Role of Pregnane X Receptor in Obesity and Glucose Homeostasis in Male Mice

Spruiell, Krisstonia; Richardson, Ricardo M.; Cullen, John M.; Awumey, Emmanuel M.; Gonzalez, Frank J.; Gyamfi, Maxwell Afari

doi:10.1074/jbc.m113.494575

Cited by 88 publications

(108 citation statements)

References 73 publications

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“…The dichotomy of resistance to DIO and altered glucose homeostasis that we noted is not unprecedented (9,50) and would suggest that in IL-15R␣ Ϫ/Ϫ mice, the increased utilization of fatty acids competes with utilization of glucose as a substrate (12,26,42). Similarly, muscle-specific PGC-1␣ overexpression also induces a muscle oxidative phenotype with constitutively higher fat oxidation at the expense of glucose tolerance (9).…”

Section: Discussionmentioning

confidence: 73%

IL-15Rα is a determinant of muscle fuel utilization, and its loss protects against obesity

Loro

Seifert

Moffat

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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is the widely expressed primary binding partner for IL-15. Because of the wide distribution in nonlymphoid tissues like skeletal muscle, adipose, or liver, IL-15/IL-15R␣ take part in physiological and metabolic processes not directly related to immunity. In fast muscle, lack of IL-15R␣ promotes an oxidative switch, with increased mitochondrial biogenesis and fatigue resistance. These effects are predicted to reproduce some of the benefits of exercise and, therefore, improve energy homeostasis. However, the direct effects of IL-15R␣ on metabolism and obesity are currently unknown. We report that mice lacking IL-15R␣ (IL-15R␣ Ϫ/Ϫ ) are resistant to diet-induced obesity (DIO). High-fat diet-fed IL-15R␣ Ϫ/Ϫ mice have less body and liver fat accumulation than controls. The leaner phenotype is associated with increased energy expenditure and enhanced fatty acid oxidation by muscle mitochondria. Despite being protected against DIO, IL-15R␣ Ϫ/Ϫ are hyperglycemic and insulin-resistant. These findings identify novel roles for IL-15R␣ in metabolism and obesity.interleukin-15 receptor alpha; diet-induced obesity; muscle; fatty acid oxidation; fatigue recovery; glucose homeostasis ACCUMULATION OF EXCESSIVE body fat is a physiological consequence of unnecessary caloric intake. With greater worldwide food production, often the caloric intake largely exceeds the physiological energy requirements, and as a result, the obesity pandemic is growing at alarming rates in both developed and developing countries (21,47). Apart from the role of environmental factors, particularly an energy-dense diet and sedentary lifestyle, obesity also has important genetic determinants that have been conserved across species. Identifying the molecular mechanisms regulating metabolic efficiency (the capacity to convert energy intake into storable energy forms) is of great interest because of the low success in using caloric restriction as a means to manage obesity. Indeed, a number of pathways have been recently identified that reduce the extent of dietinduced obesity (DIO) by decreasing metabolic efficiency rather than energy input (8,10,11,43,56,59,60). Targeting these pathways with pharmacological approaches may also have the advantage of reproducing some of the benefits normally associated with physical exercise. Together with caloric restriction, exercise is a mainstay of a healthy life style and contributes to the control of metabolic efficiency. In addition to converting energy into movement, exercise increases the rates of lipolysis and fat oxidation, promotes heat dissipation (49, 53), and causes long-term changes in the expression of numerous genes, including IL-15R␣/IL-15 (55).IL-15 and its primary binding partner IL-15R␣ have emerged as important regulators of cell functions in both lymphoid and nonlymphoid tissues. Their transcripts are detectable in a variety of tissues, including skeletal muscle, liver, or adipose (http://biogps.org/#gotoϭwelcome). Some of the proposed noncanonical roles of IL-15/IL-15R␣ signaling are mediating anabolic...

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Section: Discussionmentioning

confidence: 73%

IL-15Rα is a determinant of muscle fuel utilization, and its loss protects against obesity

Loro

Seifert

Moffat

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Total RNA was isolated from frozen liver tissues using the Trizol reagent according to the manufacturer's protocol (Invitrogen, Carlsbard, CA). Total RNA (5 mg) was reverse transcribed into cDNA with random hexamer primers using a Tetro cDNA Synthesis Kit (Bioline, Taunton, MA) as we previously described (Spruiell et al, 2014b). The cDNA was then diluted 20-fold with water and subjected to real-time quantitative polymerase chain reaction (PCR) by the SensiFast SYBR Hi-ROX Kit (Bioline) to quantify the mRNA levels of peroxisome proliferator-activated receptor a (PPARa), PPARg, sterol regulatory element-binding protein-1c (SREBP-1c), CPT1 (carnitine palmitoyltransferase 1), ACOX-1 (acylCoA Oxidase 1), L-FABP-1 (liver-type fatty acid-binding protein 1), microsomal triglyceride transfer protein (MTTP), fatty acid translocase (CD36), ACC-1a (acetyl-CoA carboxylase 1a), FAS (fatty acid synthase), SCD1 (stearoyl-CoA desaturase-1), and phosphatidylethanolamine N-methyltransferase (PEMT).…”

Section: Methodsmentioning

confidence: 99%

Pregnane X Receptor–Humanized Mice Recapitulate Gender Differences in Ethanol Metabolism but Not Hepatotoxicity

Spruiell

Gyamfi

Yeyeodu

et al. 2015

J Pharmacol Exp Ther

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Both human and rodent females are more susceptible to developing alcoholic liver disease following chronic ethanol (EtOH) ingestion. However, little is known about the relative effects of acute EtOH exposure on hepatotoxicity in female versus male mice. The nuclear receptor pregnane X receptor (PXR; NR1I2) is a broad-specificity sensor with species-specific responses to toxic agents. To examine the effects of the human PXR on acute EtOH toxicity, the responses of male and female PXRhumanized (hPXR) transgenic mice administered oral binge EtOH (4.5 g/kg) were analyzed. Basal differences were observed between hPXR males and females in which females expressed higher levels of two principal enzymes responsible for EtOH metabolism, alcohol dehydrogenase 1 and aldehyde dehydrogenase 2, and two key mediators of hepatocyte replication and repair, cyclin D1 and proliferating cell nuclear antigen. EtOH ingestion upregulated hepatic estrogen receptor a, cyclin D1, and CYP2E1 in both genders, but differentially altered lipid and EtOH metabolism. Consistent with higher basal levels of EtOH-metabolizing enzymes, blood EtOH was more rapidly cleared in hPXR females. These factors combined to provide greater protection against EtOH-induced liver injury in female hPXR mice, as revealed by markers for liver damage, lipid peroxidation, and endoplasmic reticulum stress. These results indicate that female hPXR mice are less susceptible to acute binge EtOH-induced hepatotoxicity than their male counterparts, due at least in part to the relative suppression of cellular stress and enhanced expression of enzymes involved in both EtOH metabolism and hepatocyte proliferation and repair in hPXR females.

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“…Thus, PXR plays an important role in the xenobiotic metabolism and excretion. In addition to this well-known function, recent studies have expanded the roles of PXR, which include the regulation of glucose or lipid metabolisms in the liver (Sui et al, 2011;Chang and Waxman, 2006;Hukkanen, 2012;Gotoh and Negishi, 2015;Spruiell et al, 2014). In addition, we have recently demonstrated that PXR activation enhances hepatocyte proliferation mediated by CAR or peroxisome proliferator-activated receptor α (PPARα) activation: Although treatment of mice with pregnenolone 16α-carbonitrile (PCN), a PXR agonist, alone did not induce hepatocyte proliferation, co-treatment of mice with PCN and CAR or PPARα agonist showed intense hepatocyte proliferation compared to single treatment with CAR or PPARα agonist (Shizu et al, 2013), which probably results from the PXR-mediated down-regulation of cell cycle suppressor genes (Shizu et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Acceleration of murine hepatocyte proliferation by imazalil through the activation of nuclear receptor PXR

et al. 2018

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-The nuclear receptor pregnane X receptor (PXR) plays a major role in the xenobiotic-induced expression of drug-metabolizing enzymes. PXR activation is also associated with several adverse events in the liver. Especially, the receptor enhances hepatocyte proliferation mediated by chemical liver tumor promoters, suggesting that exposure to PXR activators increases the risk of liver cancer. In this study, we have investigated the influences of food additives on PXR to understand their potential adverse effects when they are taken in combination with other chemical compounds. We first screened 25 food additives and related compounds for their PXR-activating ability using reporter assays in HepG2 cells expressing mouse PXR, and found that imazalil dose-dependently activated mouse PXR. Next, to investigate whether imazalil could activate mouse PXR in vivo, mice were treated with imazalil and we found that imazalil treatment increased hepatic mRNA levels of Cyp3a11, a PXR target gene. Finally, to investigate the influence of imazalil exposure on the hepatocyte proliferation induced by nuclear receptor constitutive active/androstane receptor (CAR), mice were treated with imazalil with or without mouse CAR activator TCPOBOP. Although imazalil alone did not induce hepatocyte proliferation, co-treatment with imazalil facilitated the TCPOBOP-dependent proliferation, indicated by the increases in cell proliferation marker levels, Ki-67-positive nuclei and Mcm2 mRNA levels. These results suggest that in mice imazalil activates PXR to enhance hepatocyte proliferation mediated by CAR-activating liver tumor promoters.

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Role of Pregnane X Receptor in Obesity and Glucose Homeostasis in Male Mice

Cited by 88 publications

References 73 publications

IL-15Rα is a determinant of muscle fuel utilization, and its loss protects against obesity

IL-15Rα is a determinant of muscle fuel utilization, and its loss protects against obesity

Pregnane X Receptor–Humanized Mice Recapitulate Gender Differences in Ethanol Metabolism but Not Hepatotoxicity

Acceleration of murine hepatocyte proliferation by imazalil through the activation of nuclear receptor PXR

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