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• W2164548123 abstract "Adiposity is commonly associated with adipose tissue dysfunction and many overnutrition-related metabolic diseases including type 2 diabetes. Much attention has been paid to reducing adiposity as a way to improve adipose tissue function and systemic insulin sensitivity. PFKFB3/iPFK2 is a master regulator of adipocyte nutrient metabolism. Using PFKFB3+/− mice, the present study investigated the role of PFKFB3/iPFK2 in regulating diet-induced adiposity and systemic insulin resistance. On a high-fat diet (HFD), PFKFB3+/− mice gained much less body weight than did wild-type littermates. This was attributed to a smaller increase in adiposity in PFKFB3+/− mice than in wild-type controls. However, HFD-induced systemic insulin resistance was more severe in PFKFB3+/− mice than in wild-type littermates. Compared with wild-type littermates, PFKFB3+/− mice exhibited increased severity of HFD-induced adipose tissue dysfunction, as evidenced by increased adipose tissue lipolysis, inappropriate adipokine expression, and decreased insulin signaling, as well as increased levels of proinflammatory cytokines in both isolated adipose tissue macrophages and adipocytes. In an in vitro system, knockdown of PFKFB3/iPFK2 in 3T3-L1 adipocytes caused a decrease in the rate of glucose incorporation into lipid but an increase in the production of reactive oxygen species. Furthermore, knockdown of PFKFB3/iPFK2 in 3T3-L1 adipocytes inappropriately altered the expression of adipokines, decreased insulin signaling, increased the phosphorylation states of JNK and NFκB p65, and enhanced the production of proinflammatory cytokines. Together, these data suggest that PFKFB3/iPFK2, although contributing to adiposity, protects against diet-induced insulin resistance and adipose tissue inflammatory response. Adiposity is commonly associated with adipose tissue dysfunction and many overnutrition-related metabolic diseases including type 2 diabetes. Much attention has been paid to reducing adiposity as a way to improve adipose tissue function and systemic insulin sensitivity. PFKFB3/iPFK2 is a master regulator of adipocyte nutrient metabolism. Using PFKFB3+/− mice, the present study investigated the role of PFKFB3/iPFK2 in regulating diet-induced adiposity and systemic insulin resistance. On a high-fat diet (HFD), PFKFB3+/− mice gained much less body weight than did wild-type littermates. This was attributed to a smaller increase in adiposity in PFKFB3+/− mice than in wild-type controls. However, HFD-induced systemic insulin resistance was more severe in PFKFB3+/− mice than in wild-type littermates. Compared with wild-type littermates, PFKFB3+/− mice exhibited increased severity of HFD-induced adipose tissue dysfunction, as evidenced by increased adipose tissue lipolysis, inappropriate adipokine expression, and decreased insulin signaling, as well as increased levels of proinflammatory cytokines in both isolated adipose tissue macrophages and adipocytes. In an in vitro system, knockdown of PFKFB3/iPFK2 in 3T3-L1 adipocytes caused a decrease in the rate of glucose incorporation into lipid but an increase in the production of reactive oxygen species. Furthermore, knockdown of PFKFB3/iPFK2 in 3T3-L1 adipocytes inappropriately altered the expression of adipokines, decreased insulin signaling, increased the phosphorylation states of JNK and NFκB p65, and enhanced the production of proinflammatory cytokines. Together, these data suggest that PFKFB3/iPFK2, although contributing to adiposity, protects against diet-induced insulin resistance and adipose tissue inflammatory response. IntroductionAs demonstrated by numerous data generated from high fat diet (HFD) 3The abbreviations used are: HFDhigh fat dietiPFK2inducible 6-phosphofructo-2-kinaseF26P2fructose-2,6-bisphosphate6PFK16-phosphofructo-1-kinasePPARαperoxisome proliferator-activated receptor αPGC1peroxisome proliferative-activated receptor γ, coactivator 1CPT1carnitine palmitoyltransferase-1JNKc-Jun N-terminal kinaseNFκBnuclear factor κBTNFαtumor necrosis factor αILinterleukinDMEMDulbecco's modified Eagle's mediumROSreactive oxygen speciesLFDlow fat diet. -fed rodents, overnutrition is associated with adiposity and systemic insulin resistance. For example, feeding an HFD to rats for 10 weeks causes a significant increase in visceral fat mass, which is accompanied by a decrease in systemic insulin sensitivity as evidenced by decreased rate of clamp glucose infusion (1Kusunoki M. Hara T. Tsutsumi K. Nakamura T. Miyata T. Sakakibara F. Sakamoto S. Ogawa H. Nakaya Y. Storlien L.H. Diabetologia. 2000; 43: 875-880Crossref PubMed Scopus (72) Google Scholar). Similarly, after a feeding of HFD for 20 weeks, both of the two different strains of wild-type mice gain a significant increase in fat mass, which is associated with systemic insulin resistance and glucose intolerance (2Gallou-Kabani C. Vigé A. Gross M.S. Rabès J.P. Boileau C. Larue-Achagiotis C. Tomé D. Jais J.P. Junien C. Obesity. 2007; 15: 1996-2005Crossref PubMed Scopus (172) Google Scholar). A recent study even indicates that feeding an HFD to mice for only 6 weeks is sufficient to induce adiposity and systemic insulin resistance (3Llagostera E. Carmona M.C. Vicente M. Escorihuela R.M. Kaliman P. FEBS Letters. 2009; 583: 2121-2125Crossref PubMed Scopus (10) Google Scholar). Furthermore, as documented in mice lacking the myotonic dystrophy protein kinase, a larger augmentation in adiposity is accompanied by a greater increase in the severity of systemic insulin resistance (3Llagostera E. Carmona M.C. Vicente M. Escorihuela R.M. Kaliman P. FEBS Letters. 2009; 583: 2121-2125Crossref PubMed Scopus (10) Google Scholar). Because of this, adiposity has been generally viewed as an important contributor of systemic insulin resistance (3Llagostera E. Carmona M.C. Vicente M. Escorihuela R.M. Kaliman P. FEBS Letters. 2009; 583: 2121-2125Crossref PubMed Scopus (10) Google Scholar, 4Kahn B.B. Flier J.S. J. Clin. Invest. 2000; 106: 473-481Crossref PubMed Scopus (2410) Google Scholar, 5Miyazaki Y. Glass L. Triplitt C. Wajcberg E. Mandarino L.J. DeFronzo R.A. Am. J. Physiol. Endocrinol. Metab. 2002; 283: E1135-E1143Crossref PubMed Scopus (209) Google Scholar, 6Ghibaudi L. Cook J. Farley C. van Heek M. Hwa J.J. Obesity. 2002; 10: 956-963Crossref Scopus (158) Google Scholar, 7Krekoukia M. Nassis G.P. Psarra G. Skenderi K. Chrousos G.P. Sidossis L.S. Metabolism. 2007; 56: 206-213Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). On the other hand, reducing adiposity has been considered as an effective way to reverse systemic insulin resistance (1Kusunoki M. Hara T. Tsutsumi K. Nakamura T. Miyata T. Sakakibara F. Sakamoto S. Ogawa H. Nakaya Y. Storlien L.H. Diabetologia. 2000; 43: 875-880Crossref PubMed Scopus (72) Google Scholar, 8Air E.L. Strowski M.Z. Benoit S.C. Conarello S.L. Salituro G.M. Guan X.M. Liu K. Woods S.C. Zhang B.B. Nat. Med. 2002; 8: 179-183Crossref PubMed Scopus (142) Google Scholar). However, adiposity is not necessarily associated with systemic insulin resistance. This is particularly true in genetically modified mice and in mice treated with pharmacological agents (9Zhang J. Fu M. Cui T. Xiong C. Xu K. Zhong W. Xiao Y. Floyd D. Liang J. Li E. Song Q. Chen Y.E. Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 10703-10708Crossref PubMed Scopus (215) Google Scholar, 10Combs T.P. Pajvani U.B. Berg A.H. Lin Y. Jelicks L.A. Laplante M. Nawrocki A.R. Rajala M.W. Parlow A.F. Cheeseboro L. Ding Y.Y. Russell R.G. Lindemann D. Hartley A. Baker G.R. Obici S. Deshaies Y. Ludgate M. Rossetti L. Scherer P.E. Endocrinology. 2004; 145: 367-383Crossref PubMed Scopus (442) Google Scholar, 11Muurling M. Mensink R.P. Pijl H. Romijn J.A. Havekes L.M. Voshol P.J. Metabolism. 2003; 52: 1078-1083Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 12Gavrilova O. Haluzik M. Matsusue K. Cutson J.J. Johnson L. Dietz K.R. Nicol C.J. Vinson C. Gonzalez F.J. Reitman M.L. J. Biol. Chem. 2003; 278: 34268-34276Abstract Full Text Full Text PDF PubMed Scopus (621) Google Scholar, 13Stienstra R. Duval C. Keshtkar S. van der Laak J. Kersten S. Müller M. J. Biol. Chem. 2008; 283: 22620-22627Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar). Following the investigation into the insight of altered systemic insulin sensitivity, it has been suggested that adipose tissue dysfunction is far more important than adiposity in terms of causing systemic insulin resistance (13Stienstra R. Duval C. Keshtkar S. van der Laak J. Kersten S. Müller M. J. Biol. Chem. 2008; 283: 22620-22627Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 14Evans R.M. Barish G.D. Wang Y.X. Nat. Med. 2004; 10: 355-361Crossref PubMed Scopus (1257) Google Scholar, 15Qatanani M. Lazar M.A. Genes Dev. 2007; 21: 1443-1455Crossref PubMed Scopus (539) Google Scholar, 16Bullen Jr., J.W. Bluher S. Kelesidis T. Mantzoros C.S. Am. J. Physiol. Endocrinol. Metab. 2007; 292: E1079-E1086Crossref PubMed Scopus (119) Google Scholar).Mounting evidence points to a pivotal role for overnutrition-related inflammation in causing adipose tissue dysfunction and thereby systemic insulin resistance. In mice fed an HFD, chronic low grade inflammation in adipose tissue is evident and characterized by an increase in macrophage infiltration and proinflammatory cytokine production (17Weisberg S.P. McCann D. Desai M. Rosenbaum M. Leibel R.L. Ferrante Jr., A.W. J. Clin. Invest. 2003; 112: 1796-1808Crossref PubMed Scopus (7308) Google Scholar, 18Lumeng C.N. DeYoung S.M. Bodzin J.L. Saltiel A.R. Diabetes. 2007; 56: 16-23Crossref PubMed Scopus (758) Google Scholar). This brings about adipose tissue dysfunction, demonstrated by an increase in the production pro-hyperglycemic factors such as free fatty acids and resistin and a decrease in the production of anti-hyperglycemic factors such as adiponectin (4Kahn B.B. Flier J.S. J. Clin. Invest. 2000; 106: 473-481Crossref PubMed Scopus (2410) Google Scholar, 15Qatanani M. Lazar M.A. Genes Dev. 2007; 21: 1443-1455Crossref PubMed Scopus (539) Google Scholar, 19Rosen E.D. Spiegelman B.M. Nature. 2006; 444: 847-853Crossref PubMed Scopus (1569) Google Scholar, 20Badman M.K. Flier J.S. Gastroenterology. 2007; 132: 2103-2115Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar). These changes, along with increased production of proinflammatory cytokines such as tumor necrosis factor α (TNFα) and interleukin 6 (IL-6) from both adipocytes and adipose tissue macrophages, impair insulin signaling in insulin-sensitive tissues including the liver and skeletal muscle, leading to systemic insulin resistance (21Hotamisligil G.S. Peraldi P. Budavari A. Ellis R. White M.F. Spiegelman B.M. Science. 1996; 271: 665-668Crossref PubMed Scopus (2177) Google Scholar, 22Cheung A.T. Ree D. Kolls J.K. Fuselier J. Coy D.H. Bryer-Ash M. Endocrinology. 1998; 139: 4928-4935Crossref PubMed Google Scholar, 23Cheung A.T. Wang J. Ree D. Kolls J.K. Bryer-Ash M. Diabetes. 2000; 49: 810-819Crossref PubMed Scopus (72) Google Scholar, 24Boden G. Cheung P. Stein T.P. Kresge K. Mozzoli M. Am. J. Physiol. Endocrinol. Metab. 2002; 283: E12-E19Crossref PubMed Scopus (183) Google Scholar, 25Berg A.H. Combs T.P. Du X. Brownlee M. Scherer P.E. Nat. Med. 2001; 7: 947-953Crossref PubMed Scopus (2187) Google Scholar, 26Kabir M. Catalano K.J. Ananthnarayan S. Kim S.P. Van Citters G.W. Dea M.K. Bergman R.N. Am. J. Physiol. Endocrinol. Metab. 2005; 288: E454-E461Crossref PubMed Scopus (244) Google Scholar). In contrast, treatment with thiazolidinediones ameliorates adipose tissue inflammation, which in turn contributes, at least in part, to the reversal of diet-induced adipose tissue dysfunction and systemic insulin resistance (13Stienstra R. Duval C. Keshtkar S. van der Laak J. Kersten S. Müller M. J. Biol. Chem. 2008; 283: 22620-22627Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 27Xu H. Barnes G.T. Yang Q. Tan G. Yang D. Chou C.J. Sole J. Nichols A. Ross J.S. Tartaglia L.A. Chen H. J. Clin. Invest. 2003; 112: 1821-1830Crossref PubMed Scopus (5110) Google Scholar). For this reason, adipose tissue inflammation is of particular importance to the regulation of systemic insulin sensitivity.PFKFB3 is the gene that codes for the inducible 6-phosphofructo-2-kinase (iPFK2) that is highly expressed in adipose tissue (28Atsumi T. Nishio T. Niwa H. Takeuchi J. Bando H. Shimizu C. Yoshioka N. Bucala R. Koike T. Diabetes. 2005; 54: 3349-3357Crossref PubMed Scopus (56) Google Scholar). PFKFB3/iPFK2 generates fructose-2,6-bisphosphate (F26P2), which in turn activates 6-phosphofructo-1-kinase (6PFK1) to enhance glycolysis (29Okar D.A. Wu C. Lange A.J. Advances in Enzyme Regulation. Vol. 44. Elsevier, New York2004: 123-154Google Scholar, 30Rider M.H. Bertrand L. Vertommen D. Michels P.A. Rousseau G.G. Hue L. Biochem. J. 2004; 381: 561-579Crossref PubMed Scopus (275) Google Scholar). This effect is involved in adipocyte lipogenesis and triglyceride synthesis (28Atsumi T. Nishio T. Niwa H. Takeuchi J. Bando H. Shimizu C. Yoshioka N. Bucala R. Koike T. Diabetes. 2005; 54: 3349-3357Crossref PubMed Scopus (56) Google Scholar). However, it is unknown whether the metabolic properties of PFKFB3/iPFK2 are related to the regulation of adipose tissue function, in particular adipose tissue inflammatory response. The present study provides evidence to support a novel role for PFKFB3/iPFK2 in regulating diet-induced systemic insulin resistance and adipose tissue inflammatory response in a manner independent of adiposity.DISCUSSIONFeeding an HFD to mice induces adiposity, which is associated with adipose tissue dysfunction, a key contributor of systemic insulin resistance (42Haugen F. Drevon C.A. Proc. Nutr. Soc. 2007; 66: 171-182Crossref PubMed Scopus (20) Google Scholar, 43Morin C.L. Eckel R.H. Marcel T. Pagliassotti M.J. Endocrinology. 1997; 138: 4665-4671Crossref PubMed Scopus (65) Google Scholar). This is the case in wild-type littermates. However, in PFKFB3+/− mice, although bringing about a much smaller increase in adiposity, feeding an HFD caused a much greater increase in the severity of HFD-induced adipose tissue dysfunction and systemic insulin resistance than in wild-type littermates. These changes were attributed, at least in part, to the increased adipose tissue inflammatory response, which was evidenced by higher levels of proinflammatory cytokines in both isolated adipose tissue macrophages and adipocytes in PFKFB3+/− mice. Consistently, in cultured adipocytes, knockdown of PFKFB3/iPFK2 caused a decrease in lipid accumulation and an increase in the status of oxidative stress, which were accompanied by enhanced inflammatory signaling, increased mRNA levels of TNFα and IL-6, and decreased insulin signaling. Together, these data argue in favor of a novel and unique role for PFKFB3/iPFK2 in regulating HFD-induced adipose tissue dysfunction and systemic insulin resistance in a manner independent of adiposity.The unique role of PFKFB3/iPFK2 in dissociating HFD-induced adiposity and adipose tissue dysfunction is attributed, at a large extent, to the metabolic properties of PFKFB3/iPFK2. Notably, PFKFB3/iPFK2 stimulates adipocyte glycolysis (28Atsumi T. Nishio T. Niwa H. Takeuchi J. Bando H. Shimizu C. Yoshioka N. Bucala R. Koike T. Diabetes. 2005; 54: 3349-3357Crossref PubMed Scopus (56) Google Scholar). An increase in PFKFB3/iPFK2-stimulated glycolysis not only provides lactate and pyruvate (which are converted into acetyl-CoA and used for lipogenesis to provide free fatty acids), but also increases the production of dihydroxyacetone phosphate, which is converted into glycerol-3-phosphate as a required substrate for adipocyte triglyceride synthesis. Upon disruption of PFKFB3/iPFK2, both glycolysis and glycolysis-derived lipogenesis and triglyceride synthesis are impaired, which is supported by the data that PFKFB3/iPFK2-knockdown adipocytes exhibited a decrease in the incorporation of glucose into lipid, and thereby adipocyte lipid accumulation. This contributes to a smaller gain in adiposity in PFKFB3+/− mice after HFD feeding. Importantly, the impairment in using glucose as a fuel due to disruption of PFKFB3/iPFK2 likely causes a compensatory increase in fatty acid oxidation, which is supported by increased expression of CPT1, as well as PPARα and PGC1 in adipose tissue of PFKFB3+/− mice. The compensatory increase in fatty acid oxidation not only contributes to a smaller gain in adiposity in PFKFB3+/− mice after HFD feeding, but more importantly, appears to trigger oxidative stress. In support of this concept, PFKFB3/iPFK2-knockdown adipocytes exhibited an increase in the production of ROS under both basal and palmitate-stimulated conditions. Furthermore, inhibition of fatty acid oxidation by etomoxir caused a marked decrease in palmitate-stimulated production of ROS in PFKFB3/iPFK2-knockdown adipocytes. In agreement with the role oxidative stress in disturbing adipokine expression and initiating the inflammatory response in adipocytes (15Qatanani M. Lazar M.A. Genes Dev. 2007; 21: 1443-1455Crossref PubMed Scopus (539) Google Scholar), the increased production of ROS in PFKFB3/iPFK2-knockdown adipocytes was associated, on the one hand, with inappropriately altered expression of resistin and adiponectin, and on the other hand, with increased phosphorylation states of JNK and NFκB p65 and increased mRNA levels of TNFα and IL-6 in PFKFB3/iPFK2-knockdown adipocytes. Apparently, PFKFB3/iPFK2 links nutrient metabolism and adipocyte function.The role of adipose tissue dysfunction in causing systemic insulin resistance has been well documented (17Weisberg S.P. McCann D. Desai M. Rosenbaum M. Leibel R.L. Ferrante Jr., A.W. J. Clin. Invest. 2003; 112: 1796-1808Crossref PubMed Scopus (7308) Google Scholar, 18Lumeng C.N. DeYoung S.M. Bodzin J.L. Saltiel A.R. Diabetes. 2007; 56: 16-23Crossref PubMed Scopus (758) Google Scholar). Indeed, this role is illustrated by at least two plausible mechanisms (4Kahn B.B. Flier J.S. J. Clin. Invest. 2000; 106: 473-481Crossref PubMed Scopus (2410) Google Scholar, 15Qatanani M. Lazar M.A. Genes Dev. 2007; 21: 1443-1455Crossref PubMed Scopus (539) Google Scholar, 19Rosen E.D. Spiegelman B.M. Nature. 2006; 444: 847-853Crossref PubMed Scopus (1569) Google Scholar, 20Badman M.K. Flier J.S. Gastroenterology. 2007; 132: 2103-2115Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar). In the first mechanism, adipose tissue dysfunction causes an increase in the production of free fatty acids, resistin, and retinol-binding protein 4 (RBP4) and a decrease in the production of adiponectin. These factors are carried to the insulin-sensitive tissues including the liver and skeletal muscle through circulation to impair insulin signaling and ultimately bring about systemic insulin resistance (24Boden G. Cheung P. Stein T.P. Kresge K. Mozzoli M. Am. J. Physiol. Endocrinol. Metab. 2002; 283: E12-E19Crossref PubMed Scopus (183) Google Scholar, 25Berg A.H. Combs T.P. Du X. Brownlee M. Scherer P.E. Nat. Med. 2001; 7: 947-953Crossref PubMed Scopus (2187) Google Scholar, 26Kabir M. Catalano K.J. Ananthnarayan S. Kim S.P. Van Citters G.W. Dea M.K. Bergman R.N. Am. J. Physiol. Endocrinol. Metab. 2005; 288: E454-E461Crossref PubMed Scopus (244) Google Scholar, 53Yao-Borengasser A. Varma V. Bodles A.M. Rasouli N. Phanavanh B. Lee M.J. Starks T. Kern L.M. Spencer 3rd, H.J. Rashidi A.A. McGehee Jr., R.E. Fried S.K. Kern P.A. J. Clin. Endocrinol. Metab. 2007; 92: 2590-2597Crossref PubMed Scopus (191) Google Scholar). In the second mechanism, adipose tissue-derived proinflammatory cytokines are similarly carried to insulin-sensitive tissues through circulation to directly impair insulin signaling in the tissues (22Cheung A.T. Ree D. Kolls J.K. Fuselier J. Coy D.H. Bryer-Ash M. Endocrinology. 1998; 139: 4928-4935Crossref PubMed Google Scholar, 54Hirosumi J. Tuncman G. Chang L. Görgün C.Z. Uysal K.T. Maeda K. Karin M. Hotamisligil G.S. Nature. 2002; 420: 333-336Crossref PubMed Scopus (2593) Google Scholar, 55Gao Z. Hwang D. Bataille F. Lefevre M. York D. Quon M.J. Ye J. J. Biol. Chem. 2002; 277: 48115-48121Abstract Full Text Full Text PDF PubMed Scopus (585) Google Scholar). In the present study, PFKFB3+/− mice exhibited an increase in the severity of HFD-induced systemic insulin resistance and glucose intolerance. This was attributed, at least in part, to increased adipose tissue dysfunction, as evidenced by increased adipose tissue lipolysis, inappropriate adipokine expression, and decreased insulin signaling, as well as increased expression of proinflammatory cytokines including TNFα and IL-6 in the adipose tissue. These data support a pivotal role for PFKFB3/iPFK2 in protecting against HFD-induced adipose tissue dysfunction, and thereby systemic insulin resistance. Moreover, because PFKFB3/iPFK2 disruption-associated changes in adipose tissue dysfunction were nearly identical to those in PFKFB3/iPFK2-knockdown adipocytes, PFKFB3/iPFK2 in adipocytes is thereby responsible largely for the regulation of adipose tissue function. It should be pointed out that PFKFB3/iPFK2 is also expressed in tissues other than adipose tissue (31Chesney J. Telang S. Yalcin A. Clem A. Wallis N. Bucala R. Biochem. Biophys. Res. Commun. 2005; 331: 139-146Crossref PubMed Scopus (40) Google Scholar). Thus, a possible role for PFKFB3/iPFK2 in non-adipose tissue in regulating systemic insulin sensitivity cannot be ruled out. However, considering the profile of PFKFB3/iPFK2 expression, the role of PFKFB3/iPFK2 in non-adipose tissue would not be as important as that in adipose tissue. Additionally, in terms of regulating systemic glucose homeostasis, dysregulated liver glucose metabolism is thought to contribute to hyperglycemia and glucose intolerance (32Wu C. Okar D.A. Newgard C.B. Lange A.J. J. Clin. Invest. 2001; 107: 91-98Crossref PubMed Scopus (68) Google Scholar, 33Wu C. Kang J.E. Peng L. Li H. Khan S.A. Hillard C.J. Okar D.A. Lange A.J. Cell Metabolism. 2005; 2: 131-140Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 34Wu C. Khan S.A. Peng L.J. Li H. Camella S.G. Lange A.J. Am. J. Physiol. Endocrinol. Metab. 2006; 291: E536-E543Crossref PubMed Scopus (25) Google Scholar). Given that the amount of iPFK2 was undetectable in the liver, dysregulated liver glucose metabolism, if existed in PFKFB3+/− mice, was likely due to a secondary effect of PFKFB3 disruption in extrahepatic tissues, in particular adipose tissue.It is also a novel finding that disruption of PFKFB3/iPFK2 exacerbated HFD-induced adipose tissue inflammatory response, which was also independent of adiposity. Additionally, the increased adipose tissue inflammatory response was independent of macrophage accumulation in adipose tissue. In a generally accepted concept, HFD-induced adipose tissue inflammatory is characterized by increased production of proinflammatory cytokines, which is positively correlated with macrophage infiltration (17Weisberg S.P. McCann D. Desai M. Rosenbaum M. Leibel R.L. Ferrante Jr., A.W. J. Clin. Invest. 2003; 112: 1796-1808Crossref PubMed Scopus (7308) Google Scholar, 18Lumeng C.N. DeYoung S.M. Bodzin J.L. Saltiel A.R. Diabetes. 2007; 56: 16-23Crossref PubMed Scopus (758) Google Scholar). However, several lines of new evidence suggest that the inflammatory status of macrophages is more important than the number of macrophages in terms of controlling the production of proinflammatory cytokines in the adipose tissue. For example, mice that lack PPARγ in macrophages exhibit fewer macrophages in adipose tissue but have higher mRNA levels of IL-6 than wild-type control mice (56Odegaard J.I. Ricardo-Gonzalez R.R. Goforth M.H. Morel C.R. Subramanian V. Mukundan L. Red Eagle A. Vats D. Brombacher F. Ferrante A.W. Chawla A. Nature. 2007; 447: 1116-1120Crossref PubMed Scopus (1563) Google Scholar). In contrast, treatment with rosiglitazone, a PPARγ agonist, increases the abundance of macrophages in adipose tissue, but decreases the production of proinflammatory cytokines such as IL-18 (13Stienstra R. Duval C. Keshtkar S. van der Laak J. Kersten S. Müller M. J. Biol. Chem. 2008; 283: 22620-22627Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar). Considering this, disruption of PFKFB3/iPFK2 appears to increase the inflammatory activity of the infiltrated macrophages. This notion is indeed supported by the data that the mRNA levels of TNFα and IL-6 were higher in macrophages isolated from PFKFB3+/− mice than in wild-type littermates. Therefore, disruption of PFKFB3/iPFK2 exacerbates HFD-induced adipose tissue inflammatory response in a manner depending on increasing macrophage inflammatory status rather than macrophage infiltration. However, further study is required to elucidate the underlying mechanisms by which disruption of PFKFB3/iPFK2 blunts HFD-induced macrophage infiltration into adipose tissue.In summary, the present study demonstrates a novel and unique role for PFKFB3/iPFK2 in regulating adiposity and adipose tissue function, and thereby systemic insulin sensitivity. This role is manifested by the fact that disruption of PFKFB3/iPFK2 ameliorates HFD-induced adiposity, but exacerbates HFD-induced adipose tissue dysfunction, in particular, adipose tissue inflammatory response, which contributes to an increase in the severity of systemic insulin resistance. Because of this, a potential risk of inducing systemic insulin resistance and enhancing adipose tissue inflammatory response should be taken into account when inhibition of PFKFB3/iPFK2 is considered as therapeutic approach. IntroductionAs demonstrated by numerous data generated from high fat diet (HFD) 3The abbreviations used are: HFDhigh fat dietiPFK2inducible 6-phosphofructo-2-kinaseF26P2fructose-2,6-bisphosphate6PFK16-phosphofructo-1-kinasePPARαperoxisome proliferator-activated receptor αPGC1peroxisome proliferative-activated receptor γ, coactivator 1CPT1carnitine palmitoyltransferase-1JNKc-Jun N-terminal kinaseNFκBnuclear factor κBTNFαtumor necrosis factor αILinterleukinDMEMDulbecco's modified Eagle's mediumROSreactive oxygen speciesLFDlow fat diet. -fed rodents, overnutrition is associated with adiposity and systemic insulin resistance. For example, feeding an HFD to rats for 10 weeks causes a significant increase in visceral fat mass, which is accompanied by a decrease in systemic insulin sensitivity as evidenced by decreased rate of clamp glucose infusion (1Kusunoki M. Hara T. Tsutsumi K. Nakamura T. Miyata T. Sakakibara F. Sakamoto S. Ogawa H. Nakaya Y. Storlien L.H. Diabetologia. 2000; 43: 875-880Crossref PubMed Scopus (72) Google Scholar). Similarly, after a feeding of HFD for 20 weeks, both of the two different strains of wild-type mice gain a significant increase in fat mass, which is associated with systemic insulin resistance and glucose intolerance (2Gallou-Kabani C. Vigé A. Gross M.S. Rabès J.P. Boileau C. Larue-Achagiotis C. Tomé D. Jais J.P. Junien C. Obesity. 2007; 15: 1996-2005Crossref PubMed Scopus (172) Google Scholar). A recent study even indicates that feeding an HFD to mice for only 6 weeks is sufficient to induce adiposity and systemic insulin resistance (3Llagostera E. Carmona M.C. Vicente M. Escorihuela R.M. Kaliman P. FEBS Letters. 2009; 583: 2121-2125Crossref PubMed Scopus (10) Google Scholar). Furthermore, as documented in mice lacking the myotonic dystrophy protein kinase, a larger augmentation in adiposity is accompanied by a greater increase in the severity of systemic insulin resistance (3Llagostera E. Carmona M.C. Vicente M. Escorihuela R.M. Kaliman P. FEBS Letters. 2009; 583: 2121-2125Crossref PubMed Scopus (10) Google Scholar). Because of this, adiposity has been generally viewed as an important contributor of systemic insulin resistance (3Llagostera E. Carmona M.C. Vicente M. Escorihuela R.M. Kaliman P. FEBS Letters. 2009; 583: 2121-2125Crossref PubMed Scopus (10) Google Scholar, 4Kahn B.B. Flier J.S. J. Clin. Invest. 2000; 106: 473-481Crossref PubMed Scopus (2410) Google Scholar, 5Miyazaki Y. Glass L. Triplitt C. Wajcberg E. Mandarino L.J. DeFronzo R.A. Am. J. Physiol. Endocrinol. Metab. 2002; 283: E1135-E1143Crossref PubMed Scopus (209) Google Scholar, 6Ghibaudi L. Cook J. Farley C. van Heek M. Hwa J.J. Obesity. 2002; 10: 956-963Crossref Scopus (158) Google Scholar, 7Krekoukia M. Nassis G.P. Psarra G. Skenderi K. Chrousos G.P. Sidossis L.S. Metabolism. 2007; 56: 206-213Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). 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Russell R.G. Lindemann D. Hartley A. Baker G.R. Obici S. Deshaies Y. Ludgate M. Rossetti L. Scherer P.E. Endocrinology. 2004; 145: 367-383Crossref PubMed Scopus (442) Google Scholar, 11Muurling M. Mensink R.P. Pijl H. Romijn J.A. Havekes L.M. Voshol P.J. Metabolism. 2003; 52: 1078-1083Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 12Gavrilova O. Haluzik M. Matsu" @default.
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