ATGL activity regulates GLUT1-mediated glucose uptake and lactate production via TXNIP stability in adipocytes

Abstract

Traditionally, lipolysis has been regarded as an enzymatic activity that liberates fatty acids as metabolic fuel. However, recent work has shown that novel substrates, including a variety of lipid compounds such as fatty acids and their derivatives, release lipolysis products that act as signaling molecules and transcriptional modulators. While these studies have expanded the role of lipolysis, the mechanisms underpinning lipolysis signaling are not fully defined. Here, we uncover a new mechanism regulating glucose uptake, whereby activation of lipolysis, in response to elevated cAMP, leads to the stimulation of thioredoxin-interacting protein (TXNIP) degradation. This, in turn, selectively induces glucose transporter 1 surface localization and glucose uptake in 3T3-L1 adipocytes and increases lactate production. Interestingly, cAMP-induced glucose uptake via degradation of TXNIP is largely dependent upon adipose triglyceride lipase (ATGL) and not hormone-sensitive lipase or monoacylglycerol lipase. Pharmacological inhibition or knockdown of ATGL alone prevents cAMP-dependent TXNIP degradation and thus significantly decreases glucose uptake and lactate secretion. Conversely, overexpression of ATGL amplifies the cAMP response, yielding increased glucose uptake and lactate production. Similarly, knockdown of TXNIP elicits enhanced basal glucose uptake and lactate secretion, and increased cAMP further amplifies this phenotype. Overexpression of TXNIP reduces basal and cAMP-stimulated glucose uptake and lactate secretion. As a proof of concept, we replicated these findings in human primary adipocytes and observed TXNIP degradation and increased glucose uptake and lactate secretion upon elevated cAMP signaling. Taken together, our results suggest a crosstalk between ATGL-mediated lipolysis and glucose uptake. Traditionally, lipolysis has been regarded as an enzymatic activity that liberates fatty acids as metabolic fuel. However, recent work has shown that novel substrates, including a variety of lipid compounds such as fatty acids and their derivatives, release lipolysis products that act as signaling molecules and transcriptional modulators. While these studies have expanded the role of lipolysis, the mechanisms underpinning lipolysis signaling are not fully defined. Here, we uncover a new mechanism regulating glucose uptake, whereby activation of lipolysis, in response to elevated cAMP, leads to the stimulation of thioredoxin-interacting protein (TXNIP) degradation. This, in turn, selectively induces glucose transporter 1 surface localization and glucose uptake in 3T3-L1 adipocytes and increases lactate production. Interestingly, cAMP-induced glucose uptake via degradation of TXNIP is largely dependent upon adipose triglyceride lipase (ATGL) and not hormone-sensitive lipase or monoacylglycerol lipase. Pharmacological inhibition or knockdown of ATGL alone prevents cAMP-dependent TXNIP degradation and thus significantly decreases glucose uptake and lactate secretion. Conversely, overexpression of ATGL amplifies the cAMP response, yielding increased glucose uptake and lactate production. Similarly, knockdown of TXNIP elicits enhanced basal glucose uptake and lactate secretion, and increased cAMP further amplifies this phenotype. Overexpression of TXNIP reduces basal and cAMP-stimulated glucose uptake and lactate secretion. As a proof of concept, we replicated these findings in human primary adipocytes and observed TXNIP degradation and increased glucose uptake and lactate secretion upon elevated cAMP signaling. Taken together, our results suggest a crosstalk between ATGL-mediated lipolysis and glucose uptake. Adipose tissue metabolism plays a critical role in maintaining healthy homeostasis for glucose and lipid metabolism (1Rosen E.D. Spiegelman B.M. Adipocytes as regulators of energy balance and glucose homeostasis.Nature. 2006; 444: 847-853Crossref PubMed Scopus (1505) Google Scholar). Insulin mediated triacylglycerol (TAG) synthesis, and its dissipation through lipolysis is an important physiological process, which is tightly controlled and under metabolic regulation (2Czech M.P. Tencerova M. Pedersen D.J. Aouadi M. Insulin signalling mechanisms for triacylglycerol storage.Diabetologia. 2013; 56: 949-964Crossref PubMed Scopus (138) Google Scholar). When in positive energy balance, during the postprandial period, insulin rapidly stimulates glucose transporter 4 (GLUT4) surface translocation, which mediates glucose uptake. This is an acute insulin-stimulated process that is followed by TAG formation (3Haeusler R.A. McGraw T.E. Accili D. Biochemical and cellular properties of insulin receptor signalling.Nat. Rev. Mol. Cell Biol. 2018; 19: 31-44Crossref PubMed Scopus (224) Google Scholar). In a similar way, the counter-regulatory process during extended periods of starvation, through the action of the lipases, adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoacylglycerol lipase (MGL), lipolysis is activated by elevated levels of cAMP, which ultimately leads to the release of free fatty acid (FFA) (4Zechner R. Zimmermann R. Eichmann T.O. Kohlwein S.D. Haemmerle G. Lass A. Madeo F. FAT SIGNALS--lipases and lipolysis in lipid metabolism and signaling.Cell Metab. 2012; 15: 279-291Abstract Full Text Full Text PDF PubMed Scopus (617) Google Scholar, 5Amri E.Z. Ailhaud G. Grimaldi P.A. Fatty acids as signal transducing molecules: Involvement in the differentiation of preadipose to adipose cells.J. Lipid Res. 1994; 35: 930-937Abstract Full Text PDF PubMed Google Scholar). Mice with a targeted deletion of the various lipases display a vast range of phenotypes involving release of FFA, which are dependent upon tissue specificity and diet composition (6Schreiber R. Xie H. Schweiger M. Of mice and men: The physiological role of adipose triglyceride lipase (ATGL).Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2019; 1864: 880-899Crossref PubMed Scopus (38) Google Scholar, 7Schoiswohl G. Stefanovic-Racic M. Menke M.N. Wills R.C. Surlow B.A. Basantani M.K. Sitnick M.T. Cai L. Yazbeck C.F. Stolz D.B. Pulinilkunnil T. O'Doherty R.M. Kershaw E.E. Impact of reduced ATGL-mediated adipocyte lipolysis on obesity-associated insulin resistance and inflammation in male mice.Endocrinology. 2015; 156: 3610-3624Crossref PubMed Scopus (92) Google Scholar, 8Dube J.J. Sitnick M.T. Schoiswohl G. Wills R.C. Basantani M.K. Cai L. Pulinilkunnil T. Kershaw E.E. Adipose triglyceride lipase deletion from adipocytes, but not skeletal myocytes, impairs acute exercise performance in mice.Am. J. Physiol. Endocrinol. Metab. 2015; 308: E879-890Crossref PubMed Scopus (26) Google Scholar). Interesting studies in this area include the roles of diacylglycerol and ceramide, reported to negatively regulate glucose uptake and lead to insulin resistance (9Sokolowska E. Blachnio-Zabielska A. The role of ceramides in insulin resistance.Front. Endocrinol. (Lausanne). 2019; 10: 577Crossref PubMed Scopus (70) Google Scholar, 10Eichmann T.O. Lass A. DAG tales: The multiple faces of diacylglycerol--stereochemistry, metabolism, and signaling.Cell. Mol. Life Sci. 2015; 72: 3931-3952Crossref PubMed Scopus (100) Google Scholar). Similarly, lipid derivatives, such as arachidonic acid and the recently discovered hydroxylated fatty acid, positively regulate glucose uptake (11Yore M.M. Syed I. Moraes-Vieira P.M. Zhang T. Herman M.A. Homan E.A. Patel R.T. Lee J. Chen S. Peroni O.D. Dhaneshwar A.S. Hammarstedt A. Smith U. McGraw T.E. Saghatelian A. et al.Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.Cell. 2014; 159: 318-332Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar, 12Nugent C. Prins J.B. Whitehead J.P. Wentworth J.M. Chatterjee V.K. O'Rahilly S. Arachidonic acid stimulates glucose uptake in 3T3-L1 adipocytes by increasing GLUT1 and GLUT4 levels at the plasma membrane. Evidence for involvement of lipoxygenase metabolites and peroxisome proliferator-activated receptor gamma.J. Biol. Chem. 2001; 276: 9149-9157Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar). In conclusion, lipolytic activity is not only a mechanism to release FFA but also it is increasingly clear that these activities play an important role in regulating other modalities of metabolism (4Zechner R. Zimmermann R. Eichmann T.O. Kohlwein S.D. Haemmerle G. Lass A. Madeo F. FAT SIGNALS--lipases and lipolysis in lipid metabolism and signaling.Cell Metab. 2012; 15: 279-291Abstract Full Text Full Text PDF PubMed Scopus (617) Google Scholar). Glucose uptake is fundamental for cell metabolism and is mediated through a set of GLUTs and their associated machinery. Specialized cells, such as adipocytes, express GLUT4, which is largely dependent on insulin signaling for activation and surface translocation (13Leto D. Saltiel A.R. Regulation of glucose transport by insulin: Traffic control of GLUT4.Nat. Rev. Mol. Cell Biol. 2012; 13: 383-396Crossref PubMed Scopus (478) Google Scholar, 14Klip A. McGraw T.E. James D.E. Thirty sweet years of GLUT4.J. Biol. Chem. 2019; 294: 11369-11381Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar). Another transporter, GLUT1, is more ubiquitously expressed and is also important for adipocyte glucose uptake. Unlike GLUT4, the machinery, signaling, and metabolic regulation in relation to GLUT1 are less studied. Some of the central molecules for the glucose uptake process, such as AS160 phosphorylation and thioredoxin-interacting protein (TXNIP) expression levels, which are directly linked to glucose uptake, are regulated by both anabolic and catabolic signals and affect both GLUT1 and GLUT4 transporter surface translocation (15Waldhart A.N. Dykstra H. Peck A.S. Boguslawski E.A. Madaj Z.B. Wen J. Veldkamp K. Hollowell M. Zheng B. Cantley L.C. McGraw T.E. Wu N. Phosphorylation of TXNIP by AKT mediates acute influx of glucose in response to insulin.Cell Rep. 2017; 19: 2005-2013Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 16Wu N. Zheng B. Shaywitz A. Dagon Y. Tower C. Bellinger G. Shen C.H. Wen J. J. McGraw T.E. Cantley L.C. degradation of TXNIP upon energy leads to enhanced glucose uptake via 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). The adipocyte both GLUT1 and GLUT4, with lipases, and a for glucose and FFA metabolism that to a variety of both anabolic and catabolic Here, we that elevated levels of cAMP rapidly TXNIP in a and release GLUT1 for surface GLUT1 surface localization stimulates glucose uptake, which to a is further to uncover a mechanism by which ATGL activity cAMP-dependent TXNIP degradation that in but not mediated glucose uptake in and fatty lipolysis also lipid and molecules that regulate metabolism through multiple including and (4Zechner R. Zimmermann R. Eichmann T.O. Kohlwein S.D. Haemmerle G. Lass A. Madeo F. FAT SIGNALS--lipases and lipolysis in lipid metabolism and signaling.Cell Metab. 2012; 15: 279-291Abstract Full Text Full Text PDF PubMed Scopus (617) Google Scholar, 5Amri E.Z. Ailhaud G. Grimaldi P.A. Fatty acids as signal transducing molecules: Involvement in the differentiation of preadipose to adipose cells.J. Lipid Res. 1994; 35: 930-937Abstract Full Text PDF PubMed Google Scholar). are studies in which ceramide, and fatty linked to lipolysis, have been shown to regulate metabolism (4Zechner R. Zimmermann R. Eichmann T.O. Kohlwein S.D. Haemmerle G. Lass A. Madeo F. FAT SIGNALS--lipases and lipolysis in lipid metabolism and signaling.Cell Metab. 2012; 15: 279-291Abstract Full Text Full Text PDF PubMed Scopus (617) Google Scholar, E. Blachnio-Zabielska A. The role of ceramides in insulin resistance.Front. Endocrinol. (Lausanne). 2019; 10: 577Crossref PubMed Scopus (70) Google Scholar, 10Eichmann T.O. Lass A. DAG tales: The multiple faces of diacylglycerol--stereochemistry, metabolism, and signaling.Cell. Mol. Life Sci. 2015; 72: 3931-3952Crossref PubMed Scopus (100) Google Scholar, R. A.R. the of insulin signalling in PubMed Scopus Google Scholar). that a protein for is rapidly also as in and with to the and observed that to cAMP for significantly reduced TXNIP at the protein also 3T3-L1 adipocytes to in a to and that degradation of TXNIP from other that the of cAMP also degradation of we multiple such as and in with and also significantly TXNIP levels Interestingly, cAMP-stimulated TXNIP protein expression are not in levels, that TXNIP degradation is a a of glucose uptake, and thus their surface TXNIP degradation has been linked to the uptake of glucose N. Zheng B. Shaywitz A. Dagon Y. Tower C. Bellinger G. Shen C.H. Wen J. J. McGraw T.E. Cantley L.C. degradation of TXNIP upon energy leads to enhanced glucose uptake via 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). In a we uptake. that as increased glucose uptake both in a and which is with TXNIP degradation and to that observed with of other cAMP such as and also increased glucose uptake in 3T3-L1 adipocytes an of of cAMP and the lactate similar to that with glucose uptake, lactate is increased with increasing of cAMP, and this also for other cAMP and protein and protein have been shown to regulate glucose uptake via TXNIP degradation (15Waldhart A.N. Dykstra H. Peck A.S. Boguslawski E.A. Madaj Z.B. Wen J. Veldkamp K. Hollowell M. Zheng B. Cantley L.C. McGraw T.E. Wu N. Phosphorylation of TXNIP by AKT mediates acute influx of glucose in response to insulin.Cell Rep. 2017; 19: 2005-2013Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 16Wu N. Zheng B. Shaywitz A. Dagon Y. Tower C. Bellinger G. Shen C.H. Wen J. J. McGraw T.E. Cantley L.C. degradation of TXNIP upon energy leads to enhanced glucose uptake via 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). AKT and inhibition control glucose uptake. with the or not the glucose uptake in 3T3-L1 adipocytes or TXNIP degradation suggest that cAMP via we also insulin signaling which to and further with our AKT inhibition observed that the significantly reduces glucose uptake in 3T3-L1 adipocytes and TXNIP degradation Interestingly, these in 3T3-L1 cell triglyceride and associated signaling However, knockdown of TXNIP in an a similar of glucose uptake as observed in adipocytes in response to TXNIP degradation the role of TXNIP as a of glucose uptake. not to cAMP with increased glucose uptake and lipid and associated which for TXNIP it is that not glucose uptake in response to cAMP, the of the GLUT1 transporter ATGL expression in not to cAMP as a signal for TXNIP degradation and glucose uptake and cAMP levels in adipocytes also leads to phosphorylation of to phosphorylation to the lactate observed by glucose for lactate secretion, we the that inhibition not in the cAMP response, which involvement of and to of of the or similar activated by we the similar observed that not at the that is for a of which is the lipase activated in response to elevated signal for lipolysis M. M. R. S. Eichmann T.O. S. C. C. N. R. et inhibition of adipose triglyceride lipase insulin resistance and in 2017; PubMed Scopus Google Scholar, mechanisms regulating 2006; PubMed Scopus Google Scholar). Interestingly, we that to the TXNIP degradation as shown by and and As and linked to TXNIP we that also the cAMP on glucose uptake and lactate and further the of in lipolysis by the lipolytic ATGL by both cAMP and of and observed that the cAMP-stimulated secretion phosphorylation in the that ATGL activity as reported M. M. R. S. Eichmann T.O. S. C. C. N. R. et inhibition of adipose triglyceride lipase insulin resistance and in 2017; PubMed Scopus Google Scholar, N. Schweiger M. M. Eichmann T.O. E. J. C. I. Lass A. G. C. R. Zimmermann R. R. of adipose triglyceride Chem. Biol. 2013; PubMed Scopus Google In conclusion, these results that ATGL activity is for cAMP-induced and TXNIP glucose uptake in 3T3-L1 further a between glucose and lipid metabolism regulated by ATGL lipolysis is by and which work in to TAG to fatty acids and suggest that lipolysis leads to degradation of and linked to increased glucose uptake and lactate secretion. the of these lipases to the observed of glucose uptake, lactate secretion, and TXNIP we or in 3T3-L1 adipocytes In with our we that glucose uptake is largely regulated through ATGL activity as knockdown of ATGL the This is similar to the which is a of ATGL and Unlike and knockdown a response to cAMP in of glucose uptake and lactate and In with these we that knockdown of only ATGL to inhibition of TXNIP degradation further our results with knockdown for ATGL a observed similar to and knockdown of ATGL the glucose uptake and TXNIP degradation and Overexpression of ATGL in 3T3-L1 adipocytes elicits a in glucose uptake and lactate secretion This further the that ATGL-mediated lipolysis is for cAMP-induced glucose uptake and lactate secretion. GLUTs are the for glucose uptake. Adipocytes express both GLUT1 and GLUT4 is a transporter, GLUT1 regulation in adipocytes is not fully H. K. M. J. of glucose uptake and GLUT4 expression in human adipocyte J. Metab. PubMed Scopus Google Scholar, B. J. E. The translocation of the glucose transporter GLUT1 and GLUT4 in is regulated by J. PubMed Scopus Google Scholar, N. H. of of glucose in adipocytes from PubMed Scopus (38) Google Scholar). TXNIP as a for glucose uptake through both GLUT1 and GLUT4 (15Waldhart A.N. Dykstra H. Peck A.S. Boguslawski E.A. Madaj Z.B. Wen J. Veldkamp K. Hollowell M. Zheng B. Cantley L.C. McGraw T.E. Wu N. Phosphorylation of TXNIP by AKT mediates acute influx of glucose in response to insulin.Cell Rep. 2017; 19: 2005-2013Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 16Wu N. Zheng B. Shaywitz A. Dagon Y. Tower C. Bellinger G. Shen C.H. Wen J. J. McGraw T.E. Cantley L.C. degradation of TXNIP upon energy leads to enhanced glucose uptake via 2013; Full Text Full Text PDF PubMed Scopus Google Scholar, S. M.A. S. TXNIP in metabolic role and 2017; PubMed Scopus Google Scholar). to knockdown GLUT1 or GLUT4 to the roles of GLUT1 and GLUT4 in 3T3-L1 adipocytes that GLUT1 knockdown glucose uptake, GLUT4 knockdown on glucose uptake in 3T3-L1 adipocytes as with a control for lactate release This that cAMP via ATGL and that this a TXNIP degradation that stimulates GLUT1 but not GLUT4 surface also a knockdown of GLUT1 through in adipocytes and as a of glucose uptake the and TXNIP in glucose uptake in 3T3-L1 adipocytes is mediated by GLUT1 and not As for surface localization of we GLUT1 and GLUT4 with and human In 3T3-L1 adipocytes, to express these we an to the surface to of GLUT1 and glucose uptake we observed a in in surface localization of GLUT1 but not of GLUT4 to cAMP as insulin rapidly GLUT4 translocation in a which by the AKT we GLUT1 surface localization by inhibition or knockdown of also that ATGL inhibition by or ATGL knockdown significantly reduces GLUT1 surface localization and we that TXNIP knockdown significantly GLUT1 surface localization and that further by In conclusion, it that the in glucose uptake in 3T3-L1 adipocytes mediated by cAMP stimulation and linked to TXNIP degradation is mediated by GLUT1 but not to knockdown TXNIP expression in 3T3-L1 adipocytes and observed that TXNIP knockdown significantly glucose uptake in the basal and also significantly the cAMP response also a on lactate secretion In a we to TXNIP with a TXNIP reduced glucose uptake in both the basal and cAMP-stimulated which in to the TXNIP knockdown Similarly, lactate secretion significantly lactate secretion, a of a to rapidly the cellular we observed that cAMP, in a reduced the which is in with TXNIP degradation glucose uptake and lactate secretion with an ATGL the in the these suggest that adipocytes, in response to acute elevated cAMP levels, which in to the of for and adipocyte with cAMP in a or with for Cell and as with the protein and as results are of for and B. multiple to the of as the on the and the physiological of these we human primary adipocytes to increased cAMP to that we have observed in 3T3-L1 adipocytes, human primary adipocytes TXNIP in response to increased cAMP stimulation also observed increased glucose uptake and lactate and In conclusion, these results that the observed in 3T3-L1 adipocytes also are in primary human As energy substrates, lipids and are for cellular production. in a of lipases, the of TAG FFA and FFA the and of which ultimately to glucose in the and by via the Glucose to release during and in the acid of directly the for reduced to which in to the and as an important energy for other S. The of energy Metab. PubMed Scopus Google Scholar). a of energy both and for are in the that are important for the of such as via the This which of to is a for the of or have levels to the we in way, fatty acid to we on from to metabolism and M.N. of in Evidence of multiple and 2006; PubMed Scopus (108) Google Scholar). that during a cellular cAMP levels are and lipases of a during which insulin levels are is an enhanced lipase activity with a in glucose uptake This is by a glucose uptake in in response to stimulation A. N. A. S. C. J. E. E. G. M. A. R. J. T. with a stimulates glucose uptake in skeletal and glucose insulin resistance and in mice with PubMed Scopus Google Scholar, M. N. J.M. T. through a signaling involving that mediates glucose uptake in skeletal 2014; PubMed Scopus Google Scholar). we in response to increased cAMP levels, a degradation of TXNIP and the activation of GLUT1, but not glucose uptake. Interestingly, this which leads to glucose uptake that we on the enzymatic activity of but not or knockdown of but not that of or TXNIP degradation and glucose uptake and the of ATGL also decreases TXNIP degradation and glucose uptake and the that during cellular levels of cAMP, and insulin levels are a cAMP-induced and TXNIP mechanism the uptake of glucose that is for cellular that this mechanism is fatty acid is the energy the glucose uptake is dependent on ATGL activity Glucose uptake is tightly linked with the expression of which is regulated by both and (15Waldhart A.N. Dykstra H. Peck A.S. Boguslawski E.A. Madaj Z.B. Wen J. Veldkamp K. Hollowell M. Zheng B. Cantley L.C. McGraw T.E. Wu N. Phosphorylation of TXNIP by AKT mediates acute influx of glucose in response to insulin.Cell Rep. 2017; 19: 2005-2013Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 16Wu N. Zheng B. Shaywitz A. Dagon Y. Tower C. Bellinger G. Shen C.H. Wen J. J. McGraw T.E. Cantley L.C. degradation of TXNIP upon energy leads to enhanced glucose uptake via 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). TXNIP levels both the and of glucose uptake. Here, we observed that and AKT both of which have been to regulate glucose uptake and TXNIP are not linked with this of TXNIP degradation of lipolysis have been in and are new of lipolytic products as signaling and transcriptional have been (4Zechner R. Zimmermann R. Eichmann T.O. Kohlwein S.D. Haemmerle G. Lass A. Madeo F. FAT SIGNALS--lipases and lipolysis in lipid metabolism and signaling.Cell Metab. 2012; 15: 279-291Abstract Full Text Full Text PDF PubMed Scopus (617) Google Scholar, E. Blachnio-Zabielska A. The role of ceramides in insulin resistance.Front. Endocrinol. (Lausanne). 2019; 10: 577Crossref PubMed Scopus (70) Google Scholar, 10Eichmann T.O. Lass A. DAG tales: The multiple faces of diacylglycerol--stereochemistry, metabolism, and signaling.Cell. Mol. Life Sci. 2015; 72: 3931-3952Crossref PubMed Scopus (100) Google Scholar, R. A.R. the of insulin signalling in PubMed Scopus Google Scholar). In this we that elevated cAMP levels, which are the primary signal for cellular lipolysis mechanisms regulating 2006; PubMed Scopus Google are associated with degradation of protein for of GLUTs (15Waldhart A.N. Dykstra H. Peck A.S. Boguslawski E.A. Madaj Z.B. Wen J. Veldkamp K. Hollowell M. Zheng B. Cantley L.C. McGraw T.E. Wu N. Phosphorylation of TXNIP by AKT mediates acute influx of glucose in response to insulin.Cell Rep. 2017; 19: 2005-2013Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 16Wu N. Zheng B. Shaywitz A. Dagon Y. Tower C. Bellinger G. Shen C.H. Wen J. J. McGraw T.E. Cantley L.C. degradation of TXNIP upon energy leads to enhanced glucose uptake via 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). we that ATGL activity is for TXNIP degradation. TXNIP degradation leads to GLUT1 surface localization and glucose uptake, which is to This by of or ATGL Taken together, the are with a that GLUT1 glucose uptake for in cellular cAMP levels are elevated and GLUT4 is it as an glucose in the postprandial its role in lipolysis, cAMP signaling is also critical for glucose uptake. results suggest that adipocytes have an mechanism by which glucose uptake of the have been in 3T3-L1 we have replicated the in primary human adipocytes, we not in Another of our is that from 3T3-L1 adipocytes and human primary adipocytes, we only more cell and 3T3-L1 it is that other cell not also this to regulate their glucose uptake. In conclusion, we to suggest that in adipocytes, GLUT1 glucose uptake during starvation, which is with increased cAMP levels and activated lipolysis, GLUT4 in a postprandial to the uptake of and from TXNIP ATGL and from Cell GLUT1 and GLUT4 from and from from and from from 3T3-L1 in and adipocytes as and for of mammalian to the in human with a of expression and H. Zhang S. S. M. H. D. J. S. H. T. M. et and regulate 2019; PubMed Scopus Google Scholar). 3T3-L1 with for in human from cell and to human differentiation to their differentiation and adipocyte human ATGL and TXNIP with in from and (ATGL) or (TXNIP) for from and from McGraw GLUT1 and GLUT4, with their and for cell ATGL TXNIP GLUT1 and GLUT4 with as a control from from and the set of for and cell as in the as a control the Glucose uptake in 3T3-L1 adipocytes by of by cells, as H. Zhang S. S. M. H. D. J. S. H. T. M. et and regulate 2019; PubMed Scopus Google Scholar). in with in and in glucose for of with followed by of and and for with and in from the for protein and the to for The to the cellular protein for adipocytes GLUT1 or GLUT4 for in this starvation, to surface As a positive control for GLUT4, insulin during the to GLUT4 the of on GLUT1 surface levels, with of starvation, with and with for with and with or for 1 at with and with for 1 to and to of the with and at with and from surface to as a control and from in with and to the the protein by on 4 to protein and to with the primary with or on a of the of and results expressed as with the signal observed in the control with to from adipocytes to the of 1 of the levels of by on and to in and in as cellular to with various and the to are expressed as by and of as the are the The that have of with the of this for M. B. and and and A. C. M. and S. E. and S. E. is by the and The and the and

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