Adipose Triglyceride Lipase Deficiency Causes Tissue-specific Changes in Insulin Signaling

Triacylglycerol accumulation in insulin target tissues is associated with insulin resistance. Paradoxically, mice with global targeted deletion of adipose triglyceride lipase (ATGL), the rate-limiting enzyme in triacylglycerol hydrolysis, display improved glucose tolerance and insulin sensitivity despite triacylglycerol accumulation in multiple tissues. To determine the molecular mechanisms for this phenotype, ATGL-deficient (ATGL−/−) and wild-type mice were injected with saline or insulin (10 units/kg, intraperitoneally), and then phosphorylation and activities of key insulin-signaling proteins were determined in insulin target tissues (liver, adipose tissue, and muscle). Insulin signaling and/or glucose transport was also evaluated in isolated adipocytes and skeletal muscle ex vivo. In ATGL−/− mice, insulin-stimulated phosphatidylinositol 3-kinase and Akt activities as well as phosphorylation of critical residues of IRS1 (Tyr(P)-612) and Akt (Ser(P)-473) were increased in skeletal muscle in vivo. Insulin-stimulated phosphatidylinositol 3-kinase activity and total insulin receptor and insulin receptor substrate 1, but not other parameters, were also increased in white adipose tissue in vivo. In contrast, in vivo measures of insulin signaling were decreased in brown adipose tissue and liver. Interestingly, the enhanced components of insulin signaling identified in skeletal muscle and white adipose tissue in vivo and their expected downstream effects on glucose transport were not present ex vivo. ATGL deficiency altered intramyocellular lipids as well as serum factors known to influence insulin sensitivity. Thus, skeletal muscle, rather than other tissues, primarily contributes to enhanced insulin sensitivity in ATGL−/− mice in vivo despite triacylglycerol accumulation, and both local and systemic factors contribute to tissue-specific effects of global ATGL deficiency on insulin action. Triacylglycerol accumulation in insulin target tissues is associated with insulin resistance. Paradoxically, mice with global targeted deletion of adipose triglyceride lipase (ATGL), the rate-limiting enzyme in triacylglycerol hydrolysis, display improved glucose tolerance and insulin sensitivity despite triacylglycerol accumulation in multiple tissues. To determine the molecular mechanisms for this phenotype, ATGL-deficient (ATGL−/−) and wild-type mice were injected with saline or insulin (10 units/kg, intraperitoneally), and then phosphorylation and activities of key insulin-signaling proteins were determined in insulin target tissues (liver, adipose tissue, and muscle). Insulin signaling and/or glucose transport was also evaluated in isolated adipocytes and skeletal muscle ex vivo. In ATGL−/− mice, insulin-stimulated phosphatidylinositol 3-kinase and Akt activities as well as phosphorylation of critical residues of IRS1 (Tyr(P)-612) and Akt (Ser(P)-473) were increased in skeletal muscle in vivo. Insulin-stimulated phosphatidylinositol 3-kinase activity and total insulin receptor and insulin receptor substrate 1, but not other parameters, were also increased in white adipose tissue in vivo. In contrast, in vivo measures of insulin signaling were decreased in brown adipose tissue and liver. Interestingly, the enhanced components of insulin signaling identified in skeletal muscle and white adipose tissue in vivo and their expected downstream effects on glucose transport were not present ex vivo. ATGL deficiency altered intramyocellular lipids as well as serum factors known to influence insulin sensitivity. Thus, skeletal muscle, rather than other tissues, primarily contributes to enhanced insulin sensitivity in ATGL−/− mice in vivo despite triacylglycerol accumulation, and both local and systemic factors contribute to tissue-specific effects of global ATGL deficiency on insulin action. Triacylglycerols (TAGs) 4The abbreviations used are: TAGtriacylglycerolATGLadipose triglyceride lipaseBATbrown adipose tissueDAGdiacylglycerolFAfatty acid or fatty acylFA-CoAfatty acyl-CoAIRinsulin receptorIRSinsulin receptor substratePI3Kphosphatidylinositol 3-kinaseWATwhite adipose tissueNEFAnonesterified fatty acidEDLextensor digitorum longusGTTglucose tolerance testITTinsulin tolerance testANOVAanalysis of varianceMSmass spectrometryGAPDHglyceraldehyde-3-phosphate dehydrogenaseWTwild typeHSLhormone-sensitive lipase. 4The abbreviations used are: TAGtriacylglycerolATGLadipose triglyceride lipaseBATbrown adipose tissueDAGdiacylglycerolFAfatty acid or fatty acylFA-CoAfatty acyl-CoAIRinsulin receptorIRSinsulin receptor substratePI3Kphosphatidylinositol 3-kinaseWATwhite adipose tissueNEFAnonesterified fatty acidEDLextensor digitorum longusGTTglucose tolerance testITTinsulin tolerance testANOVAanalysis of varianceMSmass spectrometryGAPDHglyceraldehyde-3-phosphate dehydrogenaseWTwild typeHSLhormone-sensitive lipase. are the predominant form of energy storage in animals. The ability to store and release this energy in response to variable energy availability requires a carefully regulated balance between TAG synthesis and hydrolysis. In the setting of chronic energy excess, however, TAGs and other lipid metabolites accumulate in adipose tissue as well as in metabolically relevant non-adipose tissues where they have been proposed to contribute to cellular dysfunction via a process known as lipotoxicity (1Schaffer J.E. Curr. Opin. Lipidol. 2003; 14: 281-287Crossref PubMed Scopus (702) Google Scholar, 2Unger R.H. Endocrinology. 2003; 144: 5159-5165Crossref PubMed Scopus (563) Google Scholar, 3van Herpen N.A. Schrauwen-Hinderling V.B. Physiol. Behav. 2008; 94: 231-241Crossref PubMed Scopus (353) Google Scholar). Indeed, intracellular TAG accumulation has been repeatedly associated with metabolic dysfunction, a relationship that is particularly strong for insulin resistance (1Schaffer J.E. Curr. Opin. Lipidol. 2003; 14: 281-287Crossref PubMed Scopus (702) Google Scholar, 2Unger R.H. Endocrinology. 2003; 144: 5159-5165Crossref PubMed Scopus (563) Google Scholar, 3van Herpen N.A. Schrauwen-Hinderling V.B. Physiol. Behav. 2008; 94: 231-241Crossref PubMed Scopus (353) Google Scholar). Despite this strong association, however, intracellular TAG accumulation is not always associated with insulin resistance (4Liu L. Zhang Y. Chen N. Shi X. Tsang B. Yu Y.H. J. Clin. Invest. 2007; 117: 1679-1689Crossref PubMed Scopus (266) Google Scholar) and may even be associated with insulin sensitivity, as is the case with highly trained endurance athletes (the so-called “athlete paradox”) (5Goodpaster B.H. He J. Watkins S. Kelley D.E. J. Clin. Endocrinol. Metab. 2001; 86: 5755-5761Crossref PubMed Scopus (639) Google Scholar). Thus, the contribution of intracellular TAGs and TAG metabolism per se to lipotoxicity remains controversial. What is clear is that lipid-induced insulin resistance is a major risk factor for morbidity and mortality from a variety of causes, including overt diabetes mellitus, nonalcoholic fatty liver disease, and cardiovascular disease. Hence, understanding the mechanisms by which dysregulated TAG metabolism contributes to steatosis, lipotoxicity, and insulin resistance is essential to understanding and treating these increasingly prevalent disorders. triacylglycerol adipose triglyceride lipase brown adipose tissue diacylglycerol fatty acid or fatty acyl fatty acyl-CoA insulin receptor insulin receptor substrate phosphatidylinositol 3-kinase white adipose tissue nonesterified fatty acid extensor digitorum longus glucose tolerance test insulin tolerance test analysis of variance mass spectrometry glyceraldehyde-3-phosphate dehydrogenase wild type hormone-sensitive lipase. triacylglycerol adipose triglyceride lipase brown adipose tissue diacylglycerol fatty acid or fatty acyl fatty acyl-CoA insulin receptor insulin receptor substrate phosphatidylinositol 3-kinase white adipose tissue nonesterified fatty acid extensor digitorum longus glucose tolerance test insulin tolerance test analysis of variance mass spectrometry glyceraldehyde-3-phosphate dehydrogenase wild type hormone-sensitive lipase. Although no mechanistic data have been identified directly linking intracellular TAGs per se to insulin resistance, lipotoxicity may occur when the capacity of the lipid droplets to effectively store TAGs is exceeded. Several other lipid metabolites that are products of TAG hydrolysis (i.e. diacylglyerols (DAGs), fatty acids (FAs), fatty acyl-CoAs (FA-CoAs), and ceramides) have been shown to directly or indirectly interfere with insulin signaling and glucose transport via a variety of mechanisms (6Shulman G.I. J. Clin. Invest. 2000; 106: 171-176Crossref PubMed Scopus (2173) Google Scholar, 7Summers S.A. Prog. Lipid Res. 2006; 45: 42-72Crossref PubMed Scopus (627) Google Scholar, 8Lewis G.F. Carpentier A. Adeli K. Giacca A. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). insulin to the insulin receptor The of residues the and phosphorylation of by of phosphatidylinositol 3-kinase and which in the downstream effects of The lipid metabolites have been shown to phosphorylation and phosphorylation of phosphorylation of activity and Akt and (6Shulman G.I. J. Clin. Invest. 2000; 106: 171-176Crossref PubMed Scopus (2173) Google Scholar, 7Summers S.A. Prog. Lipid Res. 2006; 45: 42-72Crossref PubMed Scopus (627) Google Scholar, 8Lewis G.F. Carpentier A. Adeli K. Giacca A. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). mechanisms by which these lipid metabolites may influence glucose and insulin for substrate with cellular energy of of and dysfunction, and of and (6Shulman G.I. J. Clin. Invest. 2000; 106: 171-176Crossref PubMed Scopus (2173) Google Scholar, 7Summers S.A. Prog. Lipid Res. 2006; 45: 42-72Crossref PubMed Scopus (627) Google Scholar, 8Lewis G.F. Carpentier A. Adeli K. Giacca A. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). the of lipotoxicity in insulin resistance have on cellular lipid or both of which in intracellular TAGs and other intracellular lipid metabolites and not the of intracellular TAGs and TAG metabolism per se to this the of TAG metabolism in lipotoxicity and insulin resistance has been by the that the rate-limiting enzyme for TAG hydrolysis, adipose triglyceride lipase (ATGL), has been identified A. A. PubMed Scopus Google Scholar, S. J. PubMed Scopus Google Scholar, B. J. PubMed Scopus Google Scholar). ATGL has been in adipose tissue where the hydrolysis of fatty acyl TAGs A. A. PubMed Scopus Google Scholar). ATGL is also in other tissues, including muscle, and 2006; PubMed Scopus Google where contribution to tissue-specific and systemic metabolism is well with global targeted deletion of ATGL have in TAG hydrolysis, to TAG accumulation in tissues A. J. S. 2006; PubMed Scopus Google Scholar). despite increased and TAG accumulation, which are associated with insulin resistance, ATGL−/− mice enhanced glucose tolerance and insulin sensitivity A. J. S. 2006; PubMed Scopus Google Scholar). has been to the of systemic on energy substrate availability A. J. S. 2006; PubMed Scopus Google Scholar). the contribution of altered tissue-specific insulin to this has not been ATGL−/− mice a for the contribution of intracellular TAG accumulation to glucose and insulin intracellular TAG accumulation is from systemic and also from the of other intracellular lipid In ATGL−/− mice from the other in which increased is associated with insulin sensitivity in that enhanced of adipose tissue mass and systemic not lipid in ATGL−/− mice A. Y. G.I. J. Clin. Invest. 2007; 117: PubMed Scopus Google Scholar, S. S. J. A. A. S. 2008; PubMed Scopus Google Scholar). The of this were to the mechanisms by which TAG hydrolysis and intracellular TAG accumulation of global ATGL deficiency glucose tolerance and insulin sensitivity and to the contribution of tissue-specific in insulin to this that global ATGL deficiency in mice not energy substrate availability but also tissue-specific in insulin action. were with a with to and were in with by the of were by the and ATGL−/− mice were on a and as A. J. S. 2006; PubMed Scopus Google Scholar). The targeted ATGL was then the for mice were by or ATGL−/− to ATGL−/− mice morbidity and mortality as well as and in response to A. J. S. 2006; PubMed Scopus Google were of mice than of was determined in mice glucose was a insulin and glucose tolerance and mice were injected with insulin per of or with per of by the insulin was determined the insulin and were determined was determined as N. K. L. PubMed Scopus Google Scholar). nonesterified fatty acids and TAGs were determined the and the was to and J. Physiol. PubMed Scopus Google Scholar) with was on in per of of were with of and then by of for the of glucose or to for to determine total were then for and glucose in the was glucose glucose was by from total insulin signaling in mice were injected with insulin per mice were by and tissues were muscle insulin signaling ex were from mice by and for in were then for in with or were in and were in were for and were was by and to and total proteins were identified by the and (Tyr(P)-612) and (Ser(P)-473) and and were a analysis was of tissue and muscle, of white and brown muscle, were to with of or of from to Akt tissue were to for with of to The were and and Akt activities were determined as J. Clin. Invest. PubMed Scopus Google Scholar). transport muscle ex vivo was determined to A. A. 2000; PubMed Scopus Google Scholar) with and extensor digitorum longus were from mice by were then for in with and by for in with transport was by in and for To determine and insulin-stimulated glucose transport in were with and with of saline or the were and in the were and for in of and for in the was determined by for and glucose transport was in isolated adipocytes was determined in which glucose is directly to transport as L. Endocrinology. PubMed Scopus Google Scholar). adipocytes were isolated from by of isolated adipocytes was used to determine the and of J. Lipid Res. PubMed Google Scholar). The adipocytes were with in a of serum and for with 1, or adipocytes was by the with for The was by and the in the was determined by of lipids in skeletal muscle was as 2001; PubMed Scopus Google Scholar). analysis of and muscle lipids were the of J. J. PubMed Google Scholar). The was a of and lipid were TAG lipids were in by TAG was determined a To determine lipid were in of by of of and for of and of acid were 2006; PubMed Scopus Google Scholar). lipid the was a of and lipids were in and acid for were by mass a to the lipid were directly in and acid and the were determined by to the of 2008; PubMed Scopus Google Scholar). was from tissues lipid tissue with of of total was was determined by were in in of and were for by of for and for was determined by the and to of as and analysis was to determine that of was the of was by of of that and of of in and are as between were by test or analysis of variance as were by analysis was multiple glucose transport isolated was used to a a variable with no of were of improved glucose tolerance and insulin sensitivity were identified in ATGL−/− mice on a A. J. S. 2006; PubMed Scopus Google the of global ATGL deficiency on glucose and insulin sensitivity in mice on a ATGL−/− mice on a increased with wild-type mice as as of than mice on a A. J. S. 2006; PubMed Scopus Google Scholar). in was to increased mass and not to altered mass The which both and glucose serum glucose in ATGL−/− mice and glucose as well as a the with improved glucose Interestingly, of serum insulin the serum insulin that enhanced glucose tolerance in ATGL−/− mice these is in to mechanisms and that ATGL deletion may insulin in response to a glucose The which primarily glucose serum glucose in ATGL−/− mice insulin as well as a the improved insulin sensitivity. and were even for the in and were also in mice not To determine the contribution of substrate availability to glucose in ATGL−/− mice, evaluated serum glucose and a and serum lipids a glucose and a not between ATGL−/− and mice, with A. J. S. 2006; PubMed Scopus Google Scholar). serum glucose was in mice of serum glucose decreased in ATGL−/− mice and than mice of availability of serum lipid and was in ATGL−/− mice a and with enhanced on glucose was in ATGL−/− mice with mice in both and Thus, a in both lipid and substrate contributes to the glucose tolerance in ATGL−/− To global ATGL deficiency contributes to insulin and glucose in ATGL−/− mice, evaluated insulin signaling in liver. Insulin-stimulated phosphorylation of the and as well as Akt were not in ATGL−/− mice and insulin-stimulated phosphorylation of IRS1 and Akt was decreased in ATGL−/− mice and of total proteins to was between not insulin-stimulated and activities were and insulin-stimulated Akt activity was decreased in ATGL−/− mice that ATGL deficiency contributes to in insulin signaling the of that enhanced insulin signaling in liver not contribute to insulin sensitivity in ATGL−/− To ATGL deficiency insulin and glucose in ATGL−/− mice, evaluated insulin signaling in brown and white adipose tissue in vivo as well as glucose isolated white adipocytes ex vivo. of insulin signaling in brown adipose tissue of ATGL−/− mice a as was for insulin-stimulated phosphorylation of IRS1 and Akt activity but no in activity not with insulin signaling downstream of the In contrast, in white adipose tissue in insulin-stimulated of the IRS1 as well as phosphorylation of Akt were in ATGL−/− mice and Despite no in phosphorylation of these total and IRS1 to were increased in ATGL−/− mice in total IRS1 was associated with increased insulin-stimulated activity but not Akt activity in ATGL−/− data in to liver and insulin was not may even be in of ATGL−/− To these evaluated ex vivo glucose transport in isolated white Lipid per and glucose transport were both increased in ATGL-deficient with a between glucose and J. Clin. Invest. PubMed Scopus Google Scholar). insulin-stimulated glucose transport for for and the for insulin for for were not between even for in glucose transport data that enhanced glucose transport white adipocytes contributes to improved glucose in ATGL−/− mice and that insulin-stimulated glucose transport is not despite increased lipid data also that the in activity in vivo not improved insulin-stimulated glucose transport adipocytes ex vivo. To global ATGL deficiency contributes to skeletal muscle insulin and glucose evaluated insulin signaling in skeletal muscle in vivo and ex vivo as well as glucose transport in skeletal muscle ex vivo. that ATGL was in of by was for for and for In skeletal muscle in insulin-stimulated phosphorylation was in ATGL−/− phosphorylation of IRS1 and Akt was and Akt phosphorylation to be increased and in ATGL−/− of total proteins to was between not The in IRS1 and Akt phosphorylation was associated with increased insulin-stimulated and Akt activities and as well as increased glucose in skeletal muscle of ATGL−/− that increased in vivo insulin signaling in skeletal muscle contributes to enhanced insulin sensitivity in ATGL−/− Interestingly, of insulin signaling in skeletal muscle ex vivo that insulin-stimulated phosphorylation of Akt and Akt was or in ATGL−/− mice and In the in insulin-stimulated and Akt activities in skeletal muscle in vivo when insulin was in skeletal muscle ex vivo and glucose in skeletal muscle was enhanced in vivo A. J. S. 2006; PubMed Scopus Google glucose transport was and insulin-stimulated glucose transport was in ATGL−/− mice ex vivo were for not that between in vivo and ex vivo are not of in muscle or of these data that tissue-specific as well as systemic effects influence glucose and insulin in skeletal muscle of ATGL−/− To the mechanisms the between in vivo and ex vivo insulin in skeletal muscle of ATGL−/− mice, evaluated the of both local and systemic factors in this to local the intramyocellular lipid of ATGL−/− intramyocellular TAG were increased in ATGL−/− mice as by of lipid skeletal muscle and the of TAG hydrolysis be expected to other lipid were increased In contrast, were in ATGL−/− mice and both total and were in ATGL−/− mice with the of which was have been in skeletal muscle insulin resistance, evaluated mechanisms for their by analysis of in their synthesis and and and/or hydrolysis lipase with in mice, and were and were in ATGL−/− mice data that of to TAG and/or in hydrolysis may contribute to increased in ATGL−/− to systemic the of factors known to glucose and insulin sensitivity (i.e. a proposed of skeletal muscle insulin resistance, was decreased in serum of ATGL−/− mice In contrast, serum and were between not Thus, in to serum may contribute to increased in vivo insulin in skeletal muscle of ATGL−/− TAG accumulation in insulin target tissues is associated with insulin signaling to insulin resistance and overt the of intramyocellular TAGs with insulin sensitivity in athletes the that TAG accumulation per se is in this process (5Goodpaster B.H. He J. Watkins S. Kelley D.E. J. Clin. Endocrinol. Metab. 2001; 86: 5755-5761Crossref PubMed Scopus (639) Google Scholar). Thus, the mechanisms by which intracellular TAG accumulation tissue insulin and the of TAG metabolism in this process with global targeted deletion of ATGL have improved glucose tolerance and insulin sensitivity despite increased and TAG accumulation in insulin target tissues as liver and Thus, ATGL−/− mice a to the relationship between intracellular TAG metabolism and insulin resistance. that improved glucose tolerance and insulin sensitivity in ATGL−/− mice is not to energy substrate availability but also to tissue-specific in insulin action. that skeletal muscle primarily contributes to improved insulin sensitivity in ATGL−/− mice and that both local and systemic factors influence tissue-specific insulin in the setting of ATGL ATGL−/− mice on a enhanced glucose tolerance and insulin sensitivity despite increased in with in mice on a A. J. S. 2006; PubMed Scopus Google Scholar). and mechanisms may contribute to this In of the glucose is enhanced in ATGL−/− mice a glucose despite the of a insulin The availability of serum lipid in ATGL−/− mice, even in the on glucose as energy substrate as by increased and of tissue and serum glucose and A. J. S. 2006; PubMed Scopus Google Scholar, J. Physiol. Endocrinol. Metab. PubMed Scopus Google Scholar). of lipid and glucose substrate may also to enhanced in vivo in muscle and liver a for these tissues in glucose in ATGL−/− mice A. J. S. 2006; PubMed Scopus Google Scholar). data in isolated adipocytes ex vivo that adipose tissue contributes to this process as Interestingly, the in insulin in ATGL−/− mice ATGL in insulin from Indeed, J. J. PubMed Scopus Google Scholar) have shown that ATGL is highly in where TAG hydrolysis and and insulin both in and in vivo. data increased TAG in A. J. S. 2006; PubMed Scopus Google Scholar) and isolated J. J. PubMed Scopus Google Scholar) from ATGL−/− mice that in the lipid contribute to the in Thus, ATGL−/− mice both enhanced glucose and insulin Although is clear that ATGL−/− mice have improved glucose the of ATGL deficiency on insulin sensitivity is mechanisms with effects in tissues. insulin sensitivity is determined by the of insulin in insulin target tissues as adipose tissue, and skeletal the of a metabolic on insulin and be for of these tissues Metab. Clin. PubMed Scopus Google Scholar, Y. J. 2003; PubMed Scopus Google Scholar, J. Endocrinol. Metab. 2000; PubMed Scopus Google Scholar). is in ATGL−/− mice in which insulin signaling in vivo is increased in skeletal muscle, or increased in and decreased in and liver. data that enhanced insulin signaling in skeletal muscle, rather than other tissues, is the to insulin sensitivity in ATGL−/− mechanisms to the tissue-specific in insulin the response to energy substrate tissue-specific effects from TAG hydrolysis (i.e. in the intracellular lipid or systemic effects from tissue-specific to the (i.e. release of factors as or lipids The of these factors is by the of global ATGL deficiency on insulin in skeletal muscle is the for glucose TAG accumulation is associated with of this process (i.e. insulin J. Metab. PubMed Scopus Google Scholar). both and that TAGs accumulate skeletal muscle in ATGL−/− Despite this intramyocellular TAG accumulation, in vivo insulin signaling is enhanced in skeletal muscle of ATGL−/− mice as by increased phosphorylation of signaling downstream of the and increased activity of and as well as increased of are even in the of energy substrate which insulin resistance to glucose for Interestingly, these in skeletal muscle insulin signaling are even in the case of Akt ex vivo glucose skeletal muscle is increased in vivo A. J. S. 2006; PubMed Scopus Google glucose transport is and insulin-stimulated glucose transport is decreased in ATGL−/− mice ex vivo. in in vivo ex vivo are not to be to in muscle or of ATGL ATGL was in and ex vivo were in of data have as effects of ATGL deficiency on intramyocellular lipid metabolism influence insulin and glucose transport skeletal and systemic effects the in vivo effects of ATGL deficiency on insulin in skeletal muscle and are to the local ATGL deficiency has local effects on skeletal muscle lipid metabolism that may influence insulin in that ATGL deficiency in intramyocellular TAG accumulation, even in the setting of systemic with a critical for ATGL in intramyocellular TAG hydrolysis. TAG hydrolysis and also be expected to not other lipid as is for and Interestingly, are increased in skeletal muscle of ATGL−/− is that skeletal of which TAGs and insulin resistance J. Physiol. Endocrinol. Metab. 2007; PubMed Scopus Google Scholar). In contrast, skeletal of which also TAGs and insulin sensitivity (4Liu L. Zhang Y. Chen N. Shi X. Tsang B. Yu Y.H. J. Clin. Invest. 2007; 117: 1679-1689Crossref PubMed Scopus (266) Google Scholar). In global deletion of in accumulation of intramyocellular but not TAGs J. PubMed Scopus Google Scholar, B. Endocrinology. 2003; 144: PubMed Scopus Google Scholar, S. J. G.I. J. Physiol. Endocrinol. Metab. PubMed Scopus Google Scholar). Thus, in TAG metabolism have effects on skeletal muscle insulin despite effects on intracellular TAG data the that ATGL deficiency cellular of on TAG per se that may influence insulin action. data that of of and/or in hydrolysis may contribute to this in in ATGL−/− however, is known the relationship between and other to in skeletal of proteins as the ATGL A. Metab. 2006; PubMed Scopus Google and lipid proteins of the and of have been shown to with ATGL in adipocytes J. 2007; PubMed Scopus Google but their in skeletal muscle TAG metabolism and insulin remains have been directly in lipid-induced insulin resistance via of and of insulin-stimulated IRS1 phosphorylation and activity S. J. Physiol. Behav. 2008; 94: PubMed Scopus Google Scholar). has been that the metabolic to cellular and/or the of present also influence the of on insulin sensitivity S. J. Physiol. Behav. 2008; 94: PubMed Scopus Google Scholar). Thus, remains increased or a of these factors the ex vivo glucose transport in skeletal muscle of ATGL−/− In to the local global ATGL deficiency systemic effects that influence tissue-specific insulin action. the of increased insulin signaling in skeletal muscle in vivo but not ex vivo factors in these of factors known to influence insulin sensitivity a in serum but no in or in ATGL−/− is that has been to insulin resistance 2007; PubMed Google Scholar). that insulin resistance, that (i.e. insulin sensitivity N. K. L. PubMed Scopus Google Scholar). Thus, a in may contribute to the enhanced in vivo insulin in skeletal muscle of ATGL−/− In decreased of serum or other lipids may influence skeletal muscle in vivo insulin in ATGL−/− mice by to the in intramyocellular of other systemic factors that have not been is to that the systemic effects from tissue-specific by ATGL these is that ATGL deficiency also has and on insulin in adipose tissue is the for TAG storage and a in the of energy data that phosphorylation of insulin signaling and Akt activity are total of the and IRS1 as well as activity are increased in in vivo. Thus, insulin is or even increased in of ATGL−/− mice in vivo. The of in insulin sensitivity or insulin in adipocytes ex vivo that a of ATGL deficiency on insulin is not ex vivo. In contrast, glucose transport is increased in has been shown that glucose transport is to J. Clin. Invest. PubMed Scopus Google however, glucose transport is to Thus, the of insulin resistance in adipose tissue and isolated adipocytes of ATGL−/− mice, despite increased and lipid is data that the ability of adipocytes to the of TAG is in ATGL deficiency and that TAG accumulation in adipocytes is not to insulin action. in to ATGL deficiency in vivo insulin signaling in the of lipid for phosphorylation of Akt and Akt activity are decreased in of ATGL−/− is of the tissues by TAG of ATGL in and to A. J. S. 2006; PubMed Scopus Google Scholar). Interestingly, in in vivo insulin signaling in liver are to identified in a increased TAG accumulation per se or other factor contributes to the in vivo insulin resistance in these tissues was not evaluated in this as they were for skeletal muscle is clear that liver contribute to the enhanced insulin sensitivity of ATGL−/− In these data that ATGL deficiency to in the insulin signaling that are in insulin target tissues. insulin signaling in vivo is increased in skeletal muscle, or increased in and decreased in and liver. Thus, increased insulin in skeletal muscle, rather than other insulin target tissues, primarily contributes to improved insulin sensitivity in ATGL−/− mice in vivo. in skeletal muscle insulin in vivo ex vivo that both local and systemic factors contribute to these ATGL deficiency cellular of on TAG per se that may influence lipid metabolism and insulin action. with tissue-specific in ATGL are essential to the of ATGL in these metabolic In that the relationship between ATGL with other cellular proteins in intracellular TAG metabolism (i.e. and may critical the mechanisms by which intracellular TAG metabolism contributes to glucose and insulin action. be in the understanding and of metabolic disease.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.