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The adipose tissue-derived hormone adiponectin improves insulin sensitivity and its circulating levels are decreased in obesity-induced insulin resistance. Here, we report the generation of a mouse line with a genomic disruption of the adiponectin locus. We aimed to identify whether these mice develop insulin resistance and which are the primary target tissues affected in this model. Using euglycemic/insulin clamp studies, we demonstrate that these mice display severe hepatic but not peripheral insulin resistance. Furthermore, we wanted to test whether the lack of adiponectin magnifies the impairments of glucose homeostasis in the context of a dietary challenge. When exposed to high fat diet, adiponectin null mice rapidly develop glucose intolerance. Specific PPARγ agonists such as thiazolidinediones (TZDs) improve insulin sensitivity by mechanisms largely unknown. Circulating adiponectin levels are significantly up-regulated in vivo upon activation of PPARγ. Both TZDs and adiponectin have been shown to activate AMP-activated protein kinase (AMPK) in the same target tissues. We wanted to address whether the ability of TZDs to improve glucose tolerance is dependent on adiponectin and whether this improvement involved AMPK activation. We demonstrate that the ability of PPARγ agonists to improve glucose tolerance in ob/ob mice lacking adiponectin is diminished. Adiponectin is required for the activation of AMPK upon TZD administration in both liver and muscle. In summary, adiponectin is an important contributor to PPARγ-mediated improvements in glucose tolerance through mechanisms that involve the activation of the AMPK pathway. The adipose tissue-derived hormone adiponectin improves insulin sensitivity and its circulating levels are decreased in obesity-induced insulin resistance. Here, we report the generation of a mouse line with a genomic disruption of the adiponectin locus. We aimed to identify whether these mice develop insulin resistance and which are the primary target tissues affected in this model. Using euglycemic/insulin clamp studies, we demonstrate that these mice display severe hepatic but not peripheral insulin resistance. Furthermore, we wanted to test whether the lack of adiponectin magnifies the impairments of glucose homeostasis in the context of a dietary challenge. When exposed to high fat diet, adiponectin null mice rapidly develop glucose intolerance. Specific PPARγ agonists such as thiazolidinediones (TZDs) improve insulin sensitivity by mechanisms largely unknown. Circulating adiponectin levels are significantly up-regulated in vivo upon activation of PPARγ. Both TZDs and adiponectin have been shown to activate AMP-activated protein kinase (AMPK) in the same target tissues. We wanted to address whether the ability of TZDs to improve glucose tolerance is dependent on adiponectin and whether this improvement involved AMPK activation. We demonstrate that the ability of PPARγ agonists to improve glucose tolerance in ob/ob mice lacking adiponectin is diminished. Adiponectin is required for the activation of AMPK upon TZD administration in both liver and muscle. In summary, adiponectin is an important contributor to PPARγ-mediated improvements in glucose tolerance through mechanisms that involve the activation of the AMPK pathway. Adiponectin/ACRP30 (adipocyte complement-related protein of 30 kDa), an adipocyte-specific secretory protein, has been shown to modulate insulin sensitivity; however, the mechanism(s) by which it acts are not fully understood (1Combs T.P. Berg A.H. Obici S. Scherer P.E. Rossetti L. J. Clin. Inv. 2001; 108: 1875-1881Crossref PubMed Scopus (794) Google Scholar). A number of clinical studies revealed a strong link between whole body insulin sensitivity and circulating adiponectin levels (2Pajvani U.B. Scherer P.E. Curr. Diab. Rep. 2003; 3: 207-213Crossref PubMed Scopus (215) Google Scholar). Furthermore, circulating adiponectin is negatively correlated with the body mass index (3Arita Y. Kihara S. Ouchi N. Takahashi M. Maeda K. Miyagawa J. Hotta K. Shimomura I. Nakamura T. Miyaoka K. Kuriyama H. Nishida M. Yamashita S. Okubo K. Matsubara K. Muraguchi M. Ohmoto Y. Funahashi T. Matsuzawa Y. Biochem. Biophys. Res. Commun. 1999; 257: 79-83Crossref PubMed Scopus (4076) Google Scholar). Weight reduction leads to a significant increase in adiponectin plasma levels slightly preceding improvements in insulin sensitivity, thus suggesting a causative role of adiponectin in enhancing insulin sensitivity (4Yang W.S. Lee W.J. Funahashi T. Tanaka S. Matsuzawa Y. Chao C.L. Chen C.L. Tai T.Y. Chuang L.M. J. Clin. Endocrinol. Metab. 2001; 86: 3815-3819Crossref PubMed Scopus (961) Google Scholar). Adiponectin null mouse models were described previously, however, with somewhat varying outcomes regarding their metabolic phenotype. Kubota et al. (5Kubota N. Terauchi Y. Yamauchi T. Kubota T. Moroi M. Matsui J. Eto K. Yamashita T. Kamon J. Satoh H. Yano W. Nagai R. Kimura S. Kadowaki T. Noda T. J. Biol. Chem. 2002; 277: 25863-25866Abstract Full Text Full Text PDF PubMed Scopus (1187) Google Scholar) noted mild insulin resistance under basal conditions in heterozygotes (60% reduction in adiponectin serum levels) and more severe insulin resistance in adiponectin null animals. This report differed from adiponectin null mice described by Maeda et al. (6Maeda N. Shimomura I. Kishida K. Nishizawa H. Matsuda M. Nagaretani H. Furuyama N. Kondo H. Takahashi M. Arita Y. Komuro R. Ouchi N. Kihara S. Tochino Y. Okutomi K. Horie M. Takeda S. Aoyama T. Funahashi T. Matsuzawa Y. Nat. Med. 2002; 8: 731-737Crossref PubMed Scopus (1814) Google Scholar) that showed nearly normal insulin sensitivity when fed on a standard laboratory diet but developed severe insulin resistance in as few as 2 weeks on a high fat/high sucrose diet. However, a third independent report of adiponectin null mice by Ma et al. (7Ma K. Cabrero A. Saha P.K. Kojima H. Li L. Chang B.H. Paul A. Chan L. J. Biol. Chem. 2002; 277: 34658-34661Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar) described an unexpected increase in fatty acid oxidation in skeletal muscle but no effect on insulin sensitivity. Adiponectin transcript levels are up-regulated in adipocytes upon treatment with thiazolindinediones (TZDs), 4The abbreviations used are: TZD, thiazolidinedione; AMPK, AMP-activated protein kinase; PPAR, peroxisome proliferator-activated receptor; ACC, acetyl-CoA carboxylase; WT, wild type; KO, knock-out; TNF, tumor necrosis factor. which parallels increased secretion and elevated adiponectin levels in the circulation (8Combs T.P. Wagner J.A. Berger J. Doebber T. Wang W.J. Zhang B.B. Tanen M. Berg A.H. O'Rahilly S. Savage D.B. Chatterjee K. Weiss S. Larson P.J. Gottesdiener K.M. Gertz B.J. Charron M.J. Scherer P.E. Moller D.E. Endocrinology. 2002; 143: 998-1007Crossref PubMed Scopus (508) Google Scholar). TZDs are a novel class of antidiabetic agents that improve systemic insulin sensitivity by enhancing glucose disposal in skeletal muscle and insulin dependent repression of gluconeogenesis in the liver (9Rangwala S.M. Lazar M.A. Trends Pharmacol. Sci. 2004; 25: 331-336Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar). In addition, they significantly reduce circulating free fatty acids and triglycerides, also known to correlate negatively with insulin sensitivity (10Lee C.H. Olson P. Evans R.M. Endocrinology. 2003; 144: 2201-2207Crossref PubMed Scopus (723) Google Scholar). Despite the widespread clinical use of these drugs (rosiglitazone and pioglitazone), the precise molecular mechanisms by which TZDs exert their insulin-sensitizing effects remain largely unknown. TZDs are specific ligands for the γ isoform of the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors that are intimately involved in the regulation of energy homeostasis (11Berger J. Bailey P. Biswas C. Cullinan C.A. Doebber T.W. Hayes N.S. Saperstein R. Smith R.G. Leibowitz M.D. Endocrinology. 1996; 137: 4189-4195Crossref PubMed Scopus (346) Google Scholar). Ligand-activated PPARγ heterodimerizes with the retinoid X receptor and regulates transcription by binding to specific PPARγ-responsive elements within promoters of target genes (12Berger J. Moller D.E. Annu. Rev. Med. 2002; 53: 409-435Crossref PubMed Scopus (2096) Google Scholar). A number of key glucoregulatory and lipogenic genes (glucokinase, GLUT4, lipoprotein lipase, adipocyte fatty acid transporter protein, fatty acyl-CoA synthase) and genes involved in energy expenditure (mitochondrial uncoupling proteins) as well as other nuclear encoded mitochondrial genes are responsive to TZDs, thus providing a putative mechanism for increased insulin sensitivity (12Berger J. Moller D.E. Annu. Rev. Med. 2002; 53: 409-435Crossref PubMed Scopus (2096) Google Scholar, 13Wilson-Fritch L. Burkart A. Bell G. Mendelson K. Leszyk J. Nicoloro S. Czech M. Corvera S. Mol. Cell. Biol. 2003; 23: 1085-1094Crossref PubMed Scopus (379) Google Scholar). PPARγ is predominantly expressed in adipose tissue with nominal expression in muscle and liver, suggesting that adipose tissue is the primary target for TZD action, and therefore anti-diabetic effects observed in liver and skeletal muscle may largely depend on PPARγ activation in adipocytes (14Fajas L. Auboeuf D. Raspe E. Schoonjans K. Lefebvre A.M. Saladin R. Najib J. Laville M. Fruchart J.C. Deeb S. Vidal-Puig A. Flier J. Briggs M.R. Staels B. Vidal H. Auwerx J. J. Biol. Chem. 1997; 272: 18779-18789Abstract Full Text Full Text PDF PubMed Scopus (1086) Google Scholar). A central role for adipose tissue in TZD action is supported by the loss of the glucose-lowering effects of TZDs in the A-ZIP/F1 lipodystrophic mouse model that lacks white adipose tissue (15Kim J.K. Fillmore J.J. Gavrilova O. Chao L. Higashimori T. Choi H. Kim H.J. Yu C. Chen Y. Qu X. Haluzik M. Reitman M.L. Shulman G.I. Diabetes. 2003; 52: 1311-1318Crossref PubMed Scopus (82) Google Scholar). Implantation of fat pads from wild type mice into these mice completely restores responsiveness to TZDs. Similarly, we have recently described a mouse model of inducible lipoatrophy that lost its ability to improve insulin sensitivity in response to TZD treatment in the fatless state (16Pajvani U.B. Trujillo M.E. Combs T.P. Iyengar P. Jelicks L. Roth K.A. Kitsis R.N. Scherer P.E. Nat. Med. 2005; 11: 797-803Crossref PubMed Scopus (236) Google Scholar). Interestingly, adipose tissue is required for the hypoglycemic effects of TZDs, whereas their efficacy as hypolipidemic agents is preserved despite the lack of fat (17Chao L. Marcus-Samuels B. Mason M.M. Moitra J. Vinson C. Arioglu E. Gavrilova O. Reitman M.L. J. Clin. Invest. 2000; 106: 1221-1228Crossref PubMed Scopus (337) Google Scholar). TZDs have also been shown to activate 5′-AMP-activated protein kinase (AMPK) in both liver and muscle (18Saha A.K. Avilucea P.R. Ye J.M. Assifi M.M. Kraegen E.W. Ruderman N.B. Biochem. Biophys. Res. Commun. 2004; 314: 580-585Crossref PubMed Scopus (196) Google Scholar). AMPK is a critical metabolic regulator that promotes glucose uptake and fatty acid oxidation. Its activity is stimulated in response to muscle contraction or stresses such as hypoxia and starvation (19Ruderman N.B. Park H. Kaushik V.K. Dean D. Constant S. Prentki M. Saha A.K. Acta. Physiol. Scand. 2003; 178: 435-442Crossref PubMed Scopus (184) Google Scholar). AMPK phosphorylation rapidly inhibits acetyl-CoA carboxylase (ACC), leading to decreased tissue malonyl-CoA content. Malonyl-CoA is an inhibitor of carnitine palmitoyl-transferase 1 the rate-limiting enzyme for β-oxidation (20Winder W.W. J. Physiol. 1999; 277: Google Scholar, D. M. Annu. Rev. Biochem. PubMed Scopus Google Scholar). The is an increase in mitochondrial fatty acid oxidation. AMPK activation in the liver has been shown to by key and M.D. G. 1996; PubMed Scopus Google Scholar). Interestingly, AMPK activation in the liver when with adiponectin T. Kamon J. Y. Y. H. S. Yamashita S. Noda M. S. K. Eto K. Y. P. P. D. Kimura S. Nagai R. B.B. Kadowaki T. Nat. Med. 2002; 8: PubMed Scopus Google and a of adiponectin to AMPK in skeletal muscle E. Saha A.K. Zhang C. Ruderman N.B. Sci. S. A. 2002; PubMed Scopus Google Scholar). Using the clamp we that the lack of adiponectin a in the of hepatic glucose glucose uptake and disposal in skeletal muscle. The is rapidly through of a high fat diet. Furthermore, that mice lacking adiponectin have an response to PPARγ We that improvements in glucose tolerance are in the of adiponectin in a model of and This is to a to AMPK upon treatment with TZDs in adiponectin null of Adiponectin mouse genomic and a the adiponectin genomic The by a and a to into the resistance The with and into by with a A of were by the in the of and by The were into and to for to line from were observed between the and of wild type and ob/ob and Adiponectin mice in adiponectin were by adiponectin null mice with mice lacking the to both The mice were to an for adiponectin and KO, of or ob/ob and wild type were from the same adiponectin for by from the for by of 30 30 and 1 and the and The were on a and the mice were by the of a for the and a for the wild type for the as described M. Y. K. Kadowaki T. Y. K. Sci. Google Scholar). mice were and to a diet or high fat diet as The diet diet with by from from protein, and from The high fat diet of from from protein, and from PPARγ studies, the were and with with or a of a of glucose and were from glucose for glucose and kinase for and adiponectin were by the of the treatment were by and tissues were and in for in mice were as described (1Combs T.P. Berg A.H. Obici S. Scherer P.E. Rossetti L. J. Clin. Inv. 2001; 108: 1875-1881Crossref PubMed Scopus (794) Google Scholar, Obici S. Scherer P.E. Rossetti L. J. Clin. Invest. 2003; PubMed Scopus Google Scholar). the in vivo A of glucose a as required to The a of high and insulin of body plasma were to glucose levels and as well as the specific activity of and The of The basal of glucose in wild type mice The insulin stimulated the by and glucose by conditions for both plasma glucose and specific activity were by in these the of the in vivo studies, mice were the and liver and muscle were in with that were in The between the of and of tissue were for The and by the and of the of mice were an glucose of of of body a of glucose in the and serum glucose were glucose to the of the were a with in 30 1 2 2 and or muscle were by and to The were with in for 1 or with in The were with or by to or were by and by in the AMPK activity and malonyl-CoA were as described D. A. Saha A.K. J. A. Ruderman N.B. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). adiponectin were by as described U.B. X. Combs T.P. Berg A.H. T. J. M. Scherer P.E. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). are as were significant were an of Adiponectin mice were by and the of the adiponectin with a resistance with of adiponectin in which 2 of the adiponectin (5Kubota N. Terauchi Y. Yamauchi T. Kubota T. Moroi M. Matsui J. Eto K. Yamashita T. Kamon J. Satoh H. Yano W. Nagai R. Kimura S. Kadowaki T. Noda T. J. Biol. Chem. 2002; 277: 25863-25866Abstract Full Text Full Text PDF PubMed Scopus (1187) Google Scholar, N. Shimomura I. Kishida K. Nishizawa H. Matsuda M. Nagaretani H. Furuyama N. Kondo H. Takahashi M. Arita Y. Komuro R. Ouchi N. Kihara S. Tochino Y. Okutomi K. Horie M. Takeda S. Aoyama T. Funahashi T. Matsuzawa Y. Nat. Med. 2002; 8: 731-737Crossref PubMed Scopus (1814) Google Scholar). We that of the and with the of the adiponectin In addition, we the expression of adiponectin protein in the circulation of mice by and by adiponectin in mice were by with normal and mice Adiponectin the effects of adiponectin on insulin action, we clamp wild type and adiponectin fed were The glucose required to slightly in mice with wild type This to the ability in mice to hepatic glucose the of peripheral glucose disposal in the were The insulin levels the clamp were in and in The specific were as and for mice and and In with metabolic studies of adiponectin null mice (5Kubota N. Terauchi Y. Yamauchi T. Kubota T. Moroi M. Matsui J. Eto K. Yamashita T. Kamon J. Satoh H. Yano W. Nagai R. Kimura S. Kadowaki T. Noda T. J. Biol. Chem. 2002; 277: 25863-25866Abstract Full Text Full Text PDF PubMed Scopus (1187) Google Scholar, N. Shimomura I. Kishida K. Nishizawa H. Matsuda M. Nagaretani H. Furuyama N. Kondo H. Takahashi M. Arita Y. Komuro R. Ouchi N. Kihara S. Tochino Y. Okutomi K. Horie M. Takeda S. Aoyama T. Funahashi T. Matsuzawa Y. Nat. Med. 2002; 8: 731-737Crossref PubMed Scopus (1814) Google when by standard glucose tolerance in glucose tolerance were in mice fed on a standard diet However, when mice were on a high fat diet for a of glucose tolerance significantly an glucose with that mice are more to insulin resistance The in the high fat diet were from from protein, and from high fat the body in and mice were insulin levels KO, WT, and insulin the glucose KO, WT, were not significantly between the Maeda et al. M. J. S. M. R. Biochem. Biophys. Res. Commun. 2002; PubMed Scopus Google Scholar) have elevated levels in adiponectin null mice (6Maeda N. Shimomura I. Kishida K. Nishizawa H. Matsuda M. Nagaretani H. Furuyama N. Kondo H. Takahashi M. Arita Y. Komuro R. Ouchi N. Kihara S. Tochino Y. Okutomi K. Horie M. Takeda S. Aoyama T. Funahashi T. Matsuzawa Y. Nat. Med. 2002; 8: 731-737Crossref PubMed Scopus (1814) Google and has been correlated with adiponectin In levels in the circulation were the of a not levels were not in adiponectin null mice with their wild type and in were they affected by treatment with not of TZDs in Adiponectin whether the insulin-sensitizing effects of TZDs are through we mice in which insulin resistance is and independent of the of plasma this we the KO, and mice into the ob/ob mice were for with the PPARγ of body or by The treatment circulating adiponectin levels in wild type mice by from treatment to the treatment glucose tolerance of body an revealed that ob/ob independent of the of adiponectin KO, KO, were when with mice WT, to treatment with However, whereas the mice their glucose mice the treatment with TZDs Both body the of the TZD treatment KO, KO, the the treatment in the wild type or not adiponectin in the to levels not significantly the TZD treatment and were in adiponectin null and wild type mice in the ob/ob not of AMPK by TZDs in whether TZD treatment affected AMPK activity in and and muscle were from mice with or for as described adiponectin levels increased on from basal to TZD treatment In liver, AMPK activity increased more and the of by in mice with whereas no effect of TZDs observed in mice A and In with these increased in the however, in AMPK activity and in and mice were observed in muscle A and However, in to liver, but no in observed In tissue AMPK by TZD treatment and In the of TZD we no in AMPK or in the of and mice Furthermore, in AMPK activity to increased and malonyl-CoA decreased in were not significant activity malonyl-CoA levels and the of and AMPK were in the muscle of adiponectin and wild type mice with or the to for of a of adiponectin glucose levels in mice (1Combs T.P. Berg A.H. Obici S. Scherer P.E. Rossetti L. J. Clin. Inv. 2001; 108: 1875-1881Crossref PubMed Scopus (794) Google Scholar, A.H. Combs T. X. M. Scherer P.E. Nat. Med. 2001; PubMed Scopus Google Scholar). the other a increase of serum adiponectin levels in a mouse model leads to improvements in insulin sensitivity to decreased hepatic glucose T.P. U.B. Berg A.H. Y. Jelicks M. L. R.G. D. A. Obici S. Y. M. Rossetti L. Scherer P.E. Endocrinology. 2004; PubMed Scopus Google Scholar). In both of these of adiponectin have been shown to improve hepatic insulin sensitivity. In under both glucose uptake in peripheral tissues not when glucose levels were in the of a (1Combs T.P. Berg A.H. Obici S. Scherer P.E. Rossetti L. J. Clin. Inv. 2001; 108: 1875-1881Crossref PubMed Scopus (794) Google Scholar, A.H. Combs T. X. M. Scherer P.E. Nat. Med. 2001; PubMed Scopus Google Scholar). the of adiponectin we a mouse model lacking differed slightly from that for described adiponectin null mice in that we and the We aimed to the metabolic of adiponectin null mice the clamp clamp from adiponectin null mice with mice the liver as the target of adiponectin The of the on the insulin sensitivity in adiponectin null in studies, we a of glucose tolerance in adiponectin null mice when with a high fat diet that by standard glucose tolerance This however, the to on insulin sensitivity of mice in adiponectin under clamp The significant impairments in hepatic glucose a and when fed a standard diet. This not in mice with glucose tolerance and an increased sensitivity of the clamp Adiponectin required to a of insulin and therefore in adiponectin levels may have effects on insulin sensitivity. adiponectin is circulating levels) and has a U.B. X. Combs T.P. Berg A.H. T. J. M. Scherer P.E. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google the serum levels of adiponectin remain with weeks to in the clinical and therefore are A of models of adipocyte-specific secretory such as or is the mild for the loss of whereas of models display more This is for and and in the of is a of the of the ob/ob on the of the In to mice the of mice lacking adiponectin is and therefore more under However, are with a number of studies that have adiponectin in insulin sensitivity as a of and insulin resistance (2Pajvani U.B. Scherer P.E. Curr. Diab. Rep. 2003; 3: 207-213Crossref PubMed Scopus (215) Google Scholar). In the we demonstrate that improvements in glucose tolerance treatment with PPARγ agonists are significantly dependent on the of adiponectin in a significant We that of adiponectin secretion from adipocytes by TZDs an important role in the action of these with an of for a of adiponectin in serum of ob/ob mice as well as mice fed a high fat diet. shown previously, such an of adiponectin slightly improvements in serum glucose and levels (8Combs T.P. Wagner J.A. Berger J. Doebber T. Wang W.J. Zhang B.B. Tanen M. Berg A.H. O'Rahilly S. Savage D.B. Chatterjee K. Weiss S. Larson P.J. Gottesdiener K.M. Gertz B.J. Charron M.J. Scherer P.E. Moller D.E. Endocrinology. 2002; 143: 998-1007Crossref PubMed Scopus (508) Google Scholar). TZD treatment of and mice of adiponectin not to an improvement of glucose as in mice that are to the of adiponectin from adipose In with this we that treatment for leads to a activation of the in significant reduction of both hepatic and malonyl-CoA content. The of TZDs to activate AMPK in adiponectin null the that the phosphorylation of AMPK is a critical of adiponectin action in liver and skeletal muscle. an of TZD action on glucose improvements in whole body insulin sensitivity are the of and of which that not involve the of AMPK in the liver or muscle the of adiponectin from TZDs adipocyte and the of free fatty acids from liver and muscle to adipose tissue T. Kamon J. H. K. K. K. T. Kubota N. Terauchi Y. K. H. A. Y. Nagai R. Kimura S. Kadowaki T. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). has been that this for the ability of TZDs to plasma free fatty acid levels and the in liver and which with insulin resistance G. Shulman G.I. J. Clin. Invest. 2002; PubMed Scopus Google Scholar). In addition, TZDs have been shown to serum levels of an by adipocytes Bailey S. Lazar M.A. 2001; PubMed Scopus Google Scholar). The of this to to The of whether expression in adipose tissue is for TZD action recently by et al. S. Chen H. Endocrinology. 2004; PubMed Scopus Google Scholar). Using they the role of in the of serum triglycerides, free fatty and glucose by TZD treatment and that is not involved in these In summary, that adiponectin is an important of the improvements of TZD on whole body glucose improvement in glucose tolerance is in adiponectin null Furthermore, studies that the ability of TZDs to activate AMPK in liver and skeletal muscle is to whether to adiponectin or AMPK have a on insulin sensitivity in with and type 2 We for and and for providing the AMPK mouse to the AMPK activity
Nawrocki et al. (Sat,) studied this question.
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