Effect of Salicylate on the Expression of Adipokines and Glucose Transporters in Human Adipocytes is Modulated by Hypoxia

Introduction

Obesity is part of a cluster of conditions known as the metabolic syndrome, which is a major risk factor for type 2 diabetes and cardiovascular disease. Obesity is associated with chronic mild inflammation and it is proposed that this may be the link between the disorder and many of its related pathologies [1]. Adipose tissue is now well established as a key endocrine organ, expressing and secreting many proteins, termed adipokines, which affect a wide range of physiological processes, including the inflammatory response [2]. The expression of a number of inflammatory adipokines, such as PAI-1 and IL6, is increased, whereas the expression of adiponectin, with its anti-inflammatory and insulin-sensitizing actions, is decreased in obesity indicating that the adipocyte itself may be integral to the development of obesity-induced inflammation [1] [2].

The events within adipose tissue in the obese state that trigger this dysregulation of adipokine expression are not clear, but appear to include oxidative stress, endoplasmic reticulum stress, and local hypoxia [1] [2]. There is accumulating evidence that adipocytes in the obese state experience hypoxia as the vasculature fails to keep up with the expansion of the adipose tissue mass [2] [3] [4] [5]. One proposal is that this local hypoxia might trigger the production of inflammatory adipokines [2] [3] [4] [5]. The effects of hypoxia on adipokine expression in cultured murine and human adipocytes are consistent with hypoxia leading to an increase in the production of inflammation-related adipokines [2] [3] [4] [5] [6]. Hypoxia would be expected to impact on other aspects of adipocyte function such as glucose metabolism, and indeed there are several reports that GLUT1 expression is increased by hypoxia in both murine and human adipocytes as well as in many other cell types [2] [3] [4] [5] [6] [7]. The possibility exists that the insulin sensitivity of adipocytes may alter in response to hypoxia. It is therefore important to take the hypoxic environment, in which adipocytes appear to exist in the obese state, into account when the responses to a particular therapeutic agent are studied.

The linking of chronic mild inflammation with the development of insulin resistance, type 2 diabetes, and cardiovascular disease has renewed interest in the role of anti-inflammatory drugs, such as the salicylates, as possible therapeutic agents for the treatment of obesity-related syndromes. Recent studies in genetically obese rodents found that high dose salicylates reversed hyperglycaemia, hyperinsulinaemia, and dyslipidaemia [8]. Pretreatment of rats with salicylates prevented the decrease of insulin-stimulated glucose uptake caused by acute lipid infusion [9]. A high dose of acetyl salicylate was found to improve insulin resistance and glucose tolerance in type 2 diabetic patients [10] and triflusal (a 4-trifluoromethyl derivative of salicylate) was found to decrease fasting blood glucose in obese nondiabetic subjects [11].

The mechanism by which salicylates exert their antidiabetic effects are not well understood, but have begun to be addressed. Possible target tissues include liver, muscle, adipose tissue, and pancreas. Salicylates have been shown to modulate the insulin signalling pathway in liver and muscle in vivo [8] [9], and in cultured adipocytes and hepatocytes [8] [12]. Salicylates appear to have a direct effect on islet function, promoting insulin secretion and attenuating the effects of inhibitors such as TNFα [11] [13] [14]. Salicylates might alter the expression of adipokines by adipocytes but this has not been addressed to date.

The aim of the present study was to determine the direct effect of salicylate on the expression of key adipokines and glucose transporters by human adipocytes under normoxic and hypoxic conditions.

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