Regulation of adiponectin and leptin gene expression in white and brown adipose tissues: influence of β3-adrenergic agonists, retinoic acid, leptin and fasting

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Abstract

Circulating adiponectin levels fall whereas leptin levels rise with obesity, suggesting that regulation of these two adipocyte-derived hormones may be simultaneously influenced by common obesity-related factors. We examined adiponectin mRNA levels in WAT and in some instances, brown adipose tissue (BAT) following fasting and refeeding, acute and chronic administration of a β3-adrenergic agonist, acute treatment with retinoic acid (RA) and a glucocorticoid, and following chronic infusion of leptin and compared the expression of adiponectin to that of leptin in each circumstance. Serum concentrations of adiponectin were also reported for most of the treatments. Fasting diminished and refeeding reversed both adiponectin and leptin gene expression. Peripheral injection of the β3-adrenergic agonist, CL316,243, suppressed both leptin and adiponectin expression in WAT. A small but significant reduction in adiponectin expression in BAT was also observed following this treatment. Although CL316,23 lowered serum leptin levels markedly, it did not affect serum adiponectin levels. A chronic 7-day infustion of CL316,243 resulted in an elevation of adiponectin expression in WAT and serum concentrations in contrast to suppressions in both mRNA and serum levels of leptin by a similar treatment as previously reported. Chronic administration of leptin did not alter adiponectin synthesis in WAT compared to controls, but prevented the reduction in adiponectin synthesis associated with pair feeding. Food restriction through pair feeding also diminished adiponectin expression in BAT. Collectively, although leptin and adiponectin are inversely correlated with obesity, leptin does not appear to participate directly in adiponectin synthesis. The short-term regulation of the two adipokine expression in WAT is somewhat similar, perhaps subjective to common control of energy balance. The long-term regulation of adiponectin expression in WAT appears to be the opposite of that of leptin and may be more sensitive to changes in adiposity or insulin sensitivity.

Introduction

Adiponectin, also known as Acrp30, AdipoQ, amp-1 and GBP28, is an adipocyte-derived hormone that plays a role in insulin function and energy homeostasis [1]. Expression and serum levels of adiponectin are diminished in humans and animals with insulin resistance and obesity [2], [3], [4], [5]. In vitro, adiponectin facilitates reduction of hepatocyte glucose production by insulin [6] and attenuates TNF-α signal transduction in macrophages, and TNF-α is one factor that potentially induces insulin resistance [7]. In vivo, adiponectin improves fatty acid utilization in liver and skeletal muscle of mice and reduces basal plasma glucose levels without affecting insulin and glucagon concentrations [6], [8], [9]. In addition, it produces weight loss in mice without affecting food intake [8]. Adiponectin may thus have important functions in the prevention and treatment of obesity and diabetes through direct regulation of lipid and glucose metabolism and modulation of insulin sensitivity.

Another adipocyte-derived hormone, leptin, elicits potent effects on energy homeostasis by suppressing food intake and stimulating energy expenditure [10], [11]. Mainly produced in white adipose tissue (WAT), both synthesis and circulating levels of leptin are correlated with adiposity in a chronic fashion [12]. Acutely, leptin synthesis can be up- or down-regulated by a number of biological signals and factors in response to changes in nutritional status. As a result, the synthesis often falls out of proportion to adiposity levels. Among some known modulators, β3-adrenergic agonists [13], [14], [15], [16], retinoic acid (RA) [17], and fasting [12], [18] acutely reduce leptin gene expression in WAT, whereas glucocorticoids and refeeding enhance leptin expression [19], [20].

While leptin synthesis is extensively studied, information on regulation of adiponectin expression is rather limited. Insulin markedly increases adiponectin secretion from 3T3-L1 adipocytes [21], [22], whereas TNF-α, dexamethasone and insulin suppress adiponectin synthesis in these adipocytes [23]. β-adrenergic stimulation by isoproterenol also inhibits adiponectin synthesis in these cells [25]. PPAR-γ agonists increase plasma adiponectin levels in mice and humans [6], [24]. Comparing adiponectin and leptin, on the one hand, both adipokines are synthesized in WAT and promote weight loss; they may hence be regulated in parallel. On the other hand, circulating adiponectin levels decrease with obesity in humans and animals as supposed to the increase in leptin with obesity, suggesting that adiponectin expression may be regulated in the opposite direction as leptin. The current study examines whether several factors directly affecting leptin gene expression also affect adiponectin expression, and additionally, whether leptin itself has an effect.

Section snippets

Animals

Male F344×Brown Norway rats (6 months of age) were obtained from Harlan Sprague–Dawley (Indianapolis, IN). Upon arrival, rats were examined and remained in quarantine for 1 week. Animals were cared for in accordance with the principles of the Guide and Use of Experimental Animals. Rats were housed individually with a 12:12 h light–dark cycle (07:00 to 19:00) and maintained on Rat Chow (Purina) ad libitum except where noted. Ambient temperature was 26 °C, thermoneutrality for these rats [26].

Chemicals

Adiponectin expression in BAT and WAT

Northern analysis of total RNA isolated from BAT, two WAT depots and brain from rats indicates the adiponectin probe binds to three mRNA species of 1.3, 1.7, and 2.5 kb in PWAT and EWAT (Fig. 1). These results are similar to those reported by others [31]. In addition, adiponectin expression was identified in BAT, but not detected in brain (Fig. 1).

Fasting and refeeding

Rats were fasted for a 48-h period followed by ad libitum refeeding over a 3-day period. Leptin mRNA levels in PWAT decreased to approximately 30% of

Discussion

Adiponectin is a unique adipocyte-derived hormone because serum levels of this hormone diminish in obesity. Considering its important functions of stimulating lipid oxidation, improving insulin sensitivity and promoting weight loss, adiponectin is regarded as a new potential anti-obesity agent. However, knowledge regarding adiponectin gene regulation and synthesis is limited. This paper addresses the impact of several factors implicated in leptin gene regulation on adiponectin synthesis in WAT

Acknowledgements

This work was supported by the Medical Research Service of the Department of Veterans Affairs and National Institute on Aging Grant AG-17047.

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