The Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in many physiological processes. Several studies indicate that AHR is also involved in energy homeostasis. Fibroblast growth factor 21 (FGF21) is an important regulator of the fasting and feeding responses. When administered to various genetic and diet-induced mouse models of obesity, FGF21 can attenuate obesity-associated morbidities. Here, we explore the role of AHR in hepatic The Aryl hydrocarbon receptor (AHR) 2 is a ligand-activated basic helix-loop-helix/Per-ARNT-Sim (bHLH-PAS) transcription factor, classically known for mediating 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced toxicity. AHR normally resides in the cytoplasm, bound to molecules of heat shock protein 90, X-associated protein 2, and p23. Upon agonist (i.e. TCDD) binding, AHR translocates to the nucleus and aryl hydrocarbon receptor nuclear translocator (ARNT) displaces the cytoplasmic complex to form an AHR-ARNT heterodimer. The AHR-ARNT complex is then able to bind dioxin response elements (DRE) in the promoter region of a wide array of genes, many of which are involved in endogenous and xenobiotic metabolism (e.g. CYP1A1, CYP1A2, and CYP1B1) (1).Several lines of evidence indicate that AHR is involved in the regulation of metabolic homeostasis. For example, TCDD activation of AHR alters the expression of various genes involved in hepatic metabolism (2). Additionally, AHR is involved in the regulation of gluconeogenesis via the AHR-responsive gene TCDD-inducible poly(ADP-ribose) polymerase (Tiparp) (3). However, these studies primarily examine the role of AHR in metabolism when activated by TCDD, a xenobiotic compound. Therefore, the physiological role of AHR in metabolic homeostasis remains poorly understood.Recently, there has been keen interest in the potential use of the metabolic hormone fibroblast growth factor 21 (FGF21) as a treatment for obesity. Administration of recombinant FGF21 in various animal models of obesity consistently results in weight loss, fat pad reduction, and improved insulin sensitivity (4, 5). Physiologically, FGF21 is induced by fasting, and acts as an endocrine hormone to induce gluconeogenesis, ketogenesis, and torpor (6). Further evidence shows that these FGF21-mediated responses depend upon direct binding of PPAR␣-RXR␣ to the Fgf21 promoter region to activate transcription (7). PPAR␣, in combination with cAMP-responsive element-binding protein, hepatocyte specific (CREBH), has also been implicated in the activation of Fgf21 expression (8). Alternatively, carbohydrate response element-binding protein (ChREBP) is known to activate Fgf21 expression under hyperglycemic conditions (9). Recent studies suggest that ChREBP-dependent transcription might also be directly involved in the FGF21-mediated control of sweet taste preference and sugar intake (10).* This work was supported by the National Institute of Food and Agriculture, U.S. Dept. of Agriculture award 2014-06624, and National Institutes of Health Grants ES004869 and E...

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor highly expressed in hepatocytes. Researchers have employed global and liver-specific conditional Ahr knockout mouse models to characterize the physiological roles of the AHR; however, the gestational timing of AHR loss in these models can complicate efforts to distinguish the direct and indirect effects of post-gestational AHR deficiency. Utilizing a novel tamoxifen-inducible AHR knockout mouse model, we analyzed the effects of hepatocyte-targeted AHR loss in adult mice. The data demonstrate that AHR deficiency significantly reduces weight gain and adiposity, and increases multilocular lipid droplet formation within perigonadal white adipose tissue (gWAT). Protein and mRNA expression of fibroblast growth factor 21 (FGF21), an important hepatokine that activates thermogenesis in brown adipose tissue (BAT) and gWAT, significantly increases upon AHR loss and correlates with a significant increase of BAT and gWAT respiratory capacity. Confirming the role of FGF21 in mediating these effects, this phenotype is reversed in mice concomitantly lacking AHR and FGF21 expression. Chromatin immunoprecipitation analyses suggest that the AHR may constitutively suppress Fgf21 transcription through binding to a newly identified xenobiotic response element within the Fgf21 promoter. The data demonstrate an important AHR-FGF21 regulatory axis that influences adipose biology and may represent a “druggable” therapeutic target for obesity and its related metabolic disorders.

The aryl hydrocarbon receptor (AHR) has been studied for over 40 years, yet our understanding of this ligand-activated transcription factor remains incomplete. Each year, novel findings continually force us to rethink the role of the AHR in mammalian biology. The AHR has historically been studied within the context of potent activation via AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), with a focus on how the AHR mediates TCDD toxicity. Research has subsequently revealed that the AHR is actively involved in distinct physiological processes ranging from the development of the liver and reproductive organs, to immune system function and wound healing. More recently, the AHR was implicated in the regulation of energy metabolism and is currently being investigated as a potential therapeutic target for obesity. In this review, we re-trace the steps through which the early toxicological studies of TCDD led to the conceptual framework for the AHR as a potential therapeutic target in metabolic disease. We additionally discuss the key discoveries that have been made concerning the role of the AHR in energy metabolism, as well as the current and future directions of the field.

Viral-mediated in vivo gene delivery methods currently dominate among therapeutic strategies within the clinical and experimental settings, albeit with well documented limitations arising from immunologic constraints. In this study, we demonstrate the utility of nonviral hepatotropic in vivo gene delivery of unpackaged expression constructs, including one encoding fibroblast growth factor 21 (FGF21). FGF21 is an important hepatokine whose expression positively correlates with therapeutic outcomes across various animal models of obesity. Our data demonstrate that FGF21 expression can be restored into the livers of immunocompetent FGF21 knockout mice for at least 2 weeks after a single injection with an FGF21 expression plasmid. In wild-type C57BL6/J mice, in vivo transfection with an FGF21-expressing plasmid induced weight loss, decreased adiposity, and activated thermogenesis in white fat within 2 weeks. Furthermore, in vivo FGF21 gene delivery protected C57BL6/J mice against diet-induced obesity by decreasing adiposity and increasing uncoupling protein 1–dependent thermogenesis in brown fat and by boosting respiratory capacity in subcutaneous and perigonadal white fat. Together, the data illustrate a facile and effective methodology for delivering prolonged protein expression specifically to the liver. We contend that this method will find utility in basic science research as a practical means to enhance in vivo studies characterizing liver protein function. We further believe our data provide a rationale for further exploring the potential clinical utility of nonviral gene therapy in mouse models of disease. Significance Statement This study presents a valuable method for nonviral gene delivery in mice that improves upon existing techniques. The data provide a rationale for further exploring the potential clinical utility of nonviral gene therapy in mouse models of disease and will likely enhance in vivo studies characterizing liver protein function.