Activation of Lipoprotein Lipase by Glucose-dependent Insulinotropic Polypeptide in Adipocytes

Glucose-dependent insulinotropic polypeptide (GIP) has been mainly studied because of its glucose-dependent insulinotropic action and its ability to regulate β-cell proliferation and survival. Considerably less is known about the effects of GIP on fat metabolism, and the present study was directed at identifying the mechanisms underlying its stimulatory action on lipoprotein lipase (LPL). In differentiated 3T3-L1 adipocytes, GIP, in the presence of insulin, increased LPL activity and triglyceride accumulation through a pathway involving increased phosphorylation of protein kinase B (PKB) and reductions in phosphorylated LKB1 and AMP-activated protein kinase (AMPK). Knockdown of AMPK using RNA interference and application of the AMPK inhibitor, Compound C, supported this conclusion. In contrast, the other major incretin hormone, glucagon-like peptide-1, exhibited no significant effects on LPL activity or PKB, LKB1, or AMPK phosphorylation. Cultured subcutaneous human adipocytes showed similar responses to GIP but with greater sensitivity. Chronic elevation of circulating GIP levels in the Vancouver diabetic fatty Zucker rat in vivo resulted in increased LPL activity and elevated triglyceride accumulation in epidydimal fat tissue, combined with a modulation of PKB, LKB1, and AMPK phosphorylation similar to that observed in vitro. This appears to be the first demonstration of a GIP-stimulated signal transduction pathway involved in increasing fat storage in adipocytes. Glucose-dependent insulinotropic polypeptide (GIP) has been mainly studied because of its glucose-dependent insulinotropic action and its ability to regulate β-cell proliferation and survival. Considerably less is known about the effects of GIP on fat metabolism, and the present study was directed at identifying the mechanisms underlying its stimulatory action on lipoprotein lipase (LPL). In differentiated 3T3-L1 adipocytes, GIP, in the presence of insulin, increased LPL activity and triglyceride accumulation through a pathway involving increased phosphorylation of protein kinase B (PKB) and reductions in phosphorylated LKB1 and AMP-activated protein kinase (AMPK). Knockdown of AMPK using RNA interference and application of the AMPK inhibitor, Compound C, supported this conclusion. In contrast, the other major incretin hormone, glucagon-like peptide-1, exhibited no significant effects on LPL activity or PKB, LKB1, or AMPK phosphorylation. Cultured subcutaneous human adipocytes showed similar responses to GIP but with greater sensitivity. Chronic elevation of circulating GIP levels in the Vancouver diabetic fatty Zucker rat in vivo resulted in increased LPL activity and elevated triglyceride accumulation in epidydimal fat tissue, combined with a modulation of PKB, LKB1, and AMPK phosphorylation similar to that observed in vitro. This appears to be the first demonstration of a GIP-stimulated signal transduction pathway involved in increasing fat storage in adipocytes. Glucose-dependent insulinotropic polypeptide (GIP) 2The abbreviations used are: GIP, glucose-dependent insulinotropic polypeptide; LPL, lipoprotein lipase; PKB, protein kinase B; AMPK, AMP-activated protein kinase; GLP-1, glucagon-like peptide-1; FA, fatty acid; VDF, Vancouver diabetic fatty; PI3K, phosphatidylinositol 3-kinase; CA, constitutively active; DN, dominant negative; TG, triglyceride(s); DMEM, Dulbecco's modified Eagle's medium; OGTT, oral glucose tolerance test; ANOVA, analysis of variance; siRNA, small interfering RNA. is a pleiotropic hormone that is released from gut endocrine cells in response to nutrient ingestion (1Brown J.C. Buchan A.M.J. McIntosh C.H.S. Pederson R.A. Schultz S.G. Makhlouf G.M. Rauner B.B. Handbook of Physiology. American Physiology Society, Bethesda, MD1989: 403-430Google Scholar, 2Pederson R.A. Walsh J. Dockray G. Gut Peptides: Biochemistry and Physiology. Raven Press, Ltd., New York1993: 217-259Google Scholar, 3Pederson R.A. McIntosh C.H.S. Encyclopedia of Endocrine Diseases.Vol. 2. Elsevier Science Publishing Co., Inc., New York2004: 202-207Crossref Google Scholar). There is strong evidence that GIP and glucagon-like peptide-1 (GLP-1) are the two most important gut-derived insulinotropic hormones, or incretins (1Brown J.C. Buchan A.M.J. McIntosh C.H.S. Pederson R.A. Schultz S.G. Makhlouf G.M. Rauner B.B. Handbook of Physiology. American Physiology Society, Bethesda, MD1989: 403-430Google Scholar, 2Pederson R.A. Walsh J. Dockray G. Gut Peptides: Biochemistry and Physiology. Raven Press, Ltd., New York1993: 217-259Google Scholar, 3Pederson R.A. McIntosh C.H.S. Encyclopedia of Endocrine Diseases.Vol. 2. Elsevier Science Publishing Co., Inc., New York2004: 202-207Crossref Google Scholar, 4Meier J.J. Nauck M.A. Diabetes-Metab. Res. Rev. 2005; 21: 91-117Crossref PubMed Scopus (244) Google Scholar). Both incretins also exert powerful positive effects on pancreatic β-cell growth, development, and survival (5Ehses J.A. Casilla V.R. Doty T. Pospisilik J.A. Winter K.D. Demuth H.-U. Pederson R.A. McIntosh C.H.S. Endocrinology. 2003; 144: 4433-4445Crossref PubMed Scopus (149) Google Scholar, 6Drucker D.J. Endocrinology. 2003; 144: 5145-5148Crossref PubMed Scopus (243) Google Scholar). A number of studies have demonstrated that GIP plays an important role in the regulation of fat metabolism (7Morgan L.M. Biochem. Soc. Trans. 1996; 24: 585-591Crossref PubMed Scopus (50) Google Scholar, 8McIntosh C.H.S. Bremsak I. Lynn F.C. Gill R. Hinke S.A. Gelling R. McKnight G. Jaspers S. Pederson R.A. Endocrinology. 1999; 140: 398-404Crossref PubMed Scopus (51) Google Scholar, 9Yip R.G.C. Wolfe M.M. Life Sci. 2000; 66: 91-103Crossref PubMed Google Scholar). GIP is released in response to administration of triglycerides (TG) (1Brown J.C. Buchan A.M.J. McIntosh C.H.S. Pederson R.A. Schultz S.G. Makhlouf G.M. Rauner B.B. Handbook of Physiology. American Physiology Society, Bethesda, MD1989: 403-430Google Scholar, 2Pederson R.A. Walsh J. Dockray G. Gut Peptides: Biochemistry and Physiology. Raven Press, Ltd., New York1993: 217-259Google Scholar), with long chain fatty acids (FAs) being responsible for stimulating secretion (1Brown J.C. Buchan A.M.J. McIntosh C.H.S. Pederson R.A. Schultz S.G. Makhlouf G.M. Rauner B.B. Handbook of Physiology. American Physiology Society, Bethesda, MD1989: 403-430Google Scholar). In dogs, GIP has been shown to promote clearance of chylomicron-associated TG from blood (10Wasada T. McCorkle K. Harris V. Kawai K. Howard B. Unger R.H. J. Clin. Invest. 1981; 68: 1106-1107Crossref PubMed Scopus (130) Google Scholar), and in rats, it has been shown to promote infusion of GIP-lowered plasma TG responses to intraduodenal fat (11Ohneda A. Kobayashi T. Nihei J. Regul. Pept. 1984; 8: 123-130Crossref PubMed Scopus (9) Google Scholar). GIP enhanced FA synthesis from acetate in adipose tissue explants (12Oben J. Morgan L. Fletcher J. Marks V. J. Endocrinol. 1991; 130: 267-272Crossref PubMed Scopus (177) Google Scholar) as well as potentiating insulin-stimulated FA incorporation into adipose tissue (13Beck B. Max J.P. Regul. Pept. 1983; 7: 3-8Crossref PubMed Scopus (71) Google Scholar) and stimulating lipoprotein lipase (LPL) activity in cultured preadipocytes (14Eckel R.H. Fujimoto W.Y. Brunzell J.D. Diabetes. 1979; 28: 1141-1142Crossref PubMed Scopus (0) Google Scholar) and mature adipocytes (15Knapper J.M.E. Puddicombe S.M. Morgan L.M. Fletcher J.M. J. Nutr. 1995; 125: 183-188PubMed Google Scholar). These studies pointed to a significant role for GIP in the regulation of adipogenesis, and its physiological importance was emphasized by the demonstration by Miyawaki et al. (16Miyawaki K. Yamada Y. Ban N. Ihara Y. Tsukiyama K. Zhou H. Fujimoto S. Oku A. Tsuda K. Toyokuni S. Hiau H. Mizunoya W. Fushiki T. Holst J.J. Makino M. Tashita A. Kobara Y. Tsubamoto Y. Jinnouchi T. Jomori T. Seino Y. Nat. Med. 2002; 8: 738-742Crossref PubMed Scopus (725) Google Scholar) that GIP receptor knock-out mice exhibited reduced adipose tissue accretion on a high fat diet. The GIP receptor is a member of the class B seven-transmembrane G protein-coupled family to which the receptors for glucagon, GLP-1, and secretin belong (17Wheeler M.B. Gelling R.W. McIntosh C.H.S. Georgiou J. Brown J.C. Pederson R.A. Endocrinology. 1995; 136: 4629-4639Crossref PubMed Google Scholar, 18Usdin T.B. Mezey E. Button D.C. Brownstein Endocrinology. PubMed Scopus Google Scholar). The of studies on the of action of GIP have been in or β-cell and have shown that receptor in the of (17Wheeler M.B. Gelling R.W. McIntosh C.H.S. Georgiou J. Brown J.C. Pederson R.A. Endocrinology. 1995; 136: 4629-4639Crossref PubMed Google Scholar) and J.A. Pederson R.A. McIntosh C.H.S. J. PubMed Scopus (50) Google Scholar). a number of protein kinase J.A. Pederson R.A. McIntosh C.H.S. J. 2002; PubMed Scopus Google Scholar), and phosphatidylinositol kinase B Winter K. M. Y. McIntosh C.H.S. J. 2005; PubMed Scopus Google Scholar, A. K. H. R. B. Endocrinol. PubMed Scopus Google Scholar). The by which GIP on adipocytes is GIP receptor has been demonstrated in rat adipocytes R.G.C. Wolfe M.M. Endocrinology. PubMed Scopus Google Scholar) and differentiated 3T3-L1 cells C.H.S. Bremsak I. Lynn F.C. Gill R. Hinke S.A. Gelling R. McKnight G. Jaspers S. Pederson R.A. Endocrinology. 1999; 140: 398-404Crossref PubMed Scopus (51) Google Scholar), in the of insulin, in the of and C.H.S. Bremsak I. 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GIP LPL activity (14Eckel R.H. Fujimoto W.Y. Brunzell J.D. Diabetes. 1979; 28: 1141-1142Crossref PubMed Scopus (0) Google Scholar, J.M.E. Puddicombe S.M. Morgan L.M. Fletcher J.M. J. Nutr. 1995; 125: 183-188PubMed Google Scholar), that it by AMPK fatty and to the and to increased D.J. Endocrinology. 2003; 144: 5145-5148Crossref PubMed Scopus (243) Google Scholar, L.M. Biochem. Soc. Trans. 1996; 24: 585-591Crossref PubMed Scopus (50) Google Scholar, B. Max J.P. Regul. Pept. 1983; 7: 3-8Crossref PubMed Scopus (71) Google Scholar). differentiated 3T3-L1 cells and human subcutaneous adipocytes, have demonstrated that GIP phosphorylation of and LKB1 and AMPK phosphorylation in the presence of insulin, in of LPL and TG Knockdown of AMPK using RNA interference and application of the AMPK Compound supported this conclusion. Chronic elevation of circulating GIP levels in the Vancouver diabetic fatty Zucker rat in vivo resulted in of LPL in epidydimal fat tissue by a similar This appears to be the first of a pathway by which GIP FA storage in adipocytes. and of 3T3-L1 3T3-L1 cells cultured in high glucose and with in to into the as C.H.S. Bremsak I. Lynn F.C. Gill R. Hinke S.A. Gelling R. McKnight G. Jaspers S. Pederson R.A. Endocrinology. 1999; 140: 398-404Crossref PubMed Scopus (51) Google Scholar). In cells was with and for which cells cultured in high glucose was in cells by and differentiated cells adipose from used in and of human preadipocytes from from and differentiated into adipocytes to the and for of the adipose tissue from the by studies on the of GIP on PKB, LKB1, and AMPK 3T3-L1 adipocytes or human adipocytes with GIP in the presence of insulin, as in the the AMPK inhibitor, Compound was at a of from on a and of the was with PKB, AMPK and Inc., by enhanced using of preadipocytes in with and and with constitutively AMPK and dominant AMPK the constitutively and dominant of AMPK, the of AMPK a in a of to A a an to was and by of using for to the cells with and differentiated into adipocytes, and by to AMPK protein Knockdown of by RNA levels of 3T3-L1 adipocytes with a of for using and for The interference of AMPK protein was by using and LPL LPL activity was used to to the activity is as activity to protein GIP and to a infusion of GIP The infusion was using an in the at the of the and epidydimal fat for in with of the of and on and of and glucose levels using a an with blood glucose levels the glucose at the in levels using a Inc., human adipocytes for with GIP or in the presence of and for by in a of The of et al. W. PubMed Scopus Google Scholar) was used to the of was to the and by and the at was of TG TG was used to TG of human adipocytes and fat to the are as with the number of in the using the analysis and was using analysis of with as in the GIP, but GLP-1, LPL in 3T3-L1 of the GIP and GLP-1, on LPL activity was first studied in 3T3-L1 adipocytes. with GIP in the presence of for resulted in in LPL with In contrast, of 3T3-L1 adipocytes with resulted in small in LPL activity that effects of GIP on LPL activity observed with of GIP of 3T3-L1 in and of AMPK and mechanisms involved in the of LPL by GIP of AMPK at by kinase AMPK is for its Biochem. Sci. PubMed Scopus Google Scholar, S.A. J. Scopus Google Scholar), in in activity of at The major kinase for of AMPK in most adipose S.A. J. Scopus Google Scholar), has been as LKB1 A. K. F.C. T. M. 2003; PubMed Scopus Google Scholar, Med. PubMed Scopus Google Scholar). of 3T3-L1 adipocytes with GIP in the presence of resulted in in phosphorylation of AMPK at and LKB1 at responses with of for AMPK and for LKB1 In GIP phosphorylation of at with an of phosphorylation of AMPK and LKB1 A and and increased phosphorylation of by GIP and for of 3T3-L1 adipocytes with in the presence of resulted in no significant in phosphorylation of PKB, LKB1, or AMPK These well with the of of on LPL no significant effects on phosphorylation of AMPK, LKB1, or in 3T3-L1 adipocytes. for of 3T3-L1 adipocytes with GIP as in the to 2. is the of phosphorylation of AMPK LKB1 and in the presence of are effects of GIP on AMPK LKB1 and using analysis and are of was using with in GIP of the phosphorylation of and by is for M. B. N. J. 1996; Scopus Google Scholar), the and the was studied using the of PI3K, and of reduced levels of and responses to GIP the other of increased levels of phosphorylated LKB1 and AMPK, and GIP no significant on levels of phosphorylated kinase B and the of LPL activity was and responses to GIP These that is an of the GIP-stimulated and LKB1 of AMPK and the and AMPK in the regulation of LPL 3T3-L1 adipocytes or of AMPK 3T3-L1 adipocytes demonstrated increased levels that reduced by with GIP or high of In contrast, levels of reduced in 3T3-L1 adipocytes the was by GIP or There no significant in the phosphorylation levels of and LKB1 with the of or with 3T3-L1 adipocytes with B and In 3T3-L1 adipocytes LPL that was to GIP of increased LPL and GIP resulted in a that is an of LPL activity of and cells was to GIP, to that was involved in LPL of cells with an AMPK inhibitor, Compound C, resulted in a in levels in phosphorylation levels of and LKB1 B and levels to effects of the AMPK increased LPL but it was increased by GIP RNA of resulted in similar a in levels no in and LKB1 phosphorylation and and increased LPL activity that was to GIP with siRNA, GIP increased LPL a role for AMPK in LPL with as an is involved for the regulation of LPL of AMPK on kinase phosphorylation. 3T3-L1 adipocytes with GIP in the presence or of AMPK for to cells a and GIP using or and of AMPK on LPL is the of using on kinase phosphorylation. 3T3-L1 adipocytes with or and with GIP using or and of on LPL of RNA of was using with of GIP and on GIP was demonstrated to regulate the levels of phosphorylation and LPL activity in 3T3-L1 adipocytes, the in the This be to GIP receptor C.H.S. Bremsak I. Lynn F.C. Gill R. Hinke S.A. Gelling R. McKnight G. Jaspers S. Pederson R.A. Endocrinology. 1999; 140: 398-404Crossref PubMed Scopus (51) Google Scholar) with adipocytes. the responses of human adipocytes similar to the 3T3-L1 adipocytes. with GIP in the presence of for resulted in a in LPL with effects of GIP on LPL activity observed with of exert significant on LPL activity In of AMPK and LKB1 phosphorylation and in phosphorylation with GIP as as no significant on phosphorylation. LPL was with increased TG was shown in with GIP in the presence of for resulted in a in TG accumulation with no significant cells with levels of in the increased with the or for that GIP modulation of the in increased LPL activity and of GIP on in GIP regulate LPL in GIP was to or Zucker rats, the being an of J.A. S.G. Demuth R. W. McIntosh C.H.S. Pederson R.A. Diabetes. 2002; PubMed Scopus (244) Google Scholar). shown in blood glucose levels in fatty increased with and demonstrated glucose GIP administration no significant effects on or glucose or in or glucose in showed a small with the GIP infusion with and this was with increased in the There no in the in fatty GIP GIP blood glucose levels blood glucose levels the levels levels in a LPL activity was elevated in fat from with of with GIP, fat LPL activity was increased in and with GIP infusion resulted in increased and reduced and B and in as well as These well with the in in 3T3-L1 and human adipocytes. TG was elevated in fat from rats, with and of with GIP, it was increased in and These a role for GIP in the regulation of adipose tissue LPL and TG accumulation in through a have been in of the physiological of the two major incretin hormones, GIP and GLP-1, and of There is the effects of GIP on fat metabolism, it stimulatory on C.H.S. Bremsak I. Lynn F.C. Gill R. Hinke S.A. Gelling R. McKnight G. Jaspers S. Pederson R.A. Endocrinology. 1999; 140: 398-404Crossref PubMed Scopus (51) Google Scholar, R.G.C. Wolfe M.M. Endocrinology. PubMed Scopus Google Scholar) and is a of GIP secretion glucose (1Brown J.C. Buchan A.M.J. McIntosh C.H.S. Pederson R.A. Schultz S.G. Makhlouf G.M. Rauner B.B. Handbook of Physiology. American Physiology Society, Bethesda, MD1989: 403-430Google Scholar, 2Pederson R.A. Walsh J. Dockray G. Gut Peptides: Biochemistry and Physiology. Raven Press, Ltd., New York1993: 217-259Google Scholar), and GIP infusion has been shown to promote clearance of chylomicron-associated TG from blood (10Wasada T. McCorkle K. Harris V. Kawai K. Howard B. Unger R.H. J. Clin. Invest. 1981; 68: 1106-1107Crossref PubMed Scopus (130) Google Scholar) and to plasma TG responses to intraduodenal fat (11Ohneda A. Kobayashi T. Nihei J. Regul. Pept. 1984; 8: 123-130Crossref PubMed Scopus (9) Google Scholar). GIP also adipose tissue synthesis of FA from acetate (12Oben J. Morgan L. Fletcher J. Marks V. J. Endocrinol. 1991; 130: 267-272Crossref PubMed Scopus (177) Google Scholar) as well as potentiating insulin-stimulated FA incorporation into fat (13Beck B. Max J.P. Regul. Pept. 1983; 7: 3-8Crossref PubMed Scopus (71) Google Scholar) and LPL activity in cultured preadipocytes (14Eckel R.H. Fujimoto W.Y. Brunzell J.D. Diabetes. 1979; 28: 1141-1142Crossref PubMed Scopus (0) Google Scholar) and mature adipocytes (15Knapper J.M.E. Puddicombe S.M. Morgan L.M. Fletcher J.M. J. Nutr. 1995; 125: 183-188PubMed Google Scholar). The physiological importance of the was emphasized by the demonstration by Miyawaki et al. (16Miyawaki K. Yamada Y. Ban N. Ihara Y. Tsukiyama K. Zhou H. Fujimoto S. Oku A. Tsuda K. Toyokuni S. Hiau H. Mizunoya W. Fushiki T. Holst J.J. Makino M. Tashita A. Kobara Y. Tsubamoto Y. Jinnouchi T. Jomori T. Seino Y. Nat. Med. 2002; 8: 738-742Crossref PubMed Scopus (725) Google Scholar) that fat in GIP receptor knock-out mice a high fat was reduced with the underlying mechanisms by which GIP fatty incorporation into adipose tissue LPL is by and in a K. R. G. R. 2002; PubMed Scopus Google Scholar, M. R.H. J. Res. 2002; PubMed Scopus Google Scholar). In adipose tissue, the storage for TG, LPL activity is by and by in which fatty acids for in the LPL activity is by and by K. R. G. R. 2002; PubMed Scopus Google Scholar, M. R.H. J. Res. 2002; PubMed Scopus Google Scholar). LPL activity in 3T3-L1 adipocytes M. L. J. L. J. PubMed Google Scholar) and adipose tissue K. R. G. R. 2002; PubMed Scopus Google Scholar) but its activity in the N. M.A. E. B. 1999; PubMed Scopus Google Scholar). 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J. 2000; PubMed Scopus Google Scholar). and the presence of cells that or to also have to a The of LPL activity have been mainly a of the increased levels of GIP of the activity be the in increased LPL The of cells to this of a of AMPK reduced and this was with in LPL activity to levels to observed GIP in cells A and The of GIP to cells a in LPL This be by the levels have been AMPK activity for stimulating LPL studies with this have shown that protein levels to the and that are for of activity of the A. M. 2000; PubMed Scopus Google Scholar). the cells to of activity is a The of AMPK in the regulation of LPL was using with an AMPK and Both resulted in reduced levels of increased LPL and to GIP and Compound as a at the of AMPK G. R. Y. Y. J. M. J. T. N. N. J. Clin. Invest. PubMed Scopus Google Scholar), and the in levels is in with studies on a L. Biochem. PubMed Scopus Google Scholar), cells S. J. Res. PubMed Scopus Google Scholar), and pancreatic β-cell B. Scholar). on that of phosphorylation at by with resulted in increased phosphorylation of LKB1 at and AMPK at that is a in this similar to the The underlying mechanisms are of a for LKB1 be the ability of to AMPK in the has been shown to a phosphorylation of AMPK in a in phosphorylation S. R. V. A. T. L. J. PubMed Scopus Google Scholar). have evidence LKB1 in the action of GIP on the it has been shown in an β-cell that of increasing as GIP, also AMPK activity of protein kinase kinase through of protein kinase A J. PubMed Scopus Google Scholar). be of to this also in adipose The increased LPL activity and reduced AMPK phosphorylation with the in the T. B. J. 2005; PubMed Scopus Google Scholar), AMPK in increased LPL this is with the role of LPL in fatty acids to the a and for in in studies on human adipocytes and in vivo studies on rats, GIP administration be shown to TG a with the increased LPL The reduced AMPK phosphorylation and increased LPL activity is in of the regulation of LPL in J. Res. 1996; PubMed Google Scholar, Biochem. J. PubMed Scopus Google Scholar, M. R.H. J. Res. 2002; PubMed Scopus Google Scholar), and of the of the in responses to GIP in differentiated 3T3-L1 adipocytes responses studied in the presence of insulin, because in its GIP mainly as a hormone C.H.S. Bremsak I. Lynn F.C. Gill R. Hinke S.A. Gelling R. McKnight G. Jaspers S. Pederson R.A. Endocrinology. 1999; 140: 398-404Crossref PubMed Scopus (51) Google Scholar, 9Yip R.G.C. Wolfe M.M. Life Sci. 2000; 66: 91-103Crossref PubMed Google Scholar), and its stimulatory action on is also The responses to GIP are The for this is and the the of of that an of action have no evidence for the of with differentiated 3T3-L1 the of GIP with in the of for this it was that GIP on adipocytes mainly to receptors J. N. S.A. PubMed Scopus Google Scholar), the on of the receptor PubMed Scopus Google Scholar) at to but no significant effects that it be to of receptor or in 3T3-L1 adipocytes, to the responses to GIP to with of GIP C.H.S. Bremsak I. Lynn F.C. Gill R. Hinke S.A. Gelling R. McKnight G. Jaspers S. Pederson R.A. Endocrinology. 1999; 140: 398-404Crossref PubMed Scopus (51) Google Scholar), and it has been shown that with number R.H. Fujimoto W.Y. Brunzell J.D. J. 1981; Google Scholar). the of human subcutaneous adipocytes and that to GIP at as as well the physiological a infusion of of GIP in the Zucker rat to a modulation of PKB, LKB1, AMPK, and LPL similar to that observed in 3T3-L1 adipocytes These in vivo studies are by the that GIP and long administration from with the infusion the demonstrated no major in circulating glucose or levels with The showed a small but significant in glucose was no in the of showed increased fat TG and in similar to observed with the in studies that the responses observed to GIP or blood glucose In GIP similar activity with the major incretin hormone, GLP-1, and levels and protein kinase A and with The receptor is also in adipocytes H. Y. J. J. PubMed Scopus Google Scholar), but demonstrated effects on PKB, LKB1, AMPK, and LPL in human and 3T3-L1 adipocytes. These receptor or from GIP in In GIP is to an important role in fat by increasing LPL activity in adipocytes, and a is involved in this This appears to be the first the mechanisms underlying the action of GIP on fat GIP on adipose tissue with in circulating GIP levels be increased by its effects be in with its an action the for GIP receptor with an of for the of and with

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