臨床検査49巻13号

2005年12月発行

今月の主題 メタボリックシンドローム メタボリックシンドロームの臨床検査

レジスチン

著者： 山内敏正¹ 門脇孝¹

所属機関： ¹東京大学大学院医学系研究科糖尿病・代謝内科統合的分子代謝疾患科学講座

ページ範囲：P.1689 - P.1695

〔SUMMARY〕　レジスチンは肥満で増加するアディポカインである．レジスチンTgは，インスリン抵抗性，欠損マウスはインスリン感受性であった．レジスチンは，肝臓でAMKを不活化させ，糖新生を増加させる．脂肪組織では，SOCS3を増加させ，インスリン抵抗性を惹起させる．ヒトにおいて，レジスチンはマクロファージに発現している．レジスチンには相同性は高いが組織分布が異なるRELMα，βが存在し，RELM βのTgは高脂肪食下で，MAPKの活性化を介して，肝臓でインスリン抵抗性を惹起し，糖尿病，高脂血症，脂肪肝を呈する．〔臨床検査　49：1689-1695，2005〕

参考文献

１) Shulman GI：Cellular mechanisms of insulin resistance. J Clin Invest　106：171-176, 2000

２) Yuan M, Konstantopoulos N, Lee J, et al：Reversal of obesity-and diet-induced insulin resistance with salicylates or target disruption of IKKbeta. Science　293：1673-1677, 2001

３) Hirosumi J, Tuncman G, Chang L, et al：A central role for JNK in obesity and insulin resistance. Nature　420：333-336, 2002

４) Shimomura I, Hammer RE, Ikemoto S, et al：Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature　401：73-76, 1999

５) Oral EA, Simha V, Ruiz E, et al：Leptin-replacement therapy for lipodystrophy. N Engl J Med　346：570-578, 2002

６) Yamauchi T, Kamon J, Waki H, et al：The mechanisms by which both heterozygous PPARgamma deficiency and PPARgamma agonist improve insulin resistance. J Biol Chem　276：41245-41254, 2001

７) Yamauchi T, Oike Y, Kamon J, et al：Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice. Nature Genetics　30：221-226, 2002

８) Yamauchi T, Waki H, Kamon J, et al：Inhibition of RXR and PPARγ ameliorates diet-inducedobesity and type 2 diabetes. J Clin Invest　108：1001-1013, 2001

９) Yamauchi T, Kamon J, Waki H, et al：The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature Med　7：941-946, 2001

10) Yamauchi T, Kamon, J, Minokoshi Y, et al：Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nature Med　8：1288-1295, 2002

11) Yamauchi T, Kamon J, Waki H, et al：Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis. J Biol Chem　278：2461-2468, 2003

12) Yamauchi T, Kamon J, Ito Y, et al：Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature　423：762-769, 2003

13) Tsuchida A, Yamauchi T, Ito Y, et al：Insulin/Foxo1 pathway regulates expression levels of adiponectin receptors and adiponectin sensitivity. J Biol Chem published on line on Apr 29, 2004

14) Narasimhan ML, Coca MA, Jin J, et al：Osmotin is a homolog of mammalian adiponectin and controls apoptosis in yeast through a homolog of mammalian adiponectin receptor. Molecular Cell　17：171-180, 2005

15) Steppan CM, Bailey ST, Bhat S, et al：The hormone resistin links obesity to diabetes. Nature　409, 307-312, 2001

16) Rangwala SM, Rich AS, Rhoades B, et al：Abnormal glucose homeostasis due to chronic hyperresistinemia. Diabetes　53：1937-1941, 2004

17) Satoh H, Nguyen MT, Miles PD, et al：Adenovirus-mediated chronic “hyper-resistinemia” leads to in vivo insulin resistance in normal rats. J Clin Invest　114：224-231, 2004

18) Banerjee RR, Rangwala SM, Shapiro JS, et al：Regulation of fasted blood glucose by resistin. Science　303：1195-1198, 2004

19) Rajala MW, Obici S, Scherer PE, et al：Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production. J Clin Invest　111：225-230, 2003

20) Minokoshi Y, Kim YB, Peroni OD, et al：Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature　415：339-343, 2002

21) Banerjee RR, Lazar MA：Dimerization of resistin and resistin-like molecules is determined by a single cysteine. J Biol Chem　276：25970-25973, 2001

22) Patel SD, Rajala MW, Rossetti L, et al：Disulfide-dependent multimeric assembly of resistin family hormones. Science　304：1154-1158, 2004

23) Shapiro L, Scherer PE：The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor. Curr Biol　8：335-338, 1998

24) Steppan CM, Wang J, Whiteman EL, et al：Activation of SOCS-3 by resistin. Mol Cell Biol　25：1569-1575, 2005

25) Lehrke M, Reilly MP, Millington SC, et al：An inflammatory cascade leading to hyperresistinemia in humans. PLoS Med　1：e45, 2004

26) Weisberg SP, McCann D, Desai M, et al：Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest　112：1796-1808, 2003

27) Xu H, Barnes GT, Yang Q, et al：Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest　112：1821-1830, 2003

28) Osawa H, Yamada K, Onuma H, et al：The G/G genotype of a resistin single-nucleotide polymorphism at-420 increases type 2 diabetes mellitus susceptibility by inducing promoter activity through specific binding of Sp1/3. Am J Hum Genet　75：678-686, 2004

29) Steppan CM, Brown EJ, Wright CM, et al：A family of tissue-specific resistin-like molecules. Proc Natl Acad Sci USA　98：502-506, 2001

30) Kushiyama A, Shojima N, Ogihara T, et al：Resistin like molecule beta activates MAPKs, suppresses insulin signaling in hepatocytes and induces diabetes, hyperlipidemia and fatty liver in transgenic mice on a high-fat diet. J Biol Chem (in press)

31) Waki H, Yamauchi T, Kamon J, et al：Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin. J Biol Chem　278：40352-40363, 2003