Decreased secretion of adiponectin through its intracellular accumulation in adipose tissue during tobacco smoke exposur
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Decreased secretion of adiponectin through its intracellular accumulation in adipose tissue during tobacco smoke exposure Mingzhen Li1†, Chunjun Li1†, Yu Liu1, Yan Chen1, Xiangdong Wu1, Demin Yu4, Victoria P Werth2,3, Kevin Jon Williams1,5 and Ming-Lin Liu1,2,3*
Abstract Background: Cigarette smoking is associated with an increased risk of type 2 diabetes mellitus (T2DM). Smokers exhibit low circulating levels of total adiponectin (ADPN) and high-molecular-weight (HMW) ADPN multimers. Blood concentrations of HMW ADPN multimers closely correlate with insulin sensitivity for handling glucose. How tobacco smoke exposure lowers blood levels of ADPN, however, has not been investigated. In the current study, we examined the effects of tobacco smoke exposure in vitro and in vivo on the intracellular and extracellular distribution of ADPN and its HMW multimers, as well as potential mechanisms. Findings: We found that exposure of cultured adipocytes to tobacco smoke extract (TSE) suppressed total ADPN secretion, and TSE administration to mice lowered their plasma ADPN concentrations. Surprisingly, TSE caused intracellular accumulation of HMW ADPN in cultured adipocytes and in the adipose tissue of wild-type mice, while preferentially decreasing HMW ADPN in culture medium and in plasma. Importantly, we found that TSE up-regulated the ADPN retention chaperone ERp44, which colocalized with ADPN in the endoplasmic reticulum. In addition, TSE down-regulated DsbA-L, a factor for ADPN secretion. Conclusions: Tobacco smoke exposure traps HMW ADPN intracellularly, thereby blocking its secretion. Our results provide a novel mechanism for hypoadiponectinemia, and may help to explain the increased risk of T2DM in smokers. Keywords: Adiponectin, Tobacco smoke, Adipocytes
Findings Introduction
Over 1.3 billion people smoke worldwide, and even more are exposed to second-hand smoke. Smokers often exhibit impairments in insulin-mediated glucose handling and an increased incidence of type 2 diabetes mellitus (T2DM) [1]. Smoking cessation improves these conditions [2]. Nevertheless, mechanisms by which smoking impairs insulin-stimulated glucose metabolism and increases T2DM are still unclear. * Correspondence: [email protected] † Equal contributors 1 Section of Endocrinology, Diabetes & Metabolic Diseases, Temple University School of Medicine, Philadelphia, PA, USA 2 Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Full list of author information is available at the end of the article
Adiponectin (ADPN), an insulin-sensitizing adipokine secreted from adipose tissue, circulates in three different multimeric forms – namely, trimers (low molecularweight, LMW), heximers (medium molecular-weight, MMW), and larger multimers (high molecular-weight, HMW) [3]. HMW ADPN is considered the most active form of ADPN [4,5], and peripheral insulin sensitivity for handling glucose closely correlates with blood levels of HMW ADPN [3-6]. Smokers exhibit low blood leve
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