Translational Medical Research Commons^™

Retraction Note: Obesity-Induced Adipokine Imbalance Impairs Mouse Pulmonary Vascular Endothelial Function And Primes The Lung For Injury, Dilip Shah, Freddy Romero, Michelle Duong, Nadan Wang, Bishnuhari Paudyal, Benjamin T Suratt, Caleb B Kallen, Jianxin Sun, Ying Zhu, Kenneth Walsh, Ross Summer

Center for Translational Medicine Faculty Papers

The Authors have retracted this Article. Afer publication of this Article, concerns have been raised about irregularities in the western blot data. In particular, the following bands appear to be duplicated: – Fig. 1e HFD/p-Src lane 1 and 3; – Fig. 4c NCD/Ve-cadherin lane 1 and 3 – Fig. 5e HFD+APN/ICAM-1 lane 1 and 2 – Fig. 5f HFD/beta-catenin lane 2 and HFD+APN/beta-catenin lane 1 – Fig. S1d HFD/beta-catenin all lanes – Fig. S4c NCD/beta-catenin lane 1 and 3. Additionally, the beta-catenin subpanel in Fig. 5f was subsequently reused in another study [1] and described as showing GRP87. Te Authors …

Prediction Of Neonatal Birthweight Associated With Maternal Obesity And Diabetes, Laura Gleason, Rebekah Mccurdy, Md, Mph

Phase 1

Introduction: To design a model that will predict neonatal birth weight within obese mothers by diabetic status.

Methods: A secondary data analysis of an RCT (NCT 02909582) was utilized to create a neonatal birth weight prediction model. Women (n=325) with a BMI > 35 kg/m2 from a tertiary academic institution, 2016 – 2019, were included to estimate the risk of large for gestational age (LGA) infants and neonatal birth weight based on maternal prepregnancy BMI and diabetic status. LGA was defined as an infant birth weight > 90th percentile. Analysis included Chi-square, t-test, multivariate logistic and linear regression.

Results: Mean birthweight did …

Obesity And Obstructive Airways Disease: Clinical Correlates And Therapeutic Considerations, John Magagna, Cali Loblundo, Raymond B. Penn, Deepak A. Deshpande, Ajay P. Nayak

Student Papers, Posters & Projects

Obese patients are more likely to suffer from severe asthma symptoms and less likely to be able to control them. In obese patients, there is evidence that shows decreased efficacy of inhaled corticosteroids and beta-2 adrenergic agonists, the core treatment options for achieving and maintaining asthma control. This may be due to mechanical reasons like decreased ventilation and medication delivery, but there are many more pathologies of obesity that interact with pathways of both asthma pathology and asthma control. This review explores the epidemiological significance of obesity, many physiological changes in patients with obesity, the physiological interactions of asthma and …

Sphk2−/− Mice Are Protected From Obesity And Insulin Resistance, Shwetha Ravichandran, Brian S. Finlin, Philip A. Kern, Sabire Özcan

Clinical and Translational Science Faculty Publications

Sphingosine kinases phosphorylate sphingosine to sphingosine 1‑phosphate (S1P), which functions as a signaling molecule. We have previously shown that sphingosine kinase 2 (Sphk2) is important for insulin secretion. To obtain a better understanding of the role of Sphk2 in glucose and lipid metabolism, we have characterized 20- and 52-week old Sphk2^−/− mice using glucose and insulin tolerance tests and by analyzing metabolic gene expression in adipose tissue. A detailed metabolic characterization of these mice revealed that aging Sphk2^−/− mice are protected from metabolic decline and obesity compared to WT mice. Specifically, we found that 52-week old …

Obesity-Induced Endoplasmic Reticulum Stress Causes Lung Endothelial Dysfunction And Promotes Acute Lung Injury, Dilip Shah, Freddy Romero, Zhi Guo, Jianxin Sun, Jonathan C. Li, Caleb Kallen, Ulhas P. Naik, Ross Summer

Center for Translational Medicine Faculty Papers

Conclusion

• Lung endothelial dysfunction in DIO mice coincides with increased endoplasmic reticulum (ER) stress.
• Fatty acids in obese serum induce ER stress in the pulmonary endothelium leading to pulmonary endothelial cell dysfunction.
• Reducing protein load in the endoplasmic reticulum of pulmonary endothelial cells might protect against ARDS in obese individuals.

Targeting Iκb Kinase Β In Adipocyte Lineage Cells For Treatment Of Obesity And Metabolic Dysfunctions, Robert N. Helsley, Yipeng Sui, Se-Hyung Park, Zun Liu, Richard G. Lee, Beibei Zhu, Philip A. Kern, Changcheng Zhou

Clinical and Translational Science Faculty Publications

IκB kinase β (IKKβ), a central coordinator of inflammation through activation of nuclear factor-κB, has been identified as a potential therapeutic target for the treatment of obesity-associated metabolic dysfunctions. In this study, we evaluated an antisense oligonucleotide (ASO) inhibitor of IKKβ and found that IKKβ ASO ameliorated diet-induced metabolic dysfunctions in mice. Interestingly, IKKβ ASO also inhibited adipocyte differentiation and reduced adiposity in high-fat (HF)-fed mice, indicating an important role of IKKβ signaling in the regulation of adipocyte differentiation. Indeed, CRISPR/Cas9-mediated genomic deletion of IKKβ in 3T3-L1 preadipocytes blocked these cells differentiating into adipocytes. To further elucidate the role of …

Impact Of Sleep And Circadian Disruption On Energy Balance And Diabetes: A Summary Of Workshop Discussions, Deanna M. Arble, Joseph Bass, Cecilia Diniz Behn, Matthew P. Butler, Etienne Challet, Charles Czeisler, Christopher M. Depner, Joel Elmquist, Paul Franken, Michael A. Grandner, Erin C. Hanlon, Alex C. Keene, Michael J. Joyner, Ilia Karatsoreos, Philip A. Kern, Samuel Klein, Christopher J. Morris, Allan I. Pack, Satchidananda Panda, Louis J. Ptacek, Naresh M. Punjabi, Paolo Sassone-Corsi, Frank A. Scheer, Richa Saxena, Elizabeth R. Seaquest, Matthew S. Thimgan, Eve Van Cauter, Kenneth P. Wright

Clinical and Translational Science Faculty Publications

A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact …

Obesity And Cancer Screening According To Race And Gender., Heather Bittner Fagan, Richard Wender, Ronald E Myers, Nicholas Petrelli

Department of Family & Community Medicine Faculty Papers

The relationship between obesity and cancer screening varies by screening test, race, and gender. Most studies on cervical cancer screening found a negative association between increasing weight and screening, and this negative association was most consistent in white women. Recent literature on mammography reports no association with weight. However, some studies show a negative association in white, but not black, women. In contrast, obese/overweight men reported higher rates of prostate-specific antigen (PSA) testing. Comparison of prostate cancer screening, mammography, and Pap smears implies a gender difference in the relationship between screening behavior and weight. In colorectal cancer (CRC) screening, the …

Matrix Metalloproteinase-9 Is Increased In Obese Subjects And Decreases In Response To Pioglitazone, Resat Unal, Aiwei Yao-Borengasser, Vijayalakshmi Varma, Neda Rasouli, Craig Labbate, Philip A. Kern, Gouri Ranganathan

Clinical and Translational Science Faculty Publications

Context: The study investigated the regulation of matrix metalloproteinases (MMP)-9 in obesity-associated insulin resistance in humans.

Objectives: The objectives of the investigation were to study MMP-9 regulation by insulin resistance and pioglitazone treatment in impaired glucose tolerant subjects using adipose tissue biopsies and study the mechanism of MMP-9 regulation by pioglitazone in adipocyte cultures.

Research Design: 86 nondiabetic, weight-stable subjects between 21 and 66 yr of age were recruited in a university hospital research center setting. All subjects underwent a sc adipose tissue incisional biopsy from the lower abdominal wall and insulin sensitivity testing using a frequently sampled iv glucose …

The Impact Of Exercise Training Compared To Caloric Restriction On Hepatic And Peripheral Insulin Resistance In Obesity, Robert H. Coker, Rick H. Williams, Sophie E. Yeo, Patrick M. Kortebein, Don L. Bodenner, Philip A. Kern, William J. Evans

Clinical and Translational Science Faculty Publications

Context: It has been difficult to distinguish the independent effects of caloric restriction versus exercise training on insulin resistance.

Objective: Utilizing metabolic feeding and supervised exercise training, we examined the influence of caloric restriction vs. exercise training with and without weight loss on hepatic and peripheral insulin resistance.

Design, Participants, and Intervention: Thirty-four obese, older subjects were randomized to: caloric restriction with weight loss (CR), exercise training with weight loss (EWL), exercise training without weight loss (EX), or controls. Based on an equivalent caloric deficit in EWL and CR, we induced matched weight loss. Subjects in the EX group received …

Obesity And Cancer, Rickie Brawer, Phd, Mph, Nancy Brisbon, Md, James Plumb, Md

Department of Family & Community Medicine Faculty Papers

Obesity has become the second leading preventable cause of disease and death in the United States, trailing only tobacco use. Weight control, dietary choices, and levels of physical activity are important modifiable determinants of cancer risk. If multi-factorial approaches to prevention and management are not implemented, obesity will likely become the leading modifiable cause of death in the coming years. Physicians have a key role in integrating these approaches into clinical care and advocating for systemic prevention efforts. This article provides: 1) an introduction to the epidemiology and magnitude of childhood and adult obesity; 2) the relationship of overweight/obesity to …

Endoplasmic Reticulum Stress Markers Are Associated With Obesity In Nondiabetic Subjects, Neeraj K. Sharma, Swapan K. Das, Ashis K. Mondal, Oksana Hackney, Winston S. Chu, Philip A. Kern, Neda Rasouli, Horace J. Spencer, Aiwei Yao-Borengasser, Steven C. Elbein

Clinical and Translational Science Faculty Publications

Objective: Adipocyte and hepatocyte endoplasmic reticulum (ER) stress response is activated in dietary and genetic models of obesity in mice. We hypothesized that ER stress was also activated and associated with reduced insulin sensitivity (S_I) in human obesity.

Research Design and Methods: We recruited 78 healthy, nondiabetic individuals over a spectrum of body mass index (BMI) who underwent oral and iv glucose tolerance tests, and fasting sc adipose and muscle biopsies. We tested expression of 18 genes and levels of total and phosphorylated eukaryotic initiation factor 2α, c-jun, and c-Jun N-terminal kinase 1 in adipose tissue. We compared …

Stearoyl-Coenzyme A Desaturase 1 Gene Expression Increases After Pioglitazone Treatment And Is Associated With Peroxisomal Proliferator-Activated Receptor-Γ Responsiveness, Aiwei Yao-Borengasser, Negah Rassouli, Vijayalakshmi Varma, Angela M. Bodles, Neda Rasouli, Resat Unal, Bounleut Phanavanh, Gouri Ranganathan, Robert E. Mcgehee Jr., Philip A. Kern

Clinical and Translational Science Faculty Publications

Context and Objective: Stearoyl-coenzyme A desaturase (SCD1) is the rate-limiting enzyme that converts palmitoyl- and stearoyl-coenzyme A to palmitoleoyl- and oleoyl-cownzyme A, respectively. SCD-deficient mice are protected from obesity, and the ob/ob mouse has high levels of SCD. This study was designed to better characterize SCD1 gene and protein expression in humans with varying insulin sensitivity.

Design, Participants, and Setting: In a university hospital clinical research center setting, SCD1 gene expression was measured in sc adipose and vastus lateralis muscle of 86 nondiabetic subjects; 10 wk of pioglitazone (45 mg daily) and metformin (1000 mg twice daily) treatment were assessed …

Retinol Binding Protein 4 Expression In Humans: Relationship To Insulin Resistance, Inflammation, And Response To Pioglitazone, Aiwei Yao-Borengasser, Vijayalakshmi Varma, Angela M. Bodles, Neda Rasouli, Bounleut Phanavanh, Mi-Jeong Lee, Tasha Starks, Leslie M. Kern, Horace J. Spencer Iii, Amir Adel Rashidi, Robert E. Mcgehee Jr., Susan K. Fried, Philip A. Kern

Clinical and Translational Science Faculty Publications

Context: Retinol binding protein 4 (RBP4) was recently found to be expressed and secreted by adipose tissue, and was strongly associated with insulin resistance.

Objective: The aim was to determine the relationship between RBP4 and obesity, insulin resistance, and other markers of insulin resistance in humans.

Design and Patients: RBP4 mRNA levels in adipose tissue and muscle of nondiabetic human subjects with either normal or impaired glucose tolerance (IGT) were studied, along with plasma RBP4. RBP4 gene expression was also measured in adipose tissue fractions, and from visceral and sc adipose tissue (SAT) from surgical patients.

Setting: The study was …

The Interplay Of Obesity And Asthma, James Plumb, Rickie Brawer, Nancy Brisbon

Department of Family & Community Medicine Faculty Papers

The relationships, interactions, and association between obesity and asthma are complex, and are active sources of hypotheses and research. An association between obesity and asthma has been reported in many studies, although considerable debate about the existence of the association and its meaning still exists. Potential associative relationships may result from genetics, immune system modifications, and mechanical mechanisms. The rising prevalence of asthma and obesity in children and adults, and the significant morbidity from both, makes it imperative that clinicians recognize the importance of weight management in patients with and without asthma.

Oxpat/Pat-1 Is A Ppar-Induced Lipid Droplet Protein That Promotes Fatty Acid Utilization, Nathan E. Wolins, Benjamin K. Quaynor, James R. Skinner, Anatoly Tzekov, Michelle A. Croce, Matthew C. Gropler, Vijayalakshmi Varma, Aiwei Yao-Borengasser, Neda Rasouli, Philip A. Kern, Brian N. Finck, Perry E. Bickel

Clinical and Translational Science Faculty Publications

Lipid droplet proteins of the PAT (perilipin, adipophilin, and TIP47) family regulate cellular neutral lipid stores. We have studied a new member of this family, PAT-1, and found that it is expressed in highly oxidative tissues. We refer to this protein as "OXPAT." Physiologic lipid loading of mouse liver by fasting enriches OXPAT in the lipid droplet tissue fraction. OXPAT resides on lipid droplets with the PAT protein adipophilin in primary cardiomyocytes. Ectopic expression of OXPAT promotes fatty acid-induced triacylglycerol accumulation, long-chain fatty acid oxidation, and mRNAs associated with oxidative metabolism. Consistent with these observations, OXPAT is induced in mouse …

Adiponectin Expression From Human Adipose Tissue: Relation To Obesity, Insulin Resistance, And Tumor Necrosis Factor-Α Expression, Philip A. Kern, Gina B. Di Gregorio, Tong Lu, Negah Rassouli, Gouri Ranganathan

Clinical and Translational Science Faculty Publications

Adiponectin is a 29-kDa adipocyte protein that has been linked to the insulin resistance of obesity and lipodystrophy. To better understand the regulation of adiponectin expression, we measured plasma adiponectin and adipose tissue adiponectin mRNA levels in nondiabetic subjects with varying degrees of obesity and insulin resistance. Plasma adiponectin and adiponectin mRNA levels were highly correlated with each other (r = 0.80, P < 0.001), and obese subjects expressed significantly lower levels of adiponectin. However, a significant sex difference in adiponectin expression was observed, especially in relatively lean subjects. When men and women with a BMI2were compared, women had a twofold higher percent body fat, yet their plasma adiponectin levels were 65% higher (8.6 ± 1.1 and 14.2 ± 1.6 μg/ml in men and women, respectively; P < 0.02). Plasma adiponectin had a strong association with insulin sensitivity index (S_I) (r = 0.67, P < 0.0001, n = 51) that was not affected by sex, but no relation with insulin secretion. To separate the effects of obesity (BMI) from S_I, subjects who were discordant for S_I were matched for BMI, age, and sex. Using this approach, insulin-sensitive subjects demonstrated a twofold higher plasma level of …

Potential Role Of Tnfα And Lipoprotein Lipase As Candidate Genes For Obesity, Philip A. Kern

Clinical and Translational Science Faculty Publications

To maintain body weight, metabolic efficiency was promoted during evolution; two candidate genes for body weight regulation are lipoprotein lipase (LPL) and tumor necrosis factor-α [TNFα). Human fat cells do not synthesize lipid, but rely on LPL-mediated plasma triglyceride hydrolysis. Adipose LPL is elevated in obesity. Following weight loss, LPL is elevated further, suggesting attempts to maintain lipid stores during fasting and to replenish lipid stores during refeeding. Muscle LPL is regulated inversely to adipose LPL. Thus, an increased adipose/muscle LPL ratio would partition dietary lipid into adipose tissue and would explain some of the variability in weight gain when …