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Decreased secretion of adiponectin through its intracellular accumulation in adipose tissue during tobacco smoke exposure.

Li M, Li C, Liu Y, Chen Y, Wu X, Yu D, Werth VP, Williams KJ, Liu ML - Nutr Metab (Lond) (2015)

Bottom Line: Cigarette smoking is associated with an increased risk of type 2 diabetes mellitus (T2DM).Importantly, we found that TSE up-regulated the ADPN retention chaperone ERp44, which colocalized with ADPN in the endoplasmic reticulum.Our results provide a novel mechanism for hypoadiponectinemia, and may help to explain the increased risk of T2DM in smokers.

View Article: PubMed Central - PubMed

Affiliation: Section of Endocrinology, Diabetes & Metabolic Diseases, Temple University School of Medicine, Philadelphia, PA USA.

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.

No MeSH data available.


Related in: MedlinePlus

Tobacco smoke exposure traps HMW ADPN intracellularly. Panels A,B: Representative immunoblots of ADPN isoforms (A) and summary statistics for the ratio of HMW/LMW ADPN (B) in conditioned medium and cellular homogenates from 3T3-L1 adipocytes treated with 0% (control) or 1.5% TSE for 20 h. Isoforms of ADPN were separated by electrophoresis through 2–15% SDS-PAGE gradient gels under nonreducing and non-heat-denaturing conditions. Panel B displays means ± SEM, n = 4; P-values were computed using Student’s t-test. Panels C, D: Representative immunoblots showing the distribution of ADPN isoforms in plasma (C) and in epididymal adipose tissue (D) from wild-type mice after RPMI (control) or TSE injections.
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Fig2: Tobacco smoke exposure traps HMW ADPN intracellularly. Panels A,B: Representative immunoblots of ADPN isoforms (A) and summary statistics for the ratio of HMW/LMW ADPN (B) in conditioned medium and cellular homogenates from 3T3-L1 adipocytes treated with 0% (control) or 1.5% TSE for 20 h. Isoforms of ADPN were separated by electrophoresis through 2–15% SDS-PAGE gradient gels under nonreducing and non-heat-denaturing conditions. Panel B displays means ± SEM, n = 4; P-values were computed using Student’s t-test. Panels C, D: Representative immunoblots showing the distribution of ADPN isoforms in plasma (C) and in epididymal adipose tissue (D) from wild-type mice after RPMI (control) or TSE injections.

Mentions: Among the three different multimeric forms of ADPNs, HMW ADPN has been shown to be the most biologically active [4,5] in promoting insulin-induced glucose handling [3-6]. In the current study, we assessed the three major multimeric forms of ADPNs by immunoblots under non-reducing conditions [19]. We found that the decrease in total ADPN secretion from cultured 373-L1 adipocytes after TSE exposure (Figure 1A-E) was mainly attributable to decreased secretion of HMW ADPN (Figure 2A,B), accompanied by increased intracellular accumulation of HMW ADPN (Figure 2A,B). Likewise, we found that mice injected with TSE exhibited a loss of mainly HMW ADPN from plasma (Figure 2C) and HMW ADPN accumulated in their adipose tissue (Figure 2D).Figure 2


Decreased secretion of adiponectin through its intracellular accumulation in adipose tissue during tobacco smoke exposure.

Li M, Li C, Liu Y, Chen Y, Wu X, Yu D, Werth VP, Williams KJ, Liu ML - Nutr Metab (Lond) (2015)

Tobacco smoke exposure traps HMW ADPN intracellularly. Panels A,B: Representative immunoblots of ADPN isoforms (A) and summary statistics for the ratio of HMW/LMW ADPN (B) in conditioned medium and cellular homogenates from 3T3-L1 adipocytes treated with 0% (control) or 1.5% TSE for 20 h. Isoforms of ADPN were separated by electrophoresis through 2–15% SDS-PAGE gradient gels under nonreducing and non-heat-denaturing conditions. Panel B displays means ± SEM, n = 4; P-values were computed using Student’s t-test. Panels C, D: Representative immunoblots showing the distribution of ADPN isoforms in plasma (C) and in epididymal adipose tissue (D) from wild-type mice after RPMI (control) or TSE injections.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4465313&req=5

Fig2: Tobacco smoke exposure traps HMW ADPN intracellularly. Panels A,B: Representative immunoblots of ADPN isoforms (A) and summary statistics for the ratio of HMW/LMW ADPN (B) in conditioned medium and cellular homogenates from 3T3-L1 adipocytes treated with 0% (control) or 1.5% TSE for 20 h. Isoforms of ADPN were separated by electrophoresis through 2–15% SDS-PAGE gradient gels under nonreducing and non-heat-denaturing conditions. Panel B displays means ± SEM, n = 4; P-values were computed using Student’s t-test. Panels C, D: Representative immunoblots showing the distribution of ADPN isoforms in plasma (C) and in epididymal adipose tissue (D) from wild-type mice after RPMI (control) or TSE injections.
Mentions: Among the three different multimeric forms of ADPNs, HMW ADPN has been shown to be the most biologically active [4,5] in promoting insulin-induced glucose handling [3-6]. In the current study, we assessed the three major multimeric forms of ADPNs by immunoblots under non-reducing conditions [19]. We found that the decrease in total ADPN secretion from cultured 373-L1 adipocytes after TSE exposure (Figure 1A-E) was mainly attributable to decreased secretion of HMW ADPN (Figure 2A,B), accompanied by increased intracellular accumulation of HMW ADPN (Figure 2A,B). Likewise, we found that mice injected with TSE exhibited a loss of mainly HMW ADPN from plasma (Figure 2C) and HMW ADPN accumulated in their adipose tissue (Figure 2D).Figure 2

Bottom Line: Cigarette smoking is associated with an increased risk of type 2 diabetes mellitus (T2DM).Importantly, we found that TSE up-regulated the ADPN retention chaperone ERp44, which colocalized with ADPN in the endoplasmic reticulum.Our results provide a novel mechanism for hypoadiponectinemia, and may help to explain the increased risk of T2DM in smokers.

View Article: PubMed Central - PubMed

Affiliation: Section of Endocrinology, Diabetes & Metabolic Diseases, Temple University School of Medicine, Philadelphia, PA USA.

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.

No MeSH data available.


Related in: MedlinePlus