Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
Regulation of adiponectin and leptin gene expression in white and brown adipose tissues: influence of β3-adrenergic agonists, retinoic acid, leptin and fasting
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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