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The effects of β3-adrenoceptor agonist CL-316,243 on adiponectin, adiponectin receptors and tumor necrosis factor-α expressions in adipose tissues of obese diabetic KKAy mice

https://doi.org/10.1016/j.ejphar.2008.01.028Get rights and content

Abstract

We investigated the effects of β3-adrenoceptor agonist, 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL-316,243) in obese diabetic KKAy mice. Two weeks' subcutaneous administration of CL-316,243 reduced serum levels of glucose, insulin, triglyceride, free fatty acid and tumor necrosis factor-α (TNF-α), and increased adiponectin. Adiponectin, adiponectin receptors and β3-adrenoceptor mRNA expressions were reduced in epididymal white adipose tissue in KKAy mice, and CL-316,243 recovered these mRNA expressions. Meanwhile, CL-316,243 suppressed the overexpressed mRNA level of TNF-α in both epididymal white adipose tissue and brown adipose tissue. These data suggest that the normalization of adiponectin, adiponectin receptors and TNF-α may result in the amelioration of obesity-induced insulin resistance.

Introduction

β3-adrenoceptor is the predominant subtype of adrenoceptor expressed in adipose tissue. It mediates the major effects of adrenaline and noradrenaline in adipose tissues, such as lipolysis in white adipose tissue and thermogenesis in brown adipose tissue. In some obese animal models, such as ob/ob mice, the β3-adrenoceptor mRNA expression and function in white and brown adipose tissues are markedly reduced (Collins et al., 1994). Chronic treatments of β3-adrenoceptor agonists in obese diabetic animals were reported to reduce adiposity and improve type 2 diabetes (Kato et al., 2001, Liu et al., 1998), but the molecular mechanisms of these effects, especially the anti-diabetic effect, are largely unknown.

In recent years, it has been demonstrated that adipose tissue is not only an energy-storage organ but also an endocrine organ, secreting a variety of biologically active factors called adipokines. Among those, tumor necrosis factor-α (TNF-α) is an adipokine, which induces insulin resistance (Hotamisligil, 1999). And adiponectin is an insulin-sensitizing adipokine expressed exclusively in white adipose tissue and brown adipose tissue, concentrations of which are decreased in obesity-associated metabolic and vascular disorders (Kadowaki and Yamauchi, 2005).

Adiponectin receptor 1 and 2 mediate most effects of adiponectin. Adiponectin receptor 1 is abundantly expressed in skeletal muscle, whereas adiponectin receptor 2 is predominantly found in the liver. Both receptors are also expressed in 3T3-L1 adipocytes, and rodent and human adipose tissues (Kadowaki et al., 2006). Reports have shown that adiponectin acts as an autocrine factor in adipocytes to improve glucose uptake (Bauche et al., 2006, Wu et al., 2003).

In obese diabetic KKAy mice on high-fat diet, the mRNA expressions of adiponectin and adiponectin receptors in adipose tissues were reported to be downregulated, related with the reduced insulin sensitivity (Yamauchi et al., 2001, Tsuchida et al., 2005). To clarify the mechanisms by which β3-adrenoceptor agonist ameliorates insulin resistance in diabetic animals, we examined the chronic pharmacological effects of CL-316,243 on adiponectin, adiponectin receptors, TNF-α and β3-adrenoceptor expressions in adipose tissues of obese diabetic KKAy mice on a high-fat diet.

Section snippets

Drug

5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL-316,243) was purchased from Sigma Chemical Co (St. Louis, MO).

Animals and treatments

Six-week-old male KKAy mice and aged-matched KK mice were purchased from Nippon CLEA (Shizuoka, Japan). KKAy mouse is an obese diabetic model in which the Ay mutation is introduced onto a KK strain background. Therefore, we used KK mice as nonobese controls. Mice were housed individually and maintained on a 12 h light/dark cycle.

Body weight, food intake, and adipose tissue weights

As shown in Table 1, the age-dependent body weight gain was inhibited in the CL-316,243-treatment group compared with the control KKAy group (P < 0.05). The food intakes on day 1 and day 2 in the CL-316,243-treatment group were significantly lower than those of the control group (P < 0.01 and P < 0.05, respectively). However, the food intakes from day 3 to day 14 and the total food intake over the whole 2 weeks' administration period were not significantly different between the two groups (data not

Discussion

In this study, we confirmed that two weeks' administration of CL-316,243 improved the obesity, insulin resistance and lipid metabolism in KKAy mice (Table 1) consistent with previous reports (Liu et al., 1998, Oana et al., 2005). On the first and second days of the administration period, food intake was markedly decreased in the CL-316,243-treatment group (Table 1), but then returned to the control value after day 3. It is reported that the CL-316,243-induced food intake reduction is

References (19)

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