Effects of Aryl Hydrocarbon Receptor Deficiency on PCB-77-Induced Impairment of Glucose Homeostasis during Weight Loss in Male and Female Obese Mice.

BACKGROUND: Lipophilic polychlorinated biphenyls (PCBs) accumulate with obesity, but during weight loss, liberated PCBs act as ligands of the aryl hydrocarbon receptor (AhR) to negatively influence health. Previous studies demonstrated that PCB-77 administration to obese male mice impaired glucose tolerance during weight loss. Recent studies indicate higher toxic equivalencies of dioxin-like PCBs in exposed females than males. OBJECTIVES: We compared effects of PCB-77 on weight gain or loss and glucose homeostasis in male vs. female mice. We defined effects of AhR deficiency during weight gain or loss in male and female mice exposed to PCB-77. METHODS: Study design was vehicle (VEH) or PCB-77 administration while fed a high-fat (HF) diet for 12 wk, followed by weight loss for 4 wk. The following groups were examined: male and female C57BL/6 mice administered VEH or PCB-77, female [Formula: see text] and [Formula: see text] mice administered VEH or PCB-77, and male [Formula: see text] and [Formula: see text] mice administered PCB-77. Glucose tolerance was quantified during weight gain (week 11) and loss (week 15); liver and adipose AhR and IRS2 (insulin receptor substrate 2) mRNA abundance, and PCB-77 concentrations were quantified at week 16. RESULTS: PCB-77 attenuated development of obesity in females but not males. During weight loss, PCB-77 impaired glucose tolerance of males. AhR-deficient females (VEH) were resistant to diet-induced obesity. Compared with VEH-treated mice, HF-fed [Formula: see text] females treated with PCB-77 has less weight gain, and [Formula: see text] females had greater weight gain. During weight loss, [Formula: see text] females but not [Formula: see text] males treated with PCB-77 exhibited impaired glucose tolerance. In [Formula: see text] females administered PCB-77, IRS2 mRNA abundance was lower in adipose tissue compared with VEH-treated mice. CONCLUSION: Male and female mice responded differently to PCB-77 and AhR deficiency in body weight (BW) regulation and glucose homeostasis. AhR deficiency reversed PCB-77-induced glucose impairment of obese males losing weight but augmented glucose intolerance of females. These results demonstrate sex differences in PCB-77-induced regulation of glucose homeostasis of mice. https://doi.org/10.1289/EHP4133.

Pseudomonas aeruginosa-derived pyocyanin reduces adipocyte differentiation, body weight, and fat mass as mechanisms contributing to septic cachexia.

Pseudomonas aeruginosa, a leading cause of sepsis, produces pyocyanin, a blue-pigmented virulence factor. Sepsis is associated with cachexia, but mechanisms are unknown and conventional nutrition approaches are not effective treatments. Pyocyanin has affinity for the aryl hydrocarbon receptor (AhR), which is expressed on adipocytes and regulates adipocyte differentiation. The purpose of this study was to define in vitro and in vivo effects of pyocyanin on adipocyte differentiation and body weight regulation as relates to septic cachexia. In 3T3-L1 preadipocytes, pyocyanin activated AhR and its downstream marker CYP1a1, and reduced differentiation. Administration of pyocyanin to male C57BL/6J mice acutely reduced body temperature with altered locomotion, but caused sustained weight loss. Chronic pyocyanin administration to male and female C57BL/6J mice resulted in sustained reductions in body weight and fat mass, with adipose-specific AhR activation. Pyocyanin-treated male mice had decreased energy expenditure and physical activity, and increased adipose explant lipolysis. In females, pyocyanin caused robust reductions in body weight, adipose-specific AhR activation, and increased expression of inflammatory cytokines in differentiated adipocytes. These results demonstrate that pyocyanin reduces adipocyte differentiation and decreases body weight and fat mass in male and female mice, suggesting that pyocyanin may play a role in septic cachexia.

Adipose Tissue as a Site of Toxin Accumulation.

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, and 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 (i) highlight the physical characteristics of toxicants that enable them to partition into and remain stored in adipose tissue, (ii) discuss the specific mechanisms of action by which these toxicants act to influence adipocyte function, and (iii) 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. © 2017 American Physiological Society. Compr Physiol 7:1085-1135, 2017.

Deficiency of angiotensinogen in hepatocytes markedly decreases blood pressure in lean and obese male mice.

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

Effects of Adipocyte Aryl Hydrocarbon Receptor Deficiency on PCB-Induced Disruption of Glucose Homeostasis in Lean and Obese Mice.

BACKGROUND: Coplanar 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. OBJECTIVES: In 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 RESULTS: PCB-77 administration impaired glucose and insulin tolerance in LF (low fat diet)-fed control (AhR(fl/fl)) mice but not in adipocyte AhR-deficient mice (AhR(AdQ)). Unexpectedly, AhR(AdQ) 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 AhR(AdQ) mice administered vehicle (VEH) exhibited increased body weight, adipose mass, adipose inflammation, and impaired glucose tolerance compared with AhR(fl/fl) controls. Impairment of glucose homeostasis in response to PCB-77 was not observed in obese mice of either genotype. However, upon weight loss, AhR(fl/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 AhR(AdQ) mice exhibiting weight loss. CONCLUSIONS: Our 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.

Gender differences in circumstances surrounding first injection experience of rural injection drug users in the United States.

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.