Translational Medical Research Commons^™

Potential Benefits Of Combined Statin And Metformin Therapy On Resistance Training Response In Older Individuals, Douglas E. Long, Kate Kosmac, Cory M. Dungan, Marcas M. Bamman, Charlotte A. Peterson, Phillip A. Kern

Clinical and Translational Science Faculty Publications

Metformin and statins are currently the focus of large clinical trials testing their ability to counter age-associated declines in health, but recent reports suggest that both may negatively affect skeletal muscle response to exercise. However, it has also been suggested that metformin may act as a possible protectant of statin-related muscle symptoms. The potential impact of combined drug use on the hypertrophic response to resistance exercise in healthy older adults has not been described. We present secondary statin analyses of data from the MASTERS trial where metformin blunted the hypertrophy response in healthy participants (>65 years) following 14 weeks …

Evaluating Simulation-Based Tobacco Treatment Scenarios For Providers Delivering Treatment For People Living With Mental Illnesses, Chizimuzo T. C. Okoli, Janet Otachi, Sarret Seng, Bassema Abufarsakh, Lovoria B. Williams

Clinical and Translational Science Faculty Publications

Background: People living with mental illnesses (PMI) experience elevated tobacco use and related morbidity and mortality. Despite the availability of effective and safe tobacco treatments along with evidence that PMI are motivated and able to quit successfully, few Mental and behavioral healthcare providers (MHPs) engage PMI in such treatment. MHPs may lack the confidence or skills to engage their clients in tobacco treatment. Currently, there are limited training modalities to prepare MHPs in delivering tobacco treatment for PMI. However, animated scenario-based simulated encounters can bridge this gap to effectively provide tailored MHP training to enhance treatment delivery. Hence, the purpose …

Tumor Suppressor Par-4 Regulates Complement Factor C3 And Obesity, Nathália Araujo, James Sledziona, Sunil K. Noothi, Ravshan Burikhanov, Nikhil Hebbar, Saptadwipa Ganguly, Tripti Shrestha-Bhattarai, Beibei Zhu, Wendy S. Katz, Yi Zhang, Barry S. Taylor, Jinze Liu, Li Chen, Heidi L. Weiss, Daheng He, Chi Wang, Andrew J. Morris, Lisa A. Cassis, Mariana N. Nikolova‑Karakashian, Prabhakara R. Nagareddy, Olle Melander, B. Mark Evers, Phillip A. Kern, Vivek M. Rangnekar

Clinical and Translational Science Faculty Publications

Prostate apoptosis response-4 (Par-4) is a tumor suppressor that induces apoptosis in cancer cells. However, the physiological function of Par-4 remains unknown. Here we show that conventional Par-4 knockout (Par-4^-/-) mice and adipocyte-specific Par-4 knockout (AKO) mice, but not hepatocyte-specific Par-4 knockout mice, are obese with standard chow diet. Par-4^-/- and AKO mice exhibit increased absorption and storage of fat in adipocytes. Mechanistically, Par-4 loss is associated with mdm2 downregulation and activation of p53. We identified complement factor c3 as a p53-regulated gene linked to fat storage in adipocytes. Par-4 re-expression in adipocytes or c3 deletion reversed …

Regulatory T Cells Control Effector T Cell Inflammation In Human Prediabetes, Rui Liu, Gabriella H. Pugh, Erin Tevonian, Katherine Thompson, Douglas A. Lauffenburger, Philip A. Kern, Barbara S. Nikolajczyk

Clinical and Translational Science Faculty Publications

A disparate array of plasma/serum markers provides evidence for chronic inflammation in human prediabetes, a condition that is most closely replicated by standard mouse models of obesity and metaflammation. These remain largely nonactionable and contrast with our rich understanding of inflammation in human type 2 diabetes. New data show that inflammatory profiles produced by CD4+ T cells define human prediabetes as a unique inflammatory state. Regulatory T cells (Treg) control mitochondrial function and cytokine production by CD4+ effector T cells (Teff) in prediabetes and type 2 diabetes by supporting T helper (Th)17 or Th1 cytokine production, respectively. These data suggest …

Apoε4 Lowers Energy Expenditure In Females And Impairs Glucose Oxidation By Increasing Flux Through Aerobic Glycolysis, Brandon C. Farmer, Holden C. Williams, Nicholas A. Devanney, Margaret A. Piron, Grant K. Nation, David J. Carter, Adeline E. Walsh, Rebika Khanal, Lyndsay E. A. Young, Jude Kluemper, Gabriela Hernandez, Elizabeth J. Allenger, Rachel Mooney, Lesley R. Golden, Cathryn T. Smith, J. Anthony Brandon, Vedant A. Gupta, Philip A. Kern, Matthew S. Gentry, Josh M. Morganti, Ramon C. Sun, Lance A. Johnson

Clinical and Translational Science Faculty Publications

Background: Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer’s disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field.

Methods: Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4.

Covid-19 And The Impact On Rural And Black Church Congregants: Results Of The C-M-C Project, Lovoria B. Williams, Anita F. Fernander, Tofial Azam, Maria L. Gomez, Junghee Kang, Cassidy L. Moody, Hannah Bowman, Nancy E. Schoenberg

Clinical and Translational Science Faculty Publications

The COVID‐19 pandemic has had devastating effects on Black and rural populations with a mortality rate among Blacks three times that of Whites and both rural and Black populations experiencing limited access to COVID‐19 resources. The primary purpose of this study was to explore the health, financial, and psychological impact of COVID‐19 among rural White Appalachian and Black nonrural central Kentucky church congregants. Secondarily we sought to examine the association between sociodemographics and behaviors, attitudes, and beliefs regarding COVID‐19 and intent to vaccinate. We used a cross sectional survey design developed with the constructs of the Health Belief and Theory …

Metformin Enhances Autophagy And Normalizes Mitochondrial Function To Alleviate Aging-Associated Inflammation, Leena P. Bharath, Madhur Agrawal, Grace Mccambridge, Dequina A. Nicholas, Hatice Hasturk, Jing Liu, Lao Jiang, Rui Liu, Zhenheng Guo, Jude T. Deeney, Caroline M. Apovian, Jennifer Snyder-Cappione, Gregory S. Hawk, Rebecca M. Fleeman, Riley M. F. Pihl, Katherine Thompson, Anna C. Belkina, Licong Cui, Elizabeth A. Proctor, Philip A. Kern, Barbara S. Nikolajczyk

Clinical and Translational Science Faculty Publications

Age is a non-modifiable risk factor for the inflammation that underlies age-associated diseases; thus, anti-inflammaging drugs hold promise for increasing health span. Cytokine profiling and bioinformatic analyses showed that Th17 cytokine production differentiates CD4+ T cells from lean, normoglycemic older and younger subjects, and mimics a diabetes-associated Th17 profile. T cells from older compared to younger subjects also had defects in autophagy and mitochondrial bioenergetics that associate with redox imbalance. Metformin ameliorated the Th17 inflammaging profile by increasing autophagy and improving mitochondrial bioenergetics. By contrast, autophagy-targeting siRNA disrupted redox balance in T cells from young subjects and activated the Th17 …

The Value Of Innovation To Implementation Program (Vi2p): A Strategic Approach To Aligning And Leveraging Academic Research And Clinical Care Missions, Jing Li, Mark V. Williams, Cecilia Page, Lisa A. Cassis, Philip A. Kern, Robert S. Dipaola

Clinical and Translational Science Faculty Publications

Problem: Inefficient implementation of evidence-based care garners increasing attention as a source of suboptimal value of clinical care, and integration of quality improvement methodology into clinical practice represents a potential solution. Academic medical centers (AMCs) often have expertise in implementation science, yet it is not leveraged effectively to solve operational inefficiencies or to rapidly implement evidence-based practices (EBPs).

Approach: To leverage in-house research expertise, the University of Kentucky (UK) College of Medicine and Center for Health Services Research (CHSR) launched a pilot awards program—Value of Innovation to Implementation Program (VI2P)—across its health system and six health professional colleges. Criteria for …

Metformin Blunts Muscle Hypertrophy In Response To Progressive Resistance Exercise Training In Older Adults: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial: The Masters Trial, R. Grace Walton, Cory M. Dungan, Douglas E. Long, S. Craig Tuggle, Kate Kosmac, Bailey D. Peck, Heather M. Bush, Alejandro G. Villasante Tezanos, Gerald Mcgwin, Samuel T. Windham, Fernando Ovalle, Marcas M. Bamman, Philip A. Kern, Charlotte A. Peterson

Clinical and Translational Science Faculty Publications

Progressive resistance exercise training (PRT) is the most effective known intervention for combating aging skeletal muscle atrophy. However, the hypertrophic response to PRT is variable, and this may be due to muscle inflammation susceptibility. Metformin reduces inflammation, so we hypothesized that metformin would augment the muscle response to PRT in healthy women and men aged 65 and older. In a randomized, double-blind trial, participants received 1,700 mg/day metformin (N = 46) or placebo (N = 48) throughout the study, and all subjects performed 14 weeks of supervised PRT. Although responses to PRT varied, placebo gained more lean body …

Fatty Acid Metabolites Combine With Reduced Β Oxidation To Activate Th17 Inflammation In Human Type 2 Diabetes, Dequina A. Nicholas, Elizabeth A. Proctor, Madhur Agrawal, Anna C. Belkina, James M. Van Nostrand, Leena Panneerseelan-Bharath, Albert R. Jones Iv, Forum Raval, Blanche C. Ip, Min Zhu, Jose M. Cacicedo, Chloe Habib, Nestor Sanez-Rueda, Leah Persky, Patrick G. Sullivan, Barbara E. Corkey, Caroline M. Apovian, Philip A. Kern, Douglas A. Lauffenburger, Barbara S. Nikolajczyk

Clinical and Translational Science Faculty Publications

Mechanisms that regulate metabolites and downstream energy generation are key determinants of T cell cytokine production, but the processes underlying the Th17 profile that predicts the metabolic status of people with obesity are untested. Th17 function requires fatty acid uptake, and our new data show that blockade of CPT1A inhibits Th17-associated cytokine production by cells from people with type 2 diabetes (T2D). A low CACT:CPT1A ratio in immune cells from T2D subjects indicates altered mitochondrial function and coincides with the preference of these cells to generate ATP through glycolysis rather than fatty acid oxidation. However, glycolysis was not critical for …

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 …

A Guide For Using Nih Image J For Single Slice Cross-Sectional Area And Composition Analysis Of The Thigh From Computed Tomography, Douglas E. Long, Alejandro G. Villasante Tezanos, James N. Wise, Phillip A. Kern, Marcas M. Bamman, Charlotte A. Peterson, Richard A. Dennis

Clinical and Translational Science Faculty Publications

Reports using computed tomography (CT) to estimate thigh skeletal muscle cross-sectional area and mean muscle attenuation are often difficult to evaluate due to inconsistent methods of quantification and/or poorly described analysis methods. This CT tutorial provides step-by-step instructions in using free, NIH Image J software to quantify both muscle size and composition in the mid-thigh, which was validated against a robust commercially available software, SliceOmatic. CT scans of the mid-thigh were analyzed from 101 healthy individuals aged 65 and older. Mean cross-sectional area and mean attenuation values are presented across seven defined Hounsfield unit (HU) ranges along with the percent …

Human Body Composition And Immunity: Visceral Adipose Tissue Produces Il-15 And Muscle Strength Inversely Correlates With Nk Cell Function In Elderly Humans, Ahmad Al-Attar, Steven R. Presnell, Jody L. Clasey, Douglas E. Long, R. Grace Walton, Morgan Sexton, Marlene E. Starr, Philip A. Kern, Charlotte A. Peterson, Charles T. Lutz

Clinical and Translational Science Faculty Publications

Natural killer (NK) lymphocyte-mediated cytotoxicity and cytokine secretion control infections and cancers, but these crucial activities decline with age. NK cell development, homeostasis, and function require IL-15 and its chaperone, IL-15 receptor alpha (IL-15Rα). Macrophages and dendritic cells (DC) are major sources of these proteins. We had previously postulated that additional IL-15 and IL-15Rα is made by skeletal muscle and adipose tissue. These sources may be important in aging, when IL-15-producing immune cells decline. NK cells circulate through adipose tissue, where they may be exposed to local IL-15. The objectives of this work were to determine (1) if human muscle, …

Type 1 Diabetes Alters Lipid Handling And Metabolism In Human Fibroblasts And Peripheral Blood Mononuclear Cells, Albert R. Jones Iv, Emily L. Coleman, Nicholas R. Husni, Jude T. Deeney, Forum Raval, Devin Steenkamp, Hans Dooms, Barbara S. Nikolajczyk, Barbara E. Corkey

Clinical and Translational Science Faculty Publications

Triggers of the autoimmune response that leads to type 1 diabetes (T1D) remain poorly understood. A possibility is that parallel changes in both T cells and target cells provoke autoimmune attack. We previously documented greater Ca²⁺ transients in fibroblasts from T1D subjects than non-T1D after exposure to fatty acids (FA) and tumor necrosis factor α (TNFα). These data indicate that metabolic and signal transduction defects present in T1D can be elicited ex vivo in isolated cells. Changes that precede T1D, including inflammation, may activate atypical responses in people that are genetically predisposed to T1D. To identify such cellular differences …

The Influence Of A Kdt501, A Novel Isohumulone, On Adipocyte Function In Humans, Brian S. Finlin, Beibei Zhu, Bernard P. Kok, Cristina Godio, Philip M. Westgate, Neile Grayson, Robert Sims, Jeffrey S. Bland, Enrique Saez, Philip A. Kern

Clinical and Translational Science Faculty Publications

Objective: In a phase II clinical trial in nine obese, insulin-resistant humans, we observed that treatment with KDT501, a novel isohumulone drug, increased total and high-molecular weight (HMW) adiponectin in plasma. The objective was to determine whether KDT501 increased adiponectin secretion from subcutaneous white adipose tissue (SC WAT) and the underlying mechanism(s).

Methods: Nine obese participants with either prediabetes or with normal glucose tolerance plus three features of metabolic syndrome were part of the study. SC WAT biopsies were performed before and after 28 days of KDT501 treatment in a clinical research setting. In addition, a cold stimulus was used …

Metformin To Augment Strength Training Effective Response In Seniors (Masters): Study Protocol For A Randomized Controlled Trial, Doug E. Long, Bailey D. Peck, Jenny L. Martz, S. Craig Tuggle, Heather M. Bush, Gerald Mcgwin, Philip A. Kern, Marcas M. Bamman, Charlotte A. Peterson

Clinical and Translational Science Faculty Publications

Background: Muscle mass and strength are strong determinants of a person's quality of life and functional independence with advancing age. While resistance training is the most effective intervention to combat age-associated muscle atrophy (sarcopenia), the ability of older adults to increase muscle mass and strength in response to training is blunted and highly variable. Thus, finding novel ways to complement resistance training to improve muscle response and ultimately quality of life among older individuals is critical. The purpose of this study is to determine whether a commonly prescribed medication called metformin can be repurposed to improve the response to resistance …

Cycle Training Modulates Satellite Cell And Transcriptional Responses To A Bout Of Resistance Exercise, Kevin A. Murach, R. Grace Walton, Christopher S. Fry, Sami L. Michaelis, Jason S. Groshong, Brian S. Finlin, Philip A. Kern, Charlotte A. Peterson

Clinical and Translational Science Faculty Publications

This investigation evaluated whether moderate-intensity cycle ergometer training affects satellite cell and molecular responses to acute maximal concentric/eccentric resistance exercise in middle-aged women. Baseline and 72 h postresistance exercise vastus lateralis biopsies were obtained from seven healthy middle-aged women (56 ± 5 years, BMI 26 ± 1, VO_2max 27 ± 4) before and after 12 weeks of cycle training. Myosin heavy chain (MyHC) I- and II-associated satellite cell density and cross-sectional area was determined via immunohistochemistry. Expression of 93 genes representative of the muscle-remodeling environment was also measured via NanoString. Overall fiber size increased ~20% with cycle training ( …

Ikkβ Is Essential For Adipocyte Survival And Adaptive Adipose Remodeling In Obesity, Se-Hyung Park, Zun Liu, Yipeng Sui, Robert N. Helsley, Beibei Zhu, David K. Powell, Philip A. Kern, Changcheng Zhou

Clinical and Translational Science Faculty Publications

IκB kinase β (IKKβ), a central coordinator of inflammatory responses through activation of nuclear factor-κB (NF-κB), has been implicated as a critical molecular link between inflammation and metabolic disorders; however, the role of adipocyte IKKβ in obesity and related metabolic disorders remains elusive. Here we report an essential role of IKKβ in the regulation of adipose remodeling and adipocyte survival in diet-induced obesity. Targeted deletion of IKKβ in adipocytes does not affect body weight, food intake, and energy expenditure but results in an exaggerated diabetic phenotype when challenged with a high-fat diet (HFD). IKKβ-deficient mice have multiple histopathologies in visceral …

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 …

Insulin-Resistant Subjects Have Normal Angiogenic Response To Aerobic Exercise Training In Skeletal Muscle, But Not In Adipose Tissue, R. Grace Walton, Brian S. Finlin, Jyothi Mula, Douglas E. Long, Beibei Zhu, Christopher S. Fry, Philip M. Westgate, Jonah D. Lee, Tamara Bennett, Philip A. Kern, Charlotte A. Peterson

Clinical and Translational Science Faculty Publications

Reduced vessel density in adipose tissue and skeletal muscle is associated with obesity and may result in decreased perfusion, decreased oxygen consumption, and insulin resistance. In the presence of VEGFA, Angiopoietin-2 (Angpt2) and Angiopoietin-1 (Angpt1) are central determinants of angiogenesis, with greater Angpt2:Angpt1 ratios promoting angiogenesis. In skeletal muscle, exercise training stimulates angiogenesis and modulates transcription of VEGFA, Angpt1, and Angpt 2. However, it remains unknown whether exercise training stimulates vessel growth in human adipose tissue, and it remains unknown whether adipose angiogenesis is mediated by angiopoietin signaling. We sought to determine whether insulin-resistant subjects would display an impaired angiogenic …

Increasing Adipocyte Lipoprotein Lipase Improves Glucose Metabolism In High Fat Diet-Induced Obesity, R. Grace Walton, Beibei Zhu, Resat Unal, Michael Spencer, Manjula Sunkara, Andrew J. Morris, Richard Charnigo, Wendy Katz, Alan Daugherty, Deborah A. Howatt, Philip A. Kern, Brian S. Finlin

Clinical and Translational Science Faculty Publications

Background: Lipoprotein lipase regulates fat uptake into adipose tissue.

Results: A mouse model with increased adipose tissue lipoprotein lipase has improved glucose metabolism when challenged with a high fat diet.

Conclusion: Increasing adipose tissue lipoprotein lipase improves adipose tissue function.

Significance: Adipose tissue lipoprotein lipase protects against obesity-induced glucose and insulin intolerance.

The Effects Of Temperature And Seasons On Subcutaneous White Adipose Tissue In Humans: Evidence For Thermogenic Gene Induction, Philip A. Kern, Brian S. Finlin, Beibei Zhu, Neda Rasouli, Robert E. Mcgehee Jr., Philip M. Westgate, Esther E. Dupont-Versteegden

Clinical and Translational Science Faculty Publications

Context: Although brown adipose tissue (BAT) activity is increased by a cold environment, little is known of the response of human white adipose tissue (WAT) to the cold.

Design: We examined both abdominal and thigh subcutaneous (SC) WAT from 71 subjects who were biopsied in the summer or winter, and adipose expression was assessed after an acute cold stimulus applied to the thigh of physically active young subjects.

Results: In winter, UCP1 and PGC1 α mRNA were increased 4 to 10-fold (p<0.05) and 1.5 to 2-fold, respectively, along with beige adipose markers, and UCP1 protein was 3-fold higher in the winter. The seasonal increase in abdominal SC WAT UCP1 mRNA was considerably diminished in subjects with a BMI > 30 kg/m², suggesting that dysfunctional WAT in obesity inhibits adipose thermogenesis. After applying an acute …

Pioglitazone Treatment Reduces Adipose Tissue Inflammation Through Reduction Of Mast Cell And Macrophage Number And By Improving Vascularity, Michael Spencer, Lin Yang, Akosua Adu, Brian S. Finlin, Beibei Zhu, Lindsey R. Shipp, Neda Rasouli, Charlotte A. Peterson, Philip A. Kern

Clinical and Translational Science Faculty Publications

Context and Objective: Adipose tissue in insulin resistant subjects contains inflammatory cells and extracellular matrix components. This study examined adipose pathology of insulin resistant subjects who were treated with pioglitazone or fish oil.

Design, Setting and Participants: Adipose biopsies were examined from nine insulin resistant subjects before/after treatment with pioglitazone 45 mg/day for 12 weeks and also from 19 subjects who were treated with fish oil (1,860 mg EPA, 1,500 mg DHA daily). These studies were performed in a clinical research center setting.

Results: Pioglitazone treatment increased the cross-sectional area of adipocytes by 18% (p = 0.01), and also increased …

Regulation Of Pten Inhibition By The Pleckstrin Homology Domain Of P-Rex2 During Insulin Signaling And Glucose Homeostasis, Cindy Hodakoski, Benjamin D. Hopkins, Douglas Barrows, Sarah M. Mense, Megan Keniry, Karen E. Anderson, Philip A. Kern, Phillip T. Hawkins, Len R. Stephens, Ramon Parsons

Clinical and Translational Science Faculty Publications

Insulin activation of phosphoinositide 3-kinase (PI3K) signaling regulates glucose homeostasis through the production of phosphatidylinositol 3,4,5-trisphosphate (PIP3). The dual-specificity phosphatase and tensin homolog deleted on chromosome 10 (PTEN) blocks PI3K signaling by dephosphorylating PIP3, and is inhibited through its interaction with phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 (P-REX2). The mechanism of inhibition and its physiological significance are not known. Here, we report that P-REX2 interacts with PTEN via two interfaces. The pleckstrin homology (PH) domain of P-REX2 inhibits PTEN by interacting with the catalytic region of PTEN, and the inositol polyphosphate 4-phosphatase domain of P-REX2 provides high-affinity binding to the postsynaptic …

Omega-3 Fatty Acids Reduce Adipose Tissue Macrophages In Human Subjects With Insulin Resistance, Michael Spencer, Brian S. Finlin, Resat Unal, Beibei Zhu, Andrew J. Morris, Lindsey R. Shipp, Jonah D. Lee, R. Grace Walton, Akosua Adu, Rod Erfani, Marilyn S. Campbell, Robert E. Mcgehee Jr., Charlotte A. Peterson, Philip A. Kern

Clinical and Translational Science Faculty Publications

Fish oils (FOs) have anti-inflammatory effects and lower serum triglycerides. This study examined adipose and muscle inflammatory markers after treatment of humans with FOs and measured the effects of ω-3 fatty acids on adipocytes and macrophages in vitro. Insulin-resistant, nondiabetic subjects were treated with Omega-3-Acid Ethyl Esters (4 g/day) or placebo for 12 weeks. Plasma macrophage chemoattractant protein 1 (MCP-1) levels were reduced by FO, but the levels of other cytokines were unchanged. The adipose (but not muscle) of FO-treated subjects demonstrated a decrease in macrophages, a decrease in MCP-1, and an increase in capillaries, and subjects with the most …

An Acacb Variant Implicated In Diabetic Nephropathy Associates With Body Mass Index And Gene Expression In Obese Subjects, Lijun Ma, Mariana Murea, James A. Snipes, Alejandra Marinelarena, Jacqueline Krüger, Pamela J. Hicks, Kurt A. Langberg, Meredith A. Bostrom, Jessica N. Cooke, Daisuke Suzuki, Tetsuya Babazono, Takashi Uzu, Sydney C. W. Tang, Ashis K. Mondal, Neeraj K. Sharma, Sayuko Kobes, Peter A. Antinozzi, Matthew Davis, Swapan K. Das, Neda Rasouli, Philip A. Kern, Nathan J. Shores, Lawrence L. Rudel, Matthias Blüher, Michael Stumvoll, Donald W. Bowden, Shiro Maeda, John S. Parks, Peter Kovacs, Robert L. Hanson, Steven C. Elbein, Barry I. Freedman

Clinical and Translational Science Faculty Publications

Acetyl coenzyme A carboxylase B gene (ACACB) single nucleotide polymorphism (SNP) rs2268388 is reproducibly associated with type 2 diabetes (T2DM)-associated nephropathy (DN). ACACB knock-out mice are also protected from obesity. This study assessed relationships between rs2268388, body mass index (BMI) and gene expression in multiple populations, with and without T2DM. Among subjects without T2DM, rs2268388 DN risk allele (T) associated with higher BMI in Pima Indian children (n = 2021; p-additive = 0.029) and African Americans (AAs) (n = 177; p-additive = 0.05), with a trend in European Americans (EAs) (n = 512; p-additive = 0.09), but not …

Genetic Risk Factors For Type 2 Diabetes: A Trans-Regulatory Genetic Architecture?, Steven C. Elbein, Eric R. Gamazon, Swapan K. Das, Neda Rasouli, Philip A. Kern, Nancy J. Cox

Clinical and Translational Science Faculty Publications

To date, 68 loci have been associated with type 2 diabetes (T2D) or glucose homeostasis traits. We report here the results of experiments aimed at functionally characterizing the SNPs replicated for T2D and glucose traits. We sought to determine whether these loci were associated with transcript levels in adipose, muscle, liver, lymphocytes, and pancreatic β-cells. We found an excess of trans, rather than cis, associations among these SNPs in comparison to what was expected in adipose and muscle. Among transcripts differentially expressed (FDR < 0.05) between muscle or adipose cells of insulin-sensitive individuals and those of insulin-resistant individuals (matched on BMI), trans-regulated transcripts, in contrast to the cis-regulated ones, were enriched. The paucity of …

Adipose Tissue Extracellular Matrix And Vascular Abnormalities In Obesity And Insulin Resistance, Michael Spencer, Resat Unal, Beibei Zhu, Neda Rasouli, Robert E. Mcgehee Jr., Charlotte A. Peterson, Philip A. Kern

Clinical and Translational Science Faculty Publications

Context: Insulin resistance is associated with inflammation, fibrosis, and hypoxia in adipose tissue.

Objective: This study was intended to better characterize the extracellular matrix (ECM) and vascularity of insulin-resistant adipose tissue. Design: Adipose expression of collagens, elastin, and angiogenic factors was assessed using realtime RT-PCR and immunohistochemistry (IHC) in abdominal sc adipose tissue. Adipocyte-macrophage coculture experiments examined the effects of polarized macrophages on adipose ECM gene expression, and the effects of collagens were measured in an angiogenesis assay.

Participants and Setting: A total of 74 nondiabetic subjects participated at a University Clinical Research Center. Interventions: Interventions included baseline adipose biopsy …

Obesity And Hepatosteatosis In Mice With Enhanced Oxidative Dna Damage Processing In Mitochondria, Haihong Zhang, Chenghui Xie, Horace J. Spencer, Chunlai Zuo, Masahiro Higuchi, Gouri Ranganathan, Philip A. Kern, Ming W. Chou, Qin Huang, Bartosz Szczesny, Sankar Mitra, Amanda J. Watson, Geoffrey P. Margison, Chun-Yang Fan

Clinical and Translational Science Faculty Publications

Mitochondria play critical roles in oxidative phosphorylation and energy metabolism. Increasing evidence supports that mitochondrial DNA (mtDNA) damage and dysfunction play vital roles in the development of many mitochondria-related diseases, such as obesity, diabetes mellitus, infertility, neurodegenerative disorders, and malignant tumors in humans. Human 8-oxoguanine-DNA glycosylase 1 (hOGG1) transgenic (TG) mice were produced by nuclear microinjection. Transgene integration was analyzed by PCR. Transgene expression was measured by RT-PCR and Western blot analysis. Mitochondrial DNA damage was analyzed by mutational analyses and measurement of mtDNA copy number. Total fat content was measured by a whole-body scan using dual-energy X-ray absorptiometry. The …