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

Reduced lipolysis in hormone-sensitive lipase-deficient mice is associated with impaired glucose-stimulated insulin secretion (GSIS), suggesting that endogenous β-cell lipid stores provide signaling molecules for insulin release. Measurements of lipolysis and triglyceride (TG) lipase activity in islets from HSL−/− mice indicated the presence of other TG lipase(s) in the β-cell. Using real time-quantitative PCR, adipose triglyceride lipase (ATGL) was found to be the most abundant TG lipase in rat islets and INS832/13 cells. To assess its role in insulin secretion, ATGL expression was decreased in INS832/13 cells (ATGL-knockdown (KD)) by small hairpin RNA. ATGL-KD increased the esterification of free fatty acid (FFA) into TG. ATGL-KD cells showed decreased glucose- or Gln + Leu-induced insulin release, as well as reduced response to KCl or palmitate at high, but not low, glucose. The KATP-independent/amplification pathway of GSIS was considerably reduced in ATGL-KD cells. ATGL−/− mice were hypoinsulinemic and hypoglycemic and showed decreased plasma TG and FFAs. A hyperglycemic clamp revealed increased insulin sensitivity and decreased GSIS and arginine-induced insulin secretion in ATGL−/− mice. Accordingly, isolated islets from ATGL−/− mice showed reduced insulin secretion in response to glucose, glucose + palmitate, and KCl. Islet TG content and FFA esterification into TG were increased by 2-fold in ATGL−/− islets, but glucose usage and oxidation were unaltered. The results demonstrate the importance of ATGL and intracellular lipid signaling for fuel- and non-fuel-induced insulin secretion.

[1]  J. Leahy,et al.  Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass , 2009, Diabetologia.

[2]  L. Eliasson,et al.  A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis , 2009, Diabetologia.

[3]  M. Prentki,et al.  The islet β-cell: fuel responsive and vulnerable , 2008, Trends in Endocrinology & Metabolism.

[4]  R. Takayanagi,et al.  The lack of the C-terminal domain of adipose triglyceride lipase causes neutral lipid storage disease through impaired interactions with lipid droplets. , 2008, The Journal of clinical endocrinology and metabolism.

[5]  B. Kemp,et al.  Adipose triglyceride lipase regulation of skeletal muscle lipid metabolism and insulin responsiveness. , 2008, Molecular endocrinology.

[6]  Marc Prentki,et al.  Glycerolipid metabolism and signaling in health and disease. , 2008, Endocrine reviews.

[7]  K. Gillis,et al.  Phosphorylation of SNAP-25 at Ser187 Mediates Enhancement of Exocytosis by a Phorbol Ester in INS-1 Cells , 2008, The Journal of Neuroscience.

[8]  M. Prentki,et al.  A Role for ATP-Citrate Lyase, Malic Enzyme, and Pyruvate/Citrate Cycling in Glucose-induced Insulin Secretion* , 2007, Journal of Biological Chemistry.

[9]  J. R. McMillan,et al.  Novel duplication mutation in the patatin domain of adipose triglyceride lipase (PNPLA2) in neutral lipid storage disease with severe myopathy , 2007, Muscle & nerve.

[10]  K. He,et al.  The transcription factor PAX4 acts as a survival gene in INS-1E insulinoma cells , 2007, Oncogene.

[11]  R. Lehner,et al.  Attenuation of Adipocyte Triacylglycerol Hydrolase Activity Decreases Basal Fatty Acid Efflux* , 2007, Journal of Biological Chemistry.

[12]  R. Zechner,et al.  Adipose Triglyceride Lipase and Hormone-sensitive Lipase Are the Major Enzymes in Adipose Tissue Triacylglycerol Catabolism* , 2006, Journal of Biological Chemistry.

[13]  H. Mulder,et al.  β-Cell Lipases and Insulin Secretion , 2006, Diabetes.

[14]  M. Prentki,et al.  Fatty Acid Signaling in the β-Cell and Insulin Secretion , 2006, Diabetes.

[15]  J. Leahy,et al.  Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling , 2006, Diabetologia.

[16]  F. Ashcroft,et al.  Deletion of Nicotinamide Nucleotide Transhydrogenase , 2006, Diabetes.

[17]  E. Wagner,et al.  Defective Lipolysis and Altered Energy Metabolism in Mice Lacking Adipose Triglyceride Lipase , 2006, Science.

[18]  S. Müller,et al.  Synergy of glucose and growth hormone signalling in islet cells through ICA512 and STAT5 , 2006, Nature Cell Biology.

[19]  I. Artner,et al.  Regulation of the insulin gene by glucose and fatty acids. , 2006, The Journal of nutrition.

[20]  C. Holm,et al.  Glucose-stimulated insulin secretion correlates with beta-cell lipolysis. , 2006, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[21]  S. Müller,et al.  Nuclear translocation of an ICA512 cytosolic fragment couples granule exocytosis and insulin expression in β-cells , 2004, The Journal of cell biology.

[22]  Frank Eisenhaber,et al.  Fat Mobilization in Adipose Tissue Is Promoted by Adipose Triglyceride Lipase , 2004, Science.

[23]  H. Sul,et al.  Desnutrin, an Adipocyte Gene Encoding a Novel Patatin Domain-containing Protein, Is Induced by Fasting and Glucocorticoids , 2004, Journal of Biological Chemistry.

[24]  B. Ahrén,et al.  Glucagon-like Peptide-1 and Islet Lipolysis , 2004, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[25]  A. Pshezhetsky,et al.  Carboxylesterase 3 (EC 3.1.1.1) Is a Major Adipocyte Lipase* , 2004, Journal of Biological Chemistry.

[26]  P. Rorsman,et al.  Hormone-sensitive lipase deficiency in mouse islets abolishes neutral cholesterol ester hydrolase activity but leaves lipolysis, acylglycerides, fat oxidation, and insulin secretion intact. , 2004, Endocrinology.

[27]  M. Prentki,et al.  Hormone-sensitive lipase has a role in lipid signaling for insulin secretion but is nonessential for the incretin action of glucagon-like peptide 1. , 2004, Diabetes.

[28]  P. Rorsman,et al.  Palmitate increases L‐type Ca2+ currents and the size of the readily releasable granule pool in mouse pancreatic β‐cells , 2004, The Journal of physiology.

[29]  M. Prentki,et al.  A role for the malonyl-CoA/long-chain acyl-CoA pathway of lipid signaling in the regulation of insulin secretion in response to both fuel and nonfuel stimuli. , 2004, Diabetes.

[30]  F. Sundler,et al.  A Novel Hormone-sensitive Lipase Isoform Expressed in Pancreatic β-Cells* , 2004, Journal of Biological Chemistry.

[31]  H. Mulder,et al.  Inhibition of lipase activity and lipolysis in rat islets reduces insulin secretion. , 2004, Diabetes.

[32]  M. Prentki,et al.  Saturated fatty acids synergize with elevated glucose to cause pancreatic beta-cell death. , 2003, Endocrinology.

[33]  S. Tilghman,et al.  Glyceroneogenesis and the Triglyceride/Fatty Acid Cycle* , 2003, Journal of Biological Chemistry.

[34]  M. Prentki,et al.  Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in beta-cell adaptation and failure in the etiology of diabetes. , 2002, Diabetes.

[35]  G. Sharp,et al.  Glucose‐stimulated signaling pathways in biphasic insulin secretion , 2002, Diabetes/metabolism research and reviews.

[36]  R. Zechner,et al.  Hormone-sensitive Lipase Deficiency in Mice Causes Diglyceride Accumulation in Adipose Tissue, Muscle, and Testis* , 2002, The Journal of Biological Chemistry.

[37]  Thomas C. Südhof,et al.  β Phorbol Ester- and Diacylglycerol-Induced Augmentation of Transmitter Release Is Mediated by Munc13s and Not by PKCs , 2002, Cell.

[38]  M. Prentki,et al.  The antilipolytic agent 3,5-dimethylpyrazole inhibits insulin release in response to both nutrient secretagogues and cyclic adenosine monophosphate agonists in isolated rat islets. , 2002, Metabolism: clinical and experimental.

[39]  J. Gagliardino,et al.  Changes induced by sucrose administration on glucose metabolism in pancreatic islets in normal hamsters. , 2001, The Journal of endocrinology.

[40]  M. Jensen,et al.  Lipid metabolism during fasting. , 2001, American journal of physiology. Endocrinology and metabolism.

[41]  P. Arner,et al.  The expression of hormone-sensitive lipase in clonal beta-cells and rat islets is induced by long-term exposure to high glucose. , 2001, Diabetes.

[42]  M. Prentki,et al.  A role for hormone-sensitive lipase in glucose-stimulated insulin secretion: a study in hormone-sensitive lipase-deficient mice. , 2001, Diabetes.

[43]  D. Eizirik,et al.  Inverse relationship between cytotoxicity of free fatty acids in pancreatic islet cells and cellular triglyceride accumulation. , 2001, Diabetes.

[44]  J. Deeney,et al.  Glucagon-Like Peptide 1 Stimulates Lipolysis in Clonal Pancreatic β-Cells (HIT) , 2001 .

[45]  M. Prentki,et al.  Glucose Down-regulates the Expression of the Peroxisome Proliferator-activated Receptor-α Gene in the Pancreatic β-Cell* , 2000, The Journal of Biological Chemistry.

[46]  J. Henquin,et al.  Triggering and amplifying pathways of regulation of insulin secretion by glucose. , 2000, Diabetes.

[47]  M. Prentki,et al.  Acute Stimulation with Long Chain Acyl-CoA Enhances Exocytosis in Insulin-secreting Cells (HIT T-15 and NMRI β-Cells)* , 2000, The Journal of Biological Chemistry.

[48]  M. Prentki,et al.  Isolation of INS-1-derived cell lines with robust ATP-sensitive K+ channel-dependent and -independent glucose-stimulated insulin secretion. , 2000, Diabetes.

[49]  P. Rorsman,et al.  Hormone-sensitive lipase, the rate-limiting enzyme in triglyceride hydrolysis, is expressed and active in beta-cells. , 1999, Diabetes.

[50]  J. McGarry,et al.  A fatty acid- dependent step is critically important for both glucose- and non-glucose-stimulated insulin secretion. , 1998, The Journal of clinical investigation.

[51]  M. Dunne,et al.  Glucose activates both K(ATP) channel-dependent and K(ATP) channel-independent signaling pathways in human islets. , 1998, Diabetes.

[52]  M. Linder,et al.  SNAP-25 palmitoylation and plasma membrane targeting require a functional secretory pathway. , 1998, Molecular biology of the cell.

[53]  C. Newgard,et al.  β-Cell Function in Normal Rats Made Chronically Hyperleptinemic by Adenovirus-Leptin Gene Therapy , 1997, Diabetes.

[54]  J. McGarry,et al.  The insulinotropic potency of fatty acids is influenced profoundly by their chain length and degree of saturation. , 1997, The Journal of clinical investigation.

[55]  T. Südhof,et al.  Fatty acylation of synaptotagmin in PC12 cells and synaptosomes. , 1996, Biochemical and biophysical research communications.

[56]  J. McGarry,et al.  Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat. , 1996, The Journal of clinical investigation.

[57]  M. Solimena,et al.  ICA 512, an autoantigen of type I diabetes, is an intrinsic membrane protein of neurosecretory granules. , 1996, The EMBO journal.

[58]  G. Lopaschuk,et al.  Myocardial triglyceride turnover and contribution to energy substrate utilization in isolated working rat hearts. , 1991, The Journal of biological chemistry.

[59]  S. Bonner-Weir,et al.  REPRODUCIBLE HIGH YIELD OF RAT ISLETS BY STATIONARY IN VITRO DIGESTION FOLLOWING PANCREATIC DUCTAL OR PORTAL VENOUS COLLAGENASE INJECTION1 , 1987, Transplantation.

[60]  J. Hutton,et al.  Nucleotide and bivalent cation specificity of the insulin-granule proton translocase. , 1983, The Biochemical journal.

[61]  P. Hahn,et al.  Development of brown and white adipose tissue. , 1975, Journal of lipid research.

[62]  M. Vaughan.  The production and release of glycerol by adipose tissue incubated in vitro. , 1962, The Journal of biological chemistry.