Adiponectin Expression is Paradoxically Increased in Gold-thioglucose-induced Obesity

Abstract

Following the chemically-induced lesion of the ventromedial nucleus, gold-thioglucose treated rodents display hypothalamic leptin resistance, hyperphagia, hyperinsulinemia and obesity. Despite the exuberant hyperinsulinemia following gold-thioglucose treatment, systemic insulin sensitivity is preserved during the early phase of the obesity syndrome, resulting in extensive fat production and markedly increased leptin levels. Leptin and adiponectin levels are inversely associated in vivo. However, the reciprocal relationship between leptin and adiponectin can not be explained by in vitro observations, suggesting the involvement of the central nervous system. We measured leptin and adiponectin expression levels in gold-thioglucose obese and control mice. In this study, we show that gold-thioglucose treatment causes a profound reduction in the number of hypothalamic glucokinase transcripts in rodents. Also, we demonstrate that the adiponectin expression levels and protein content are increased in gold-thioglucose treated animals, which can explain the increased insulin sensitivity during the early phase of the obesity syndrome. Furthermore, as the increased leptin production in gold-thioglucose obese mice is not paralleled by reduced adiponectin production, our data suggest that the inverse regulation between leptin and adiponectin levels is, at least partially, mediated via the hypothalamus.

Key words

Adipokines - leptin - hypothalamus - adipose tissue - insulin sensitivity

References

• 1 Debons AF, Krimsky I, Maayan ML, Fani K, Jemenez FA. Gold thioglucose obesity syndrome.  Fed Proc. 1977;  36 143-147
• 2 Blair SC, Caterson ID, Cooney GJ. Insulin response to an intravenous glucose load during development of obesity in gold thioglucose-injected mice.  Diabetes. 1993;  42 1153-1158
• 3 Blair SC, Caterson ID, Cooney GJ. Insulin response to a spontaneously ingested standard meal during the development of obesity in GTG-injected mice.  Int J Obes Relat Metab Disord. 1996;  20 319-323
• 4 Fei H, Okano HJ, Li C, Lee GH, Zhao C, Darnell R, Friedman JM. Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues.  Proc Natl Acad Sci USA. 1997;  94 7001-7005
• 5 Satoh N, Ogawa Y, Katsuura G, Tsuji T, Masuzaki H, Hiraoka J, Okazaki T, Tamaki M, Hayase M, Yoshimasa Y, Nishi S, Hosoda K, Nakao K. Pathophysiological significance of the obese gene product, leptin, in ventromedial hypothalamus (VMH)-lesioned rats: evidence for loss of its satiety effect in VMH-lesioned rats.  Endocrinology. 1997;  138 947-954
• 6 Bryson JM, Phuyal JL, Swan V, Caterson ID. Leptin has acute effects on glucose and lipid metabolism in both lean and gold thioglucose-obese mice.  Am J Physiol. 1999;  277 417-422
• 7 Bryson JM, Phuyal JL, Proctor DR, Blair SC, Caterson ID, Cooney GJ. Plasma insulin rise precedes rise in ob mRNA expression and plasma leptin in gold thioglucose-obese mice.  Am J Physiol. 1999;  276 358-364
• 8 Le Marchand Y, Freychet P, Jeanrenaud B. Longitudinal study on the establishment of insulin resistance in hypothalamic obese mice.  Endocrinology. 1978;  102 74-85
• 9 Penicaud L, Kinebanyan MF, Ferre P, Morin J, Kande J, Smadja C, Marfaing-Jallat P, Picon L. Development of VMH obesity: in vivo insulin secretion and tissue insulin sensitivity.  Am J Physiol. 1989;  257 255-260
• 10 Blair SC, Cooney GJ, Denyer GS, Williams PF, Caterson ID. Differences in lipogenesis in tissues of control and gold-thioglucose obese mice after an isocaloric meal.  Biochim Biophys Acta. 1991;  1085 385-388
• 11 Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity.  Nat Med. 2001;  7 941-946
• 12 Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia.  J Clin Endocrinol Metab. 2001;  86 1930-1935
• 13 Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients.  Arterioscler Thromb Vasc Biol. 2000;  20 1595-1599
• 14 Hotta K, Funahashi T, Bodkin NL, Ortmeyer HK, Arita Y, Hansen BC, Matsuzawa Y. Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys.  Diabetes. 2001;  50 1126-1133
• 15 Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity.  J Biol Chem. 1996;  271 10697-106703
• 16 Arita 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. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.  Biochem Biophys Res Commun. 1999;  257 79-83
• 17 Fisher FM, McTernan PG, Valsamakis G, Chetty R, Harte AL, Anwar AJ, Starcynski J, Crocker J, Barnett AH, McTernan CL, Kumar S. Differences in adiponectin protein expression: effect of fat depots and type 2 diabetic status.  Horm Metab Res. 2002;  34 650-654
• 18 Matsubara M, Maruoka S, Katayose S. Inverse relationship between plasma adiponectin and leptin concentrations in normal-weight and obese women.  Eur J Endocrinol. 2002;  147 173-180
• 19 Inoue M, Maehata E, Yano M, Taniyama M, Suzuki S. Correlation between the adiponectin-leptin ratio and parameters of insulin resistance in patients with type 2 diabetes.  Metabolism. 2005;  54 281-286
• 20 Havel PJ. Control of energy homeostasis and insulin action by adipocyte hormones: leptin, acylation stimulating protein, and adiponectin.  Curr Opin Lipidol. 2002;  13 51-59
• 21 Zhang Y, Matheny M, Zolotukhin S, Tumer N, Scarpace PJ. Regulation of adiponectin and leptin gene expression in white and brown adipose tissues: influence of beta3-adrenergic agonists, retinoic acid, leptin and fasting.  Biochim Biophys Acta. 2002;  1584 115-122
• 22 Atzmon G, Yang XM, Muzumdar R, Ma XH, Gabriely I, Barzilai N. Differential gene expression between visceral and subcutaneous fat depots.  Horm Metab Res. 2002;  34 622-628
• 23 Ueno N, Dube MG, Inui A, Kalra PS, Kalra SP. Leptin modulates orexigenic effects of ghrelin, attenuates adiponectin and insulin levels, and selectively the dark-phase feeding as revealed by central leptin gene therapy.  Endocrinology. 2004;  145 4176-4184
• 24 Heimberg H, Bouwens L, Heremans Y, Van De Casteele M, Lefebvre V, Pipeleers D. Adult human pancreatic duct and islet cells exhibit similarities in expression and differences in phosphorylation and complex formation of the homeodomain protein Ipf-1.  Diabetes. 2000;  49 571-579
• 25 Herberg L, Coleman DL. Laboratory animals exhibiting obesity and diabetes syndromes.  Metabolism. 1977;  26 59-99
• 26 Yamauchi T, Kamon J, Waki H, Imai Y, Shimozawa N, Hioki K, Uchida S, Ito Y, Takakuwa K, Matsui J, Takata M, Eto K, Terauchi Y, Komeda K, Tsunoda M, Murakami K, Ohnishi Y, Naitoh T, Yamamura K, Ueyama Y, Froguel P, Kimura S, Nagai R, Kadowaki T. Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis.  J Biol Chem. 2003;  278 2461-2468
• 27 Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, Kumada M, Ohashi K, Sakai N, Shimomura I, Kobayashi H, Terasaka N, Inaba T, Funahashi T, Matsuzawa Y. Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice.  Circulation. 2002;  106 2767-2770
• 28 Lyngdorf LG, Gregersen S, Daugherty A, Falk E. Paradoxical reduction of atherosclerosis in apoe-deficient mice with obesity-related type 2 diabetes.  Cardiovasc Res. 2003;  59 854-862
• 29 Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI. Receptor-mediated regional sympathetic nerve activation by leptin.  J Clin Invest. 1997;  100 270-278
• 30 Kappes A, Loffler G. Influences of ionomycin, dibutyryl-cycloAMP and tumour necrosis factor-alpha on intracellular amount and secretion of apM1 in differentiating primary human preadipocytes.  Horm Metab Res. 2000;  32 548-554
• 31 Nowak L, Adamczak M, Wiecek A. Blockade of sympathetic nervous system activity by rilmenidine increases plasma adiponectin concentration in patients with essential hypertension.  Am J Hypertens. 2005;  18 1470-1475

Correspondence