Browsing by Subject "obesity"
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Item Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities(National Academy of Sciences, 2015-08-18) Chen, Yih-Wen; Harris, Robert A.; Hatahet, Zafer; Chou, Kai-ming; Department of Pharmacology and Toxicology, IU School of MedicineObesity and the metabolic syndrome have evolved to be major health issues throughout the world. Whether loss of genome integrity contributes to this epidemic is an open question. DNA polymerase η (pol η), encoded by the xeroderma pigmentosum (XP-V) gene, plays an essential role in preventing cutaneous cancer caused by UV radiation-induced DNA damage. Herein, we demonstrate that pol η deficiency in mice (pol η −/− ) causes obesity with visceral fat accumulation, hepatic steatosis, hyperleptinemia, hyperinsulinemia, and glucose intolerance. In comparison to WT mice, adipose tissue from pol η −/− mice exhibits increased DNA damage and a greater DNA damage response, indicated by up-regulation and/or phosphorylation of ataxia telangiectasia mutated (ATM), phosphorylated H2AX (γH2AX), and poly[ADP-ribose] polymerase 1 (PARP-1). Concomitantly, increased cellular senescence in the adipose tissue from pol η −/− mice was observed and measured by up-regulation of senescence markers, including p53, p16Ink4a, p21, senescence-associated (SA) β-gal activity, and SA secretion of proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) as early as 4 wk of age. Treatment of pol η −/− mice with a p53 inhibitor, pifithrin-α, reduced adipocyte senescence and attenuated the metabolic abnormalities. Furthermore, elevation of adipocyte DNA damage with a high-fat diet or sodium arsenite exacerbated adipocyte senescence and metabolic abnormalities in pol η −/− mice. In contrast, reduction of adipose DNA damage with N-acetylcysteine or metformin ameliorated cellular senescence and metabolic abnormalities. These studies indicate that elevated DNA damage is a root cause of adipocyte senescence, which plays a determining role in the development of obesity and insulin resistance.Item Assessing neuronal ciliary localization of Melanin Concentrating Hormone Receptor 1 in vivo(2021-08) Kamba, Tisianna K.; Berbari, Nicolas F.; Mastracci, Teresa; Dai, GuoliObesity is a growing pandemic that claims close to three hundred thousand lives per year in the United States alone. Despite strong interest and investment in potential treatments, obesity remains a complex and challenging disorder. In the study of obesity, mouse models have been excellent tools that help in understanding the function of different genes that contribute to this disease of energy homeostasis. However, it was surprising when disfunction in primary cilia was found to be linked to syndromic obesity. To understand the role of primary cilia in obesity, a growing subset of GPCRs have been identified to selectively localize to the organelle. Several of which have known roles in energy homeostasis. In some examples, ciliary GPCRs appear to dynamically localize to the organelle; such is the case of GPR161 and smoothened in the hedgehog signaling pathway. Thus, we were interested to see if other GPCRs dynamically localize to the primary cilia as part of their regulation of energy homeostasis. For example, the GPCR MCHR1 selectively localizes to the cilia and is involved in energy homeostasis. Although much is known about the expression of the receptor in the brain, how its ciliary subcellular localization impacts its roles in energy homeostasis is unknown. Observing neuronal cilia in vivo remains a difficult task as some of the available tools such as tagged alleles rely on overexpression of ciliary protein which may impact function. Additionally, most of the work is done in vitro, leaving much to be discovered about neuronal cilia in vivo. In this thesis, we show that using a newly constructed reporter allele mCherryMCHR1, we can see ciliary expression of MCHR1 in the brain of developing and adult mice; more specifically in the ARC and PVN. Subsequently, using a novel Artificial intelligence analysis approach, we measured the length and composition of MCHR1 positive cilia under physiological conditions associated with MCHR1 function. Although in this work we are reporting no changes in dynamic localization of MCHR1 in the hypothalamus specifically, we are not excluding the potential for changes in other regions of the brain or under other conditions; and we are suggesting that pharmacological approaches may help highlight potential ciliary GPCR dynamic localization.Item Association between obesity and bacterial vaginosis as assessed by Nugent score(Elsevier, 2019) Brookheart, Rita T.; Lewis, Warren G.; Peipert, Jeffrey F.; Lewis, Amanda L.; Allsworth, Jenifer E.; Obstetrics and Gynecology, School of MedicineBackground Bacterial vaginosis is one of the most common vaginal conditions in the U.S. Recent studies have suggested obese women have an abnormal microbiota reminiscent of BV; however, few studies have investigated the prevalence of bacterial vaginosis in overweight and obese populations. Moreover, despite the increased prevalence of obesity and bacterial vaginosis in black women, it is not known whether racial disparities exist in the relationship between obesity and bacterial vaginosis. Objective The objective of this study was to examine the relationship between body mass index and bacterial vaginosis as determined by Nugent score and to determine the influence of race in this context. Study Design We performed a cross-sectional study using patient data and vaginal smears from 5,918 participants of the Contraceptive CHOICE Project. Gram stained vaginal smears were scored using the Nugent method and categorized as BV-negative (Nugent score 0-3), BV-intermediate (Nugent score 4-6), or BV-positive (Nugent score 7-10). Body mass index was determined using Centers for Disease Control and Prevention guidelines and obese individuals were categorized as Class I, II, or III obese based on NIH and World Health Organization body mass index parameters. Linear regression was used to model mean differences in Nugent scores and Poisson regression with robust error variance was used to model prevalence of bacterial vaginosis. Results In our cohort, 50.7% of participants were black, 41.5% were white, and 5.1% were of Hispanic ethnicity with an average age of 25.3 years old. Overall, 28.1% of participants were bacterial vaginosis-positive. Bacterial vaginosis was prevalent in 21.3% of lean, 30.4% of overweight, and 34.5% of obese women (p<0.001). The distribution of bacterial vaginosis-intermediate individuals was similar across all body mass index categories. Compared to lean women, Nugent scores were highest among overweight and obese Class I women (adjusted mean difference; overweight 0.33 [95% CI 0.14, 0.51] and Class I obese 0.51 [95% CI 0.29, 0.72]). Consistent with this, overweight and obese women had a higher frequency of bacterial vaginosis compared to lean women, even after adjusting for variables including race. Among white women, the prevalence of BV was higher for overweight and Class I and Class II/III obese white women compared to lean white women, a phenomenon not observed among black women, suggesting an effect modification. Conclusion Overweight and obese women have higher Nugent scores and a greater occurrence of bacterial vaginosis compared to lean women. Black women have a greater prevalence of bacterial vaginosis independent of their body mass index compared to white women.Item Associations between trust of healthcare provider and body mass index in adolescents(Taylor & Francis, 2021-07-03) Hardin, Heather K.; Moore, Shirley M.; Moore, Scott E.; Uli, Naveen K.Adolescent obesity continues to be a serious concern around the world, placing young people at risk for chronic conditions and early death. Research has shown that social relationships are important in making health behavior changes, such as following health-care recommendations for eating and physical activity. Specifically, the trust of health-care providers has been shown to be important in making health behavior change. Evidence suggests that obese young adults are less trusting of health-care providers than their healthy weight peers, but it is not known if this also applies to obese adolescents. The purpose of this secondary analysis study was to determine relationships between the trust of health-care providers and body mass index percentile in adolescents. Participants were 224 adolescents aged 14-19 years attending a public high school in the Midwestern United States. The Wake Forest Physician Trust scale measured the trust of health-care providers. Height and weight were collected at a school screening; body mass index percentile categories were determined according to age- and sex-adjusted body mass index percentiles. One-way analysis of variance and post hoc Tukey tests showed trust scores varied significantly between body mass index percentile categories of girls. Results suggest it may be necessary for health-care providers to make additional efforts to build trust with obese adolescent girls than with other groups of adolescents.Item Baseline body mass index among children and adults undergoing allogeneic hematopoietic cell transplantation: clinical characteristics and outcomes(Nature Publishing Group, 2015-03) Gleimer, Michael; Li, Yumeng; Chang, Lawrence; Paczesny, Sophie; Hanauer, David A.; Frame, David G.; Byersdorfer, Craig A.; Reddy, Pavan R.; Braun, Thomas M.; Choi, Sung Won; Department of Pediatrics, IU School of MedicineObesity is an important public health problem that may influence the outcomes of hematopoietic cell transplantation (HCT). We studied 898 children and adults receiving first-time allogeneic hematopoietic stem cell transplants between 2004 and 2012. Pre-transplant body mass index (BMI) was classified as underweight, normal weight, overweight, or obese using the WHO classification, or age-adjusted BMI percentiles for children. The study population was predominantly Caucasian, and the median age was 51 years (5 months – 73 years). The cumulative 3-year incidence of non-relapse mortality (NRM) in underweight, normal weight, overweight, and obese patients was 20%, 19%, 20%, and 33%, respectively. Major causes of NRM were acute and chronic graft-versus-host disease (GVHD). The corresponding incidence of relapse was 30%, 41%, 37%, and 30%, respectively. Three-year overall survival was 59%, 48%, 47%, and 43%, respectively. Multivariate analysis showed that obesity was associated with higher NRM (HR 1.43, p=0.04), and lower relapse (HR 0.65, p=0.002). Pre-transplant plasma levels of ST2 and TNFR1 biomarkers were significantly higher in obese compared with normal weight patients (p=0.04 and p=0.05, respectively). The increase in NRM observed in obese patients was partially offset by lower incidence of relapse with no difference in overall survival.Item Cellular and Molecular Targets in the Neuroendocrine System That Defend Against Diabetes, Obesity, and Alzheimer's Disease(2021-09) Reilly, Austin Michael; Sheets, Patrick; Ren, Hongxia; Baucum, Anthony II; Evans-Molina, Carmella; Landreth, GaryMetabolic survival mechanisms that defend body weight and conserve energy are currently at odds with modernized society which has a food supply that is ubiquitous, calorie dense, and highly palatable. Chronic overnutrition leads to a metabolic syndrome of obesity, insulin resistance, inflammation, and cardiovascular diseases that is increasingly prevalent and threatens health on a global scale. The brain is both a victim and culprit of metabolic diseases, and prolonged metabolic dysfunction can exacerbate the pathological mechanisms underlying both metabolic and neurodegenerative diseases. Since neuroendocrine pathways comprise an essential feedback mechanism that detects circulating hormones and nutrients in order to regulate satiety, energy expenditure, and glucose homeostasis, our research goals were to characterize molecular mechanisms within neuroendocrine pathways that could be leveraged for treating obesity, diabetes, and Alzheimer’s disease. First, we identified the expression of a G protein-coupled receptor, Gpr17, in POMC neurons and discovered that it protects aged mice from high-fat diet (HFD)-induced metabolic derangements. We examined the electrophysiological properties of POMC neurons and found Gpr17 deficiency led to increased spontaneous action potentials. Moreover, Pomc-Cre-driven Gpr17 knockout (PGKO) mice, especially female knockouts, had increased POMC-derived alpha-melanocyte stimulating hormone and beta-endorphin despite a comparable level of prohormone POMC in their hypothalamic extracts. Second, we generated a highly insulin resistant mouse model with human GLUT4 promoter-driven insulin receptor knockout (GIRKO) in muscle, adipose, and GLUT4-expressing neuronal subpopulations. This genetic approach recapitulates the primary defect preceding type 2 diabetes (T2D) and revealed additional factors/mechanisms that drive the ultimate progression of overt diabetes. Third, we used 5xFAD mice as a model of Alzheimer’s disease and showed that they were more susceptible to HFD-induced metabolic dysregulation and expression of AD pathological markers in the hippocampus. Our results helped elucidate the molecular and cellular mechanisms responsible for increased AD pathology in high-fat diet-fed 5xFAD mice and suggest that metabolic dysfunctions are a therapeutic target to ameliorate AD pathology. In conclusion, metabolic diseases are pervasive and require nuanced approaches that target the neuroendocrine system in order to restore metabolic homeostasis and protect the brain from neurodegenerative processes that are associated with obesity and diabetes.Item The Changing Face of Diabetes in Youth: Lessons Learned from Studies of Type 2 Diabetes(Wiley, 2015-09) Hannon, Tamara S.; Arslanian, Silva A.; Department of Pediatrics, IU School of MedicineThe incidence of youth type 2 diabetes (T2D), linked with obesity and declining physical activity in high-risk populations, is increasing. Recent multicenter studies have led to a number of advances in our understanding of the epidemiology, pathophysiology, diagnosis, treatment, and complications of this disease. As in adult T2D, youth T2D is associated with insulin resistance, together with progressive deterioration in β cell function and relative insulin deficiency in the absence of diabetes-related immune markers. In contrast to adult T2D, the decline in β cell function in youth T2D is three- to fourfold faster, and therapeutic failure rates are significantly higher in youth than in adults. Whether the more aggressive nature of youth T2D is driven by genetic heterogeneity or physiology/metabolic maladaptation is yet unknown. Besides metformin, the lack of approved pharmacotherapeutic agents for youth T2D that target the pathophysiological mechanisms is a major barrier to optimal diabetes management. There is a significant need for effective therapeutic options, in addition to increased prevention, to halt the projected fourfold increase in youth T2D by 2050 and the consequences of heightened diabetes-related morbidity and mortality at younger ages.Item Circadian clock control of hepatic lipid metabolism: role of small heterodimer partner (Shp)(BMJ Journals, 2016-10) Wang, Li; Liangpunsakul, Suthat; Medicine, School of MedicineHepatic steatosis, the accumulation of triglyceride droplets in the hepatocytes, is a common hepatic pathology seen in subjects with obesity/metabolic syndrome and those with excessive alcohol use. The pathogenesis underlying hepatic steatosis is complex. Recent studies have shown the specific role played by the molecular clock mechanism in the control of lipid metabolism and that the disruption of these tissue clocks may lead to the disturbances in lipid homeostasis. This review reports a novel role of small heterodimer partner in maintaining triglyceride and lipoprotein homeostasis through neuronal PAS domain protein 2.Item Contribution of K+ Channels to Coronary Dysfunction in Metabolic Syndrome(2009-06-24T12:58:39Z) Watanabe, Reina; Tune, Johnathan D.Coronary microvascular function is markedly impaired by the onset of the metabolic syndrome and may be an important contributor to the increased cardiovascular events associated with this mutlifactorial disorder. Despite increasing appreciation for the role of coronary K+ channels in regulation of coronary microvascular function, the contribution of K+ channels to the deleterious influence of metabolic syndrome has not been determined. Accordingly, the overall goal of this investigation was to delineate the mechanistic contribution of K+ channels to coronary microvascular dysfunction in metabolic syndrome. Experiments were performed on Ossabaw miniature swine fed a normal maintenance diet or an excess calorie atherogenic diet that induces the classical clinical features of metabolic syndrome including obesity, insulin resistance, impaired glucose tolerance, dyslipidemia, hyperleptinemia, and atherosclerosis. Experiments involved in vivo studies of coronary blood flow in open-chest anesthetized swine as well as conscious, chronically instrumented swine and in vitro studies in isolated coronary arteries, arterioles, and vascular smooth muscle cells. We found that coronary microvascular dysfunction in the metabolic syndrome significantly impairs coronary vasodilation in response to metabolic as well as ischemic stimuli. This impairment was directly related to decreased membrane trafficking and functional expression of BKCa channels in vascular smooth muscle cells that was accompanied by augmented L-type Ca2+ channel activity and increased intracellular Ca2+ concentration. In addition, we discovered that impairment of coronary vasodilation in the metabolic syndrome is mediated by reductions in the functional contribution of voltage-dependent K+ channels to the dilator response. Taken together, findings from this investigation demonstrate that the metabolic syndrome markedly attenuates coronary microvascular function via the diminished contribution of K+ channels to the overall control of coronary blood flow. Our data implicate impaired functional expression of coronary K+ channels as a critical mechanism underlying the increased incidence of cardiac arrhythmias, infarction and sudden cardiac death in obese patients with the metabolic syndrome.Item County-level Geographic Distributions of Diabetes in Relation to Multiple Factors in the United States(IEEE, 2018-03) Oraz, Gulzhahan; Luo, Xiao; Computer and Information Science, School of ScienceThe increasing prevalence of diagnosed diabetes has drawn attention of researchers in recent years. In this study, a feature selection method based on linear regression has been used to identify the most relevant factors that are associated with diabetes prevalence from the national county health ranking data sets. Then, Expectation-Maximization clustering algorithm has been used to identify the geo-clusters of counties based on the factors and their relations to the diabetes prevalence for years from 2014 to 2017. The results have identified the unique county-level geographic disparities and trends in diabetes and the related factors over the past four years.