Effects of PCB126 on Adipose-to-Muscle Communication in an in Vitro Model

Abstract

BACKGROUND: Exposure to coplanar polychlorinated biphenyls (PCBs) is linked to the development of insulin resistance. Previous studies suggested PCB126 alters muscle mitochondrial function through an indirect mechanism. Given that PCBs are stored in fat, we hypothesized that PCB126 alters adipokine secretion, which in turn affects muscle metabolism. OBJECTIVES: We determined a) the impacts of PCB126 exposure on adipocyte cytokine/adipokine secretion in vitro; b) whether adipocyte-derived factors alter glucose metabolism and mitochondrial function in myotubes when exposed to PCB126; and c) whether preestablished insulin resistance alters the metabolic responses of adipocytes exposed to PCB126 and the communication between adipocytes and myotubes. METHODS: 3T3-L1 adipocytes were exposed to PCB126 (1-100 nM) in two insulin sensitivity conditions [insulin sensitive (IS) and insulin resistant (IR) adipocytes], followed by the measurement of secreted adipokines, mitochondrial function, and insulin-stimulated glucose uptake. Communication between adipocytes and myotubes was reproduced by exposing C2C12 myotubes or mouse primary myotubes to conditioned medium (CM) derived from IS or IR 3T3-L1 adipocytes exposed to PCB126. Mitochondrial function and insulin-stimulated glucose uptake were then determined in myotubes. RESULTS: IR 3T3-L1 adipocytes treated with PCB126 had significantly higher adipokine (adiponectin, IL-6, MCP-1, TNF-a) secretion and lower mitochondrial function, glucose uptake, and glycolysis. However, PCB126 did not significantly alter these parameters in IS adipocytes. Altered energy metabolism in IR 3T3-L1 adipocytes was linked to lower phosphorylation of AMP-activated protein kinase (p-AMPK) and higher superoxide dismutase 2 levels, an enzyme involved in reactive oxygen species detoxification. Myotubes exposed to the CM from PCB126-treated IR adipocytes had lower glucose uptake, with no alteration in glycolysis or mitochondrial function. Interestingly, p-AMPK levels were higher in myotubes exposed to the CM of PCB126-treated IR adipocytes. DISCUSSION: Taken together, these data suggest that increased adipokine secretion from IR adipocytes exposed to PCB126 might explain impaired glucose uptake in myotubes.

Acute exposure to environmentally relevant levels of DDT alters muscle mitochondrial function in vivo in rats but not in vitro in L6 myotubes: A pilot study

“…In the presence of ROS, XMEs may become impaired and thus contribute to the modification of key enzymes involved in muscle energy metabolism and lead to muscle dysfunction [54] . Besides, our lab has highlighted the induction of Cyp1a1 expression in rat muscles and in mouse C2C12 myotubes following PCB126 exposure [40] , [55] . While the expression of CYPs has not been investigated in L6 myotubes or in the current study, DDT and DDE exposure could induce a similar response in muscle cells, a mechanism we can not ignore.…”

CYP1A1, VEGFA and Adipokine Responses of Human Adipocytes Co-exposed to PCB126 and Hypoxia

“…In humans, one study reported a correlation between the plasma concentrations of some POPs and leptinemia, especially in women, but this relationship was not observed with any PCB congeners [ 66 ]. In rodents, exposure to PCB126 at doses from 0.1 to 10 μg/kg for 15 d was reported to have no effect on leptinemia [ 67 ] while in vitro, leptin secretion was not altered in 3T3-L1 cells exposed for 24 h to low doses of PCB126 (between 1 and 100 nM) [ 38 ]. Our observations, combined with previous reports, support the notions that acute PCB126 exposure does not seem to impact leptin secretion and that PCB126 does not affect the increase in leptin secretion under hypoxia, at least under the experimental conditions we tested.…”

“…Gourronc et al [ 40 ] observed a twofold increase in IL-6 secretion in cultured adipocytes following a 48-h exposure to 10 µM PCB126. On the other hand, Loiola et al [ 67 ] showed that a 15-day exposure to PCB126 up to 10 μg/kg decreased retroperitoneal adipose tissue IL-6 mRNA levels in rats, while Caron et al [ 38 ] showed no effect of a 24-h exposure to low PCB126 doses up to 100 nM on IL-6 secretion in 3T3-L1. Interestingly, TCDD, the most potent dioxin, has been demonstrated to repress LPS-induced IL-6 production in bone marrow stromal cells, suggesting that the alleged binding of activated AhR to the IL-6 XRE may, in some cases, downregulate IL-6 expression [ 68 ].…”

“…While the classical cellular response to dioxin-like compound exposure consists of an increased expression of detoxifying cytochrome enzymes, namely cytochrome P450 (an enzyme regulated by the CYP1A1 gene) [ 36 ], these pollutants have also been reported to alter adipose tissue metabolism and endocrine function. As such, PCB126 exposure has been linked to the increased secretion of leptin and pro-inflammatory cytokines such as interleukin—IL-6 and IL-8—and the decreased secretion of adiponectin [ 32 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. Most of these effects are thought to arise from the binding of PCBs to the aryl hydrocarbon receptor (AhR), a transcription factor that modulates the expression of genes bearing dioxin- and xenobiotic-response elements (DRE/XRE).…”

The gut microbiota confers the glucose-and lipid-lowering effect of Laurolitsine in db/db mice

“…The International Diabetes Federation showed that the number of people aged 20-79 years with diabetes mellitus (DM) worldwide was estimated to be 463 million in 2019. Almost 90% of these people will have type 2 diabetes mellitus (T2DM), and this number may increase to 700 million by 2045 (Caron, Ahmed et al 2020). Oral antidiabetic agents include sulfonylureas, biguanides, thiazolidinediones, alpha-glucosidase inhibitors, meglitinides and etc (Wu, Huang et al 2019).…”