Aryl hydrocarbon receptor deficiency protects mice from diet-induced adiposity and metabolic disorders through increased energy expenditure

Abstract

BACKGROUND/OBJECTIVES Epidemics of obesity and diabetes are escalating. High-calorie/high-fat food is a major cause for these global health issues, but molecular mechanisms underlying high-fat, diet-induced obesity are still not well understood. The aryl hydrocarbon receptor (AhR), a transcription factor that acts as a xenobiotic sensor, mediates environmental toxicant-induced obesity, insulin resistance and development of diabetes. AhR also influences lipid metabolism and diet-induced obesity. The effects of AhR deficiency on diet-induced obesity, hepatic steatosis and insulin resistance were examined. METHODS : Male wild type (WT), AhR null (AhR−/−) and AhR heterozygote (AhR+/−) mice were fed a normal chow diet (NCD, 10% kcal from fat) or a high-fat diet (HFD, 60% kcal from fat) for up to 14 weeks. Adiposity, adipose and liver morphology, insulin signaling, metabolic parameters and gene profiles were assessed. RESULTS AhR deficiency protected against HFD-induced obesity, hepatic steatosis, insulin resistance and inflammation. Moreover, AhR deficiency preserved insulin signaling in major metabolic tissues. These protective effects result from a higher energy expenditure in AhR-deficient mice compared to WT. Levels of transcript for both the thermogenic gene, uncoupling protein 1 (Ucp1), in brown adipose tissue and mitochondrial β-oxidation genes in muscle were significantly higher in AhR−/− and AhR+/− mice compared to WT. CONCLUSIONS This work documents a physiologically relevant function for AhR in regulation of body weight, hepatic fat deposition, insulin sensitivity and energy expenditure under HFD exposure, suggesting that AhR signaling may be developed as a potential therapeutic target for treatment of obesity and metabolic disorders.

Adipose Tissue as a Site of Toxin Accumulation

“…These data are consistent with results from mice with adipocyte-specific deficiency in AhR, where mice displayed increased body weight, fat mass, AT inflammation, and decreased glucose tolerance compared to wild type mice when fed a high fat diet (39). In direct contrast, it was recently reported that high-fat fed mice with whole body deficiency of AhR were protected from obesity, insulin resistance, and adipose inflammation (430). In another study, aged, but not young mice with whole body AhR deficiency were reported to have impaired glucose tolerance compared to wild type controls, without concomitant differences in body weight between genotype (46).…”

“…AhR is expressed in adipocytes (354), and the adipocyte AhR has recently garnered increased attention for its role not only in the xenobiotic response of AT, but also as a regulator of body weight, fat mass, and lipid homeostasis (194) (39) (430). Several studies provide evidence of AhR-mediated regulation of AT function, but results have not been consistent.…”

Obesity and fatty liver are prevented by inhibition of the aryl hydrocarbon receptor in both female and male mice

“…It is well established that obesity [2] and associated complications [3, 4] develop differently between males and females; and that gene expression profiles in liver and adipose tissue are dissimilar in male and female mice [5]. Given that the aryl hydrocarbon receptor (AHR) has a large role in obesity in male mice [6–8], we asked whether the AHR carries out a similar role in obesity for females.…”

“…These studies and recent work with B6. Ahr −/− mice, which were shown to be resistant to obesity [7, 8, 23], indicated key roles for the AHR in fat metabolism and deposition as well as a possible target for AHR-based therapeutic and preventative approaches.…”

Host-microbiome interactions: the aryl hydrocarbon receptor and the central nervous system

“…Dysregulation of lipid metabolism leading to hepatic steatosis and insulin resistance suggests that the AHR plays an important role in integrating exogenous and endogenous influences in lipid and energy metabolism [22, 23]. Findings from AHR-deficient mice show that, like GF mice [24, 25], they are protected from high fat diet-induced obesity, hepatic steatosis, and insulin resistance [26]. …”