Cassie Jaeger

ARYL HYDROCARBON RECEPTOR DEFICIENCY PROTECTS MICE FROM DIET-INDUCED ADIPOSITY AND METABOLIC DISORDERS THROUGH INCREASED ENERGY EXPENDITURE

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 with 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 with 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.

CIRCADIAN CLOCK DISRUPTION IN THE MOUSE OVARY IN RESPONSE TO 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN

Activation of the aryl hydrocarbon receptor (AhR) by the highly toxic, prototypical ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or other dioxin-like compounds compromises ovarian function by altering follicle maturation and steroid synthesis. Although alteration of transcription after nuclear translocation and heterodimerization of AhR with its binding partner, aryl hydrocarbon nuclear transporter (ARNT), is often cited as a primary mechanism for mediating the toxic effects of dioxins, recent evidence indicates that crosstalk between AhR and several other signaling pathways also occurs. Like the circadian clock genes, AhR is a member of the basic helix-loop-helix, Per-ARNT-SIM (bHLH-PAS) domain family of proteins. Thus, these studies tested the hypothesis that TCDD can act to alter circadian clock regulation in the ovary. Adult female c57bl6/J mice entrained to a typical 12h light/12h dark cycle were exposed to a single 1 μg/kg dose of TCDD by gavage. Six days after exposure, animals were released into constant darkness and ovaries were collected every 4h over a 24h period. Quantitative real-time PCR and immunoblot analysis demonstrated that TCDD exposure alters expression of the canonical clock genes, Bmal1 and Per2 in the ovary. AhR transcript and protein, which displayed a circadian pattern of expression in the ovaries of control mice, were also altered after TCDD treatment. Immunohistochemistry studies revealed co-localization of AhR with BMAL1 in various ovarian cell types. Furthermore, co-immunoprecipitation demonstrated time-of-day dependent interactions of AhR with BMAL1 that were enhanced after TCDD treatment. Collectively these studies suggest that crosstalk between classical AhR signaling and the molecular circadian clockworks may be responsible for altered ovarian function after TCDD exposure.

Role of Aryl Hydrocarbon Receptor in Circadian Clock Disruption and Metabolic Dysfunction

The prevalence of metabolic syndrome, a clustering of three or more risk factors that include abdominal obesity, increased blood pressure, and high levels of glucose, triglycerides, and high-density lipoproteins, has reached dangerous and costly levels worldwide. Increases in morbidity and mortality result from a combination of factors that promote altered glucose metabolism, insulin resistance, and metabolic dysfunction. Although diet and exercise are commonly touted as important determinants in the development of metabolic dysfunction, other environmental factors, including circadian clock disruption and activation of the aryl hydrocarbon receptor (AhR) by dietary or other environmental sources, must also be considered. AhR binds a range of ligands, which prompts protein–protein interactions with other Per-Arnt-Sim (PAS)-domain-containing proteins and subsequent transcriptional activity. This review focuses on the reciprocal crosstalk between the activated AhR and the molecular circadian clock. AhR exhibits a rhythmic expression and time-dependent sensitivity to activation by AhR agonists. Conversely, AhR activation influences the amplitude and phase of expression of circadian clock genes, hormones, and the behavioral responses of the clock system to changes in environmental illumination. Both the clock and AhR status and activation play significant and underappreciated roles in metabolic homeostasis. This review highlights the state of knowledge regarding how AhR may act together with the circadian clock to influence energy metabolism. Understanding the variety of AhR-dependent mechanisms, including its interactions with the circadian timing system that promote metabolic dysfunction, reveals new targets of interest for maintenance of healthy metabolism.

Aryl hydrocarbon receptor-deficient mice are protected from high fat diet-induced changes in metabolic rhythms

ABSTRACT High fat diet (HFD) consumption alters the synchronized circadian timing system resulting in harmful loss, gain or shift of transcriptional oscillations. The aryl hydrocarbon receptor (AhR) shares structural homology to clock genes, containing both PAS domains and basic helix-loop helix structural motifs, allowing for interaction with components of the primary circadian feedback loop. Activation of AhR alters circadian rhythmicity, primarily through inhibition of Clock/Bmal1-mediated regulation of Per1. AhR-deficient mice are protected from diet-induced metabolic dysfunction, exhibiting enhanced insulin sensitivity and glucose tolerance. This study examined whether AhR haploinsufficiency can also protect against diet-induced alterations in rhythm. After feeding AhR+/+ and AhR+/− mice an HFD (60% fat) for 15 weeks, samples were collected every 4 hours over a 24-hour period. HFD altered the rhythm of serum glucose and the metabolic transcriptome, including hepatic nuclear receptors Rev-erbα and PPARγ in wild-type c57bl6/j mice. AhR reduction provided protection against diet-induced transcriptional oscillation changes; serum glucose and metabolic gene rhythms were protected from the disruption caused by HFD feeding. These data highlight the critical role of AhR signaling in the regulation of metabolism and provide a potential therapeutic target for diseases characterized by rhythmic desynchrony.

Effectively reducing amylase testing using computer order entry in the emergency department: quality improvement without eliminating physician choice

Background Amylase and lipase, pancreatic biomarkers, are measured in acute pancreatitis diagnosis. Since amylase testing does not add diagnostic value, lipase testing alone is recommended. Despite new recommendations, many physicians and staff continue to test both amylase and lipase. Objective To reduce unnecessary diagnostic testing in acute pancreatitis. Methods The pre-checked amylase test within the Emergency Department’s Computerised Provider Order Entry (CPOE) abdominal pain order set was changed to an un-checked state but kept as an option to order with a single click. Amylase testing, lipase testing and cost were measured for one year pre- and post-intervention. Results Simple de-selection intervention reduced redundant amylase testing from 71% to 9%, resulting in a percent of decrease of 87% and an annualised saving of approximately

Effectively Reducing CK-MB Utilization Using Computer Order Entry in the Emergency Department.

719,000 in charges. Conclusion CPOE de-selection is an effective tool to reduce non-value added activity and reduce cost while maintaining quality patient care and physician choice.

Environmental factors act through aryl hydrocarbon receptor activation and circadian rhythm disruption to regulate energy metabolism

To the Editor: Money spent on health care in the United States is expected to consume 20.3% of gross domestic product by 2018 and reach

Effectiveness of a submassive pulmonary embolism protocol to standardise patient evaluation and treatment

4.4 trillion by 2020. Physicians, whose medical decisions are highly dependent on laboratory results, delegate the majority of the health care costs when making testing decisions. Historically, elevated cardiac biomarkers have aided in the diagnosis of acute myocardial infarction (AMI) and are accepted by the American College of Cardiology and the European Society of Cardiology. Although the cardiac biomarkers creatine kinase-muscle and brain type isoenzyme (CK-MB) and troponin both increase following AMI, troponin is currently recommended as the biomarker for diagnosis because of enhanced sensitivity and specificity to myocardial injury. Physicians commonly order multiple cardiac biomarker laboratory tests, potentially contributing to enhanced health care costs. A team of physicians and medical personnel at the authors’ institution recommended that CK-MB offered little added value as preselected testing in our computerized provider order entry (CPOE) system for AMI and elected to unselect CK-MB from the routine order set; nonetheless, CK-MB could be selected if needed. Baseline measurements of CK-MB testing were measured from January to March 2014 using the institution’s Cerner Discern Analytics Program. Post intervention, CK-MB testing was measured from January to March 2015. Mortality metrics were analyzed before and after the CPOE changes. Direct cost to perform CK-MB testing was calculated from the institution’s Laboratory Quality and Safety Cost Accounting System. The rate of CK-MB orders was reduced significantly from 43.7 to 6.8 CK-MB tests per day post intervention, a decline in utilization of 84%. Extrapolating testing cost to a per day rate, a decline of costs, specifically institutional cost avoidance, from pre to post intervention decreased from

Improving medication reconciliation at hospital admission, discharge and ambulatory care through a transition of care team

546 per day to

Quality improvement of delirium status communication and documentation for intensive care unit patients during daily multidisciplinary rounds

85 per day. The savings can reasonably be annualized to approximately