We examine the role of adipose tissue, typically considered an energy storage site, as a potential site of toxicant accumulation. Although the production of most persistent organic pollutants (POPs) was banned years ago, these toxicants persist in the environment due to their resistance to biodegradation and widespread distribution in various environmental forms (e.g., vapor, sediment, water). As a result, human exposure to these toxicants is inevitable. Largely due to their lipophilicity, POPs bioaccumulate in adipose tissue, resulting in greater body burdens of these environmental toxicants with obesity. POPs of major concern include polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins and furans (PCDDs/PCDFs), and polybrominated biphenyls and diphenyl ethers (PBBs/PBDEs), among other organic compounds. In this review, we 1) highlight the physical characteristics of toxicants that enable them to partition into and remain stored in adipose tissue, 2) discuss the specific mechanisms of action by which these toxicants act to influence adipocyte function, and 3) review associations between POP exposures and the development of obesity and diabetes. An area of controversy relates to the relative potential beneficial versus hazardous health effects of toxicant sequestration in adipose tissue.

BackgroundCoplanar polychlorinated biphenyls (PCBs) promote adipocyte inflammation and impair glucose homeostasis in lean mice. The diabetes-promoting effects of lipophilic PCBs have been observed only during weight loss in obese mice. The molecular mechanisms linking PCB exposures to impaired glucose metabolism are unclear.ObjectivesIn this study we tested the hypothesis that coplanar PCBs act at adipocyte aryl hydrocarbon receptors (AhRs) to promote adipose inflammation and impair glucose homeostasis in lean mice and in obese mice during weight loss.Methods and ResultsPCB-77 administration impaired glucose and insulin tolerance in LF (low fat diet)–fed control (AhRfl/fl) mice but not in adipocyte AhR–deficient mice (AhRAdQ). Unexpectedly, AhRAdQ mice exhibited increased fat mass when fed a standard LF or high fat (HF) diet. In mice fed a HF diet, both genotypes became obese, but AhRAdQ mice administered vehicle (VEH) exhibited increased body weight, adipose mass, adipose inflammation, and impaired glucose tolerance compared with AhRfl/fl controls. Impairment of glucose homeostasis in response to PCB-77 was not observed in obese mice of either genotype. However, upon weight loss, AhRfl/fl mice administered PCB-77 exhibited increased abundance of adipose tumor necrosis factor-α (TNF-α) mRNA and impaired glucose homeostasis compared with those administered VEH. In contrast, PCB-77 had no effect on TNF-α or glucose homeostasis in AhRAdQ mice exhibiting weight loss.ConclusionsOur results demonstrate that adipocyte AhR mediates PCB-induced adipose inflammation and impairment of glucose homeostasis in mice. Moreover, deficiency of AhR in adipocytes augmented the development of obesity, indicating that endogenous ligand(s) for AhR regulate adipose homeostasis.CitationBaker NA, Shoemaker R, English V, Larian N, Sunkara M, Morris AJ, Walker M, Yiannikouris F, Cassis LA. 2015. Effects of adipocyte aryl hydrocarbon receptor deficiency on PCB-induced disruption of glucose homeostasis in lean and obese mice. Environ Health Perspect 123:944–950; http://dx.doi.org/10.1289/ehp.1408594

We recently demonstrated that adipocyte deficiency of angiotensinogen ablated high fat diet-induced elevations in plasma angiotensin II concentrations and obesity-hypertension in male mice. Hepatocytes are the predominant source of systemic angiotensinogen. Therefore, in this study, we defined the contribution of hepatocyte-derived angiotensinogen to obesity-induced elevations in plasma angiotensinogen concentrations and hypertension. Male Agtfl/fl mice expressing albumin-driven Cre recombinase were bred to female Agtfl/fl mice to generate Agtfl/fl or hepatocyte-angiotensinogen deficient male mice (AgtAlb). Mice were fed a low fat or high fat diet for 16 weeks. Hepatocyte angiotensinogen deficiency had no significant effect on body weight. Plasma angiotensinogen concentrations were increased in obese Agtfl/fl mice. Hepatocyte angiotensinogen deficiency markedly reduced plasma angiotensinogen and angiotensin II concentrations in lean and obese mice. Moreover, hepatocyte angiotensinogen deficiency reduced the content and release of angiotensinogen from adipose explants. Systolic blood pressure was markedly decreased in lean (by 18 mmHg) and obese AgtAlb mice (by 54 mmHg) compared to Agtfl/fl controls. To define mechanisms, we quantified effects of angiotensin II on mRNA abundance of megalin, an angiotensinogen uptake transporter, in 3T3-L1 adipocytes. Angiotensin II stimulated adipocyte megalin mRNA abundance and decreased media angiotensinogen concentrations. These results demonstrate that hepatocytes are the predominant source of systemic angiotensinogen in both lean and obese mice. Moreover, reductions in plasma angiotensin concentrations in obese hepatocyte angiotensinogen deficient mice may have limited megalin-dependent uptake of angiotensinogen into adipocytes for the production of angiotensin II in the development of obesity-hypertension.

Background Research has demonstrated that there can be substantial gender differences in circumstances surrounding initiation of injection drug use; however, little is known about the gendered dynamics of first injection in rural areas where syringe exchange is inaccessible or among those who predominantly inject prescription medications. The present study examines gender differences in first injection experience among rural residents who predominantly inject prescription opioids. Methods Interview-administered questionnaires collected data from a sample of injection drug users (n=394) recruited from Appalachian Kentucky using respondent-driven sampling. Results Women were more likely to have initiated injection due to social-pressure (p=0.001), received the drugs as a gift (p=0.011), initiated in their partner’s home (p=0.004) and in their partner’s presence (p<0.001), been injected by their partner (p<0.001), used an unclean syringe (p=0.026), and received the syringe from their partner (p<0.001). Women were also more likely to report having engaged in sexual intercourse before or after initiation (p<0.001). Men were more likely to have personally purchased the drugs (p=0.002), to have acquired the syringe from a pharmacy/clinic (p=0.004), and to have injected with a friend (p=0.001) or family member (p=0.020). Men were also more likely to have a friend administer the first injection (p=0.007). Conclusions In this population of rural drug users, notable gender differences in injection initiation were observed. Social pressure played a more substantial role in women’s first injection experience, and male partners had an integral role in women’s initiation.

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