry

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Background:The role of CGI-58 in muscle triacylglycerol catabolism is unknown. The presence of CGI-58 increases the lipolytic activity of adipose triglyceride lipase (ATGL). Results: Muscle-specific CGI-58 deficiency causes muscle steatosis and cardiac dysfunction despite elevated ATGL protein expression. Conclusion: Muscle lipolysis critically depends on both CGI-58 and ATGL. Significance: Muscle CGI-58 deficiency provokes severe cardiac steatosis and dysfunction.

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Section: Discussionmentioning

confidence: 51%

Functional Cardiac Lipolysis in Mice Critically Depends on Comparative Gene Identification-58

Zierler

Jaeger

Pollak

et al. 2013

Journal of Biological Chemistry

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“…LAL is expressed in pancreatic beta cells Several lipases are expressed in beta cells [13,16], although Hsl/Lipe and Atgl/Pnpla2 have generally been considered the most abundant. There is, however, residual lipase activity in mouse models of HSL and ATGL depletion, so additional enzymes may contribute to lipid hydrolysis in pancreatic beta cells [11,13].…”

Section: Resultsmentioning

confidence: 99%

“…There is, however, residual lipase activity in mouse models of HSL and ATGL depletion, so additional enzymes may contribute to lipid hydrolysis in pancreatic beta cells [11,13]. To investigate lipase expression in the mouse pancreatic beta cell line, MIN6, we carried out RT-PCR (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The mechanisms underlying amplification are much less well understood than those of initiation [5][6][7][8] but the turnover of endogenous lipid stores, and consequent generation of a lipid signalling molecule, is one possibility [5,6,9,10]. Evidence for this includes the inhibition of GSIS by deletion of neutral lipases, such as hormone-sensitive lipase (HSL) [11,12] and adipose triglyceride lipase (ATGL) [13], or their pharmacological blockade using the pan lipase inhibitor orlistat [14]. In addition, at least one substrate of the neutral lipases, triacylglycerol (TG), is hydrolysed during GSIS, as witnessed by an acute glucose-stimulated, and orlistat-inhibited, release of glycerol from beta cells [9,15,16].…”

Section: Introductionmentioning

confidence: 99%

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Lysosomal acid lipase and lipophagy are constitutive negative regulators of glucose-stimulated insulin secretion from pancreatic beta cells

et al. 2013

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Aims/hypothesis Lipolytic breakdown of endogenous lipid pools in pancreatic beta cells contributes to glucosestimulated insulin secretion (GSIS) and is thought to be mediated by acute activation of neutral lipases in the amplification pathway. Recently it has been shown in other cell types that endogenous lipid can be metabolised by autophagy, and this lipophagy is catalysed by lysosomal acid lipase (LAL). This study aimed to elucidate a role for LAL and lipophagy in pancreatic beta cells. Methods We employed pharmacological and/or genetic inhibition of autophagy and LAL in MIN6 cells and primary islets. Insulin secretion following inhibition was measured using RIA. Lipid accumulation was assessed by MS and confocal microscopy (to visualise lipid droplets) and autophagic flux was analysed by western blot. Results Insulin secretion was increased following chronic (≥8 h) inhibition of LAL. This was more pronounced with glucose than with non-nutrient stimuli and was accompanied by augmentation of neutral lipid species. Similarly, following inhibition of autophagy in MIN6 cells, the number of lipid droplets was increased and GSIS was potentiated. Inhibition of LAL or autophagy in primary islets also increased insulin secretion. This augmentation of GSIS following LAL or autophagy inhibition was dependent on the acute activation of neutral lipases. Conclusions/interpretation Our data suggest that lysosomal lipid degradation, using LAL and potentially lipophagy, contributes to neutral lipid turnover in beta cells. It also serves as a constitutive negative regulator of GSIS by depletion of substrate for the non-lysosomal neutral lipases that are activated acutely by glucose.

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“…Several groups have demonstrated an important role for lipolysis and glycerolipid/free fatty acid cycling in the islet, and products of this pathway have been shown to stimulate insulin secretion (52,53). As such, we examined the effect of LXR activation on lipolysis in the islet and found the expression of two key enzymes involved in glycerolipid/free fatty acid cycling in the islet, hormone-sensitive lipase, and adipose triglyceride lipase (54,55) to be increased. Furthermore, our data showed a strong trend toward increased lipolysis in LXR-treated human islets.…”

Section: Discussionmentioning

confidence: 99%

Liver X Receptor Agonists Augment Human Islet Function through Activation of Anaplerotic Pathways and Glycerolipid/Free Fatty Acid Cycling

Ogihara

Chuang

Vestermark

et al. 2010

Journal of Biological Chemistry

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Recent studies in rodent models suggest that liver X receptors (LXRs) may play an important role in the maintenance of glucose homeostasis and islet function. To date, however, no studies have comprehensively examined the role of LXRs in human islet biology. Human islets were isolated from non-diabetic donors and incubated in the presence or absence of two synthetic LXR agonists, TO-901317 and GW3965, under conditions of low and high glucose. LXR agonist treatment enhanced both basal and stimulated insulin secretion, which corresponded to an increase in the expression of genes involved in anaplerosis and reverse cholesterol transport. Furthermore, enzyme activity of pyruvate carboxylase, a key regulator of pyruvate cycling and anaplerotic flux, was also increased. Whereas LXR agonist treatment up-regulated known downstream targets involved in lipogenesis, we observed no increase in the accumulation of intra-islet triglyceride at the dose of agonist used in our study. Moreover, LXR activation increased expression of the genes encoding hormone-sensitive lipase and adipose triglyceride lipase, two enzymes involved in lipolysis and glycerolipid/free fatty acid cycling. Chronically, insulin gene expression was increased after treatment with TO-901317, and this was accompanied by increased Pdx-1 nuclear protein levels and enhanced Pdx-1 binding to the insulin promoter. In conclusion, our data suggest that LXR agonists have a direct effect on the islet to augment insulin secretion and expression, actions that should be considered either as therapeutic or unintended side effects, as these agents are developed for clinical use.The liver X receptors (LXRs), 2 LXR␣ (NR1H3), and LXR␤ (NR1H2) are members of the nuclear hormone receptor superfamily and function to integrate lipid metabolic and inflammatory signaling (1). Upon binding to oxysterol ligands and heterodimerization with retinoid X receptors, LXRs bind to conserved LXR-responsive elements in target genes to regulate their expression. LXRs augment lipogenesis through transcriptional up-regulation of the genes encoding sterol regulatory binding-protein 1c (SREBP-1c), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD). They also function to regulate reverse cholesterol transport through the induction of genes encoding the ATP binding cassette transporters (ABCs) (2, 3). Furthermore, LXRs contribute to the regulation of innate immunity and have anti-inflammatory effects that are mediated through repression of several downstream targets of NF-B (nuclear factor light chain-enhancer of activated B cells) (4, 5).In addition to these well described effects on lipid metabolism and inflammation, LXRs also appear to play a role in the maintenance of glucose homeostasis. Oral administration of synthetic LXR agonists to diabetic rodent models, including obese db/db mice and Zucker fatty rats, results in improved glucose tolerance (6, 7). These effects of LXR agonists appear to arise in part from actions on insulin-sensitive tissues, as LXRs have been shown to enhance...

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Adipose Triglyceride Lipase Is Implicated in Fuel- and Non-fuel-stimulated Insulin Secretion

Cited by 75 publications

References 69 publications

Functional Cardiac Lipolysis in Mice Critically Depends on Comparative Gene Identification-58

Functional Cardiac Lipolysis in Mice Critically Depends on Comparative Gene Identification-58

Lysosomal acid lipase and lipophagy are constitutive negative regulators of glucose-stimulated insulin secretion from pancreatic beta cells

Liver X Receptor Agonists Augment Human Islet Function through Activation of Anaplerotic Pathways and Glycerolipid/Free Fatty Acid Cycling

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