All Title Author
Keywords Abstract

PLOS ONE  2009 

Altered Energy Homeostasis and Resistance to Diet-Induced Obesity in KRAP-Deficient Mice

DOI: 10.1371/journal.pone.0004240

Full-Text   Cite this paper   Add to My Lib

Abstract:

Obesity and related metabolic disorders have become leading causes of adult morbidity and mortality. KRAP (Ki-ras-induced actin-interacting protein) is a cytoskeleton-associated protein and a ubiquitous protein among tissues, originally identified as a cancer-related molecule, however, its physiological roles remain unknown. Here we demonstrate that KRAP-deficient (KRAP?/?) mice show enhanced metabolic rate, decreased adiposity, improved glucose tolerance, hypoinsulinemia and hypoleptinemia. KRAP?/? mice are also protected against high-fat diet-induced obesity and insulin resistance despite of hyperphagia. Notably, glucose uptake in the brown adipose tissue (BAT) in KRAP?/? mice is enhanced in an insulin-independent manner, suggesting that BAT is involved in altered energy homeostasis in KRAP?/? mice, although UCP (Uncoupling protein) expressions are not altered. Of interest is the down-regulation of fatty acid metabolism-related molecules, including acetyl-CoA carboxylase (ACC)-1, ACC-2 and fatty acid synthase in the liver of KRAP?/? mice, which could in part account for the metabolic phenotype in KRAP?/? mice. Thus, KRAP is a novel regulator in whole-body energy homeostasis and may be a therapeutic target in obesity and related diseases.

References

[1]  Zimmet P, Alberti KG, Shaw J (2001) Global and societal implications of the diabetes epidemic. Nature 414: 782–787.
[2]  Shulman GI (2000) Cellular mechanisms of insulin resistance. J Clin Invest 106: 171–176.
[3]  Kahn BB, Flier JS (2000) Obesity and insulin resistance. J Clin Invest 106: 473–481.
[4]  Eckel RH, Grundy SM, Zimmet PZ (2005) The metabolic syndrome. Lancet 365: 1415–1428.
[5]  Rosenbaum M, Leibel RL, Hirsch J (1997) Obesity. N Engl J Med 337: 396–407.
[6]  Flier JS (2004) Obesity wars: molecular progress confronts an expanding epidemic. Cell 116: 337–350.
[7]  Houten SM, Watanabe M, Auwerx J (2006) Endocrine functions of bile acids. EMBO J 25: 1419–1425.
[8]  Rosen ED, Spiegelman BM (2006) Adipocytes as regulators of energy balance and glucose homeostasis. Nature 444: 847–853.
[9]  Inokuchi J, Komiya M, Baba I, Naito S, Sasazuki T, et al. (2004) Deregulated expression of KRAP, a novel gene encoding actin-interacting protein, in human colon cancer cells. J Hum Genet 49: 46–52.
[10]  Fujimoto T, Koyanagi M, Baba I, Nakabayashi K, Kato N, et al. (2007) Analysis of KRAP expression and localization, and genes regulated by KRAP in a human colon cancer cell line. J Hum Genet 52: 978–984.
[11]  Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, et al. (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372: 425–432.
[12]  Levin N, Nelson C, Gurney A, Vandlen R, de Sauvage F (1996) Decreased food intake does not completely account for adiposity reduction after ob protein infusion. Proc Natl Acad Sci U S A 93: 1726–1730.
[13]  Friedman JM, Halaas JL (1998) Leptin and the regulation of BW in mammals. Nature 395: 763–770.
[14]  Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, et al. (2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 8: 1288–1295.
[15]  Zhou Y, Xu BC, Maheshwari HG, He L, Reed M, et al. (1997) A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). Proc Natl Acad Sci U S A 94: 13215–13220.
[16]  Greenhalgh CJ, Rico-Bautista E, Lorentzon M, Thaus AL, Morgan PO, et al. (2005) SOCS2 negatively regulates growth hormone action in vitro and in vivo. J Clin Invest 115: 397–406.
[17]  Ayuk J, Sheppard MC (2006) Growth hormone and its disorders. Postgrad Med J 82: 24–30.
[18]  Abu-Elheiga L, Brinkley WR, Zhong L, Chirala SS, Woldegiorgis G, et al. (2000) The subcellular localization of acetyl-CoA carboxylase 2. Proc Natl Acad Sci 97: 1444–1449.
[19]  Abu-Elheiga L, Matzuk MM, Abo-Hashema KA, Wakil SJ (2001) Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 291: 2613–2616.
[20]  Rousset S, Alves-Guerra MC, Mozo J, Miroux B, Cassard-Doulcier AM, et al. (2004) The biology of mitochondrial uncoupling proteins. Diabetes 53: S130–135.
[21]  Hardie DG (2005) New roles for the LKB1–>AMPK pathway. Curr Opin Cell Biol 17: 167–173.
[22]  Bianco AC, Kim BW (2006) Deiodinases: implications of the local control of thyroid hormone action. J Clin Invest 116: 2571–2579.
[23]  Rahman SM, Dobrzyn A, Lee SH, Dobrzyn P, Miyazaki M, et al. (2005) Stearoyl-CoA desaturase 1 deficiency increases insulin signaling and glycogen. Am J Physiol Endocrinol Metab 288: 381–387.
[24]  Shimizu Y, Satoh S, Yano H, Minokoshi Y, Cushman SW, et al. (1998) Effects of noradrenaline on the cell-surface glucose transporters in cultured brown adipocytes: novel mechanism for selective activation of GLUT1 glucose transporters. Biochem J 330: 397–403.
[25]  Emilsson V, Thorleifsson G, Zhang B, Leonardson AS, Zink F, et al. (2008) Genetics of gene expression and its effect on disease. Nature 452: 423–428.
[26]  Chen Y, Zhu J, Lum PY, Yang X, Pinto S, et al. (2008) Variations in DNA elucidate molecular networks that cause disease. Nature 452: 429–435.
[27]  Cohen P, Miyazaki M, Socci ND, Hagge-Greenberg A, Liedtke W, et al. (2002) Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science 297: 240–243.
[28]  Ntambi JM, Miyazaki M, Stoehr JP, Lan H, Kendziorski CM, et al. (2002) Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proc Natl Acad Sci 99: 11482–11486.
[29]  Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, et al. (2006) Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439: 484–489.
[30]  Lee MJ, Yang RZ, Gong DW, Fried SK (2007) Feeding and insulin increase leptin translation. Importance of the leptin mRNA untranslated regions. J Biol Chem 282: 72–80.
[31]  Chakrabarti P, Anno T, Manning BD, Luo Z, Kandror KV (2008) The mammalian target of rapamycin complex 1 regulates leptin biosynthesis in adipocytes at the level of translation: the role of the 5′-untranslated region in the expression of leptin messenger ribonucleic acid. Mol Endocrinol 22: 2260–2267.
[32]  Chevillard G, Clémencet MC, Etienne P, Martin P, Pineau T, et al. (2004) Molecular cloning, gene structure and expression profile of two mouse peroxisomal 3-ketoacyl-CoA thiolase genes. BMC Biochem 5: 1–13.
[33]  Shirasawa S, Sugiyama S, Baba I, Inokuchi J, Sekine S, et al. (2004) Dermatitis due to epiregulin deficiency and a critical role of epiregulin in immune-related responses of keratinocyte and macrophage. Proc Natl Acad Sci 101: 13921–13926.
[34]  Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226: 497–509.
[35]  Ichikawa M, Kanai S, Ichimaru Y, Funakoshi A, Miyasaka K (2000) The diurnal rhythm of energy expenditure differs between obese and glucose-intolerant rats and streptozotocin-induced diabetic rats. J Nutr 130: 2562–2567.
[36]  Maeda N, Miyazawa S, Shimizu K, Asai T, Yonezawa S, et al. (2006) Enhancement of anticancer activity in antineovascular therapy is based on the intratumoral distribution of the active targeting carrier for anticancer drugs. Biol Pharm Bull 29: 1936–1940.
[37]  Klein J, Fasshauer M, Ito M, Lowell BB, Benito M, et al. (1999) β3-adrenergic stimulation differentially inhibits insulin signaling and decreases insulin-induced glucose uptake in brown adipocytes. J Biol Chem 274: 34795–34802.

Full-Text

comments powered by Disqus