Publications by authors named "Douglas R Moellering"

31 Publications

Physiological Significance of Discrimination on Stress Markers, Obesity, and LDL Oxidation among a European American and African American Cohort of Females.

Int J Behav Med 2020 Apr;27(2):213-224

Department of Nutrition Sciences, School of Health Professions, University of Alabama at Birmingham, Webb Building 552, 1675 University Blvd, Birmingham, AL, 35294-3360, USA.

Background: Factors underlying physiological reactions from perceived discrimination and its relation to adverse health outcomes are not completely understood. The main purpose of this study was to test the hypothesis that experiences of discrimination (recent and lifetime) correlate with biomarkers of stress, oxidative stress, and obesity among adult females.

Method: Data on 62 females who self-identify as African American (AA; n = 31) or European American (EA; n = 31) aged 21-45 years were included. Discrimination experiences (recent and lifetime) were evaluated based on a validated instrument. Stress was assessed based on hair cortisol (HC) and salivary cortisol (SC), hsC-reactive protein (hsCRP), cardiovascular markers, and LDL-cholesterol oxidation. Obesity was measured based on BMI, waist circumference, and body fat percent. Multiple linear regression analyses were performed to evaluate the influence of experiences of discrimination.

Results: Significant differences in experiences of discrimination were observed by race (p < 0.05) and were higher in AA females. Results for the multiple regression models assessing the contribution of discrimination indicate that hsCRP and pulse were significantly associated with recent experiences of discrimination, and SC, HC, hsCRP, diastolic blood pressure (DBP), and pulse were significantly associated with lifetime experiences of discrimination when adjusted for BMI and race (p < 0.05). Finally, oxidation of LDL-cholesterol was significantly associated with salivary cortisol (p = 0.0420) when adjusted by lifetime experiences of discrimination (p = 0.0366) but not for BMI (p = 0.6252).

Conclusion: In this cross-sectional study, AA females experienced more discrimination compared to EA females. Levels of recent and lifetime experiences of discrimination were associated with some stress biomarkers. Salivary cortisol was associated with oxidation of LDL-cholesterol with shorter lag times and increased risk for cardiovascular disease.
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http://dx.doi.org/10.1007/s12529-020-09850-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883508PMC
April 2020

Hydrogen sulfide stimulates Mycobacterium tuberculosis respiration, growth and pathogenesis.

Nat Commun 2020 Jan 28;11(1):557. Epub 2020 Jan 28.

Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA.

Hydrogen sulfide (HS) is involved in numerous pathophysiological processes and shares overlapping functions with CO and •NO. However, the importance of host-derived HS in microbial pathogenesis is unknown. Here we show that Mtb-infected mice deficient in the HS-producing enzyme cystathionine β-synthase (CBS) survive longer with reduced organ burden, and that pharmacological inhibition of CBS reduces Mtb bacillary load in mice. High-resolution respirometry, transcriptomics and mass spectrometry establish that HS stimulates Mtb respiration and bioenergetics predominantly via cytochrome bd oxidase, and that HS reverses •NO-mediated inhibition of Mtb respiration. Further, exposure of Mtb to HS regulates genes involved in sulfur and copper metabolism and the Dos regulon. Our results indicate that Mtb exploits host-derived HS to promote growth and disease, and suggest that host-directed therapies targeting HS production may be potentially useful for the management of tuberculosis and other microbial infections.
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http://dx.doi.org/10.1038/s41467-019-14132-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987094PMC
January 2020

Exercise Effects on Mitochondrial Function and Lipid Metabolism during Energy Balance.

Med Sci Sports Exerc 2020 04;52(4):827-834

Department of Human Studies, University of Alabama at Birmingham, Birmingham, AL.

Introduction/purpose: Aerobic exercise training (AET) has been shown to improve mitochondrial bioenergetics and upregulate proteins related to lipid metabolism. However, it remains to be determined if these alterations associated with AET persist when measured in energy balance (EB) in the days after the last bout of training. The purpose of the study was to test the hypothesis that improvements in skeletal muscle mitochondrial function induced by AET observed in previous literature would persist when measured after restoring EB conditions 72 h removed from the last exercise bout.

Methods: Participants were 14 premenopausal women (age = 31.2 ± 6.7 yr, BMI = 26.6 ± 5.1 kg·m). The AET program required three monitored training sessions per week for 8-16 wk. Skeletal muscle biopsies were obtained at baseline and after 8-16 wk of AET (≥72 h after the last exercise bout). All food was provided for 72 h before biopsies, and EB was managed 24 h before testing within ±100 kcal of measured energy requirements using a whole-room calorimeter. Mitochondrial oxidative capacity was quantified in permeabilized muscle fibers from the vastus lateralis.

Results: We found that AET increased coupled respiration (154%) and uncoupled respiration (90%) rates using a fatty acid substrate (palmitoyl carnitine) (P < 0.05). However, when rates were normalized to complex IV activity (a marker of mitochondrial content), no significant differences were observed. In addition, there were no changes in proteins known to mediate mitochondrial biogenesis or lipid transport and metabolism after AET.

Conclusion: Eight to 16 wk of AET improved mitochondrial capacity under fatty acid substrate when assessed in EB, which appears to be due to mitochondrial biogenesis.
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http://dx.doi.org/10.1249/MSS.0000000000002190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117801PMC
April 2020

Relationship between V̇o, cycle economy, and mitochondrial respiration in untrained/trained.

J Appl Physiol (1985) 2019 12 26;127(6):1562-1568. Epub 2019 Sep 26.

Department of Human Studies, University of Alabama at Birmingham, Birmingham, Alabama.

Aerobic capacity is negatively related to locomotion economy. The purpose of this paper is to determine what effect aerobic exercise training has on the relationship between net cycling oxygen uptake (inverse of economy) and aerobic capacity [peak oxygen uptake (V̇o)], as well as what role mitochondrial coupled and uncoupled respiration may play in whole body aerobic capacity and cycling economy. Cycling net oxygen uptake and V̇o were evaluated on 31 premenopausal women before exercise training (baseline) and after 8-16 wk of aerobic training. Muscle tissue was collected from 15 subjects at baseline and post-training. Mitochondrial respiration assays were performed using high-resolution respirometry. Pre- ( = 0.46, < 0.01) and postexercise training ( = 0.62, < 0.01) V̇o and cycling net oxygen uptake were related. In addition, uncoupled and coupled fat respiration were related both at baseline ( = 0.62, < 0.01) and post-training ( = 0.89, < 01). Post-training coupled ( = 0.74, < 0.01) and uncoupled carbohydrate respiration ( = 0.52, < 05) were related to cycle net oxygen uptake. In addition, correlations between V̇o and cycle net oxygen uptake persist both at baseline and after training, even after adjusting for submaximal cycle respiratory quotient (an index of fat oxidation). These results suggest that the negative relationship between locomotion economy and aerobic capacity is increased following exercise training. In addition, it is proposed that at least one of the primary factors influencing this relationship has its foundation within the mitochondria. Strong relationships between coupled and uncoupled respiration appear to be contributing factors for this relationship. The negative relationship between cycle economy and aerobic capacity is increased following exercise training. The strong relationship between coupled and uncoupled respiration, especially after training, appears to be contributing to this negative relationship between aerobic capacity and cycling economy, suggesting that mitochondrial economy is not increased following aerobic exercise training. These results are suggestive that training programs designed to improve locomotion economy should focus on changing biomechanics.
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http://dx.doi.org/10.1152/japplphysiol.00223.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962606PMC
December 2019

Central IGF-1 protects against features of cognitive and sensorimotor decline with aging in male mice.

Geroscience 2019 04 10;41(2):185-208. Epub 2019 May 10.

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer Bldg, Rm 236, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.

Disruptions in growth hormone/insulin-like growth factor-1 (GH/IGF-1) signaling have been linked to improved longevity in mice and humans. Nevertheless, while IGF-1 levels are associated with increased cancer risk, they have been paradoxically implicated with protection from other age-related conditions, particularly in the brain, suggesting that strategies aimed at selectively increasing central IGF-1 action may have favorable effects on aging. To test this hypothesis, we generated inducible, brain-specific (TRE-IGF-1 × Camk2a-tTA) IGF-1 (bIGF-1) overexpression mice and studied effects on healthspan. Doxycycline was removed from the diet at 12 weeks old to permit post-development brain IGF-1 overexpression, and animals were monitored up to 24 months. Brain IGF-1 levels were increased approximately twofold in bIGF-1 mice, along with greater brain weights, volume, and myelin density (P < 0.05). Age-related changes in rotarod performance, exercise capacity, depressive-like behavior, and hippocampal gliosis were all attenuated specifically in bIGF-1 male mice (P < 0.05). However, chronic brain IGF-1 failed to prevent declines in cognitive function or neurovascular coupling. Therefore, we performed a short-term intranasal (IN) treatment of either IGF-1 or saline in 24-month-old male C57BL/6 mice and found that IN IGF-1 treatment tended to reduce depressive (P = 0.09) and anxiety-like behavior (P = 0.08) and improve motor coordination (P = 0.07) and unlike transgenic mice improved motor learning (P < 0.05) and visuospatial and working memory (P < 0.05). These data highlight important sex differences in how brain IGF-1 action impacts healthspan and suggest that translational approaches that target IGF-1 centrally can restore cognitive function, a possibility that should be explored as a strategy to combat age-related cognitive decline.
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http://dx.doi.org/10.1007/s11357-019-00065-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544744PMC
April 2019

Associations of Mitochondrial Fatty Acid Oxidation with Body Fat in Premenopausal Women.

J Nutr Metab 2017 24;2017:7832057. Epub 2017 Oct 24.

Department of Human Studies, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA.

Higher fatty acid (FA) oxidation rates have been reported in obese individuals compared to lean counterparts; however whether this reflects a shift in substrate-specific oxidative capacity at the level of the skeletal muscle mitochondria has not been examined. The purpose of this study was to test the hypothesis that in situ measures of skeletal muscle mitochondria FA oxidation would be positively associated with total body fat. Participants were 38 premenopausal women (BMI = 26.5 ± 4.3 kg/m). Total and regional fat were assessed by dual-energy X-ray absorptiometry (DXA). Mitochondrial FA oxidation was assessed in permeabilized myofibers using high-resolution respirometry and a palmitoyl carnitine substrate. We found positive associations of total fat mass with State 3 (ADP-stimulated respiration) ( = 0.379, < 0.05) and the respiratory control ratio (RCR, measure of mitochondrial coupling) ( = 0.348, < 0.05). When participants were dichotomized by high or low body fat percent, participants with high total body fat displayed a higher RCR compared to those with low body fat ( < 0.05). There were no associations between any measure of regional fat and mitochondrial FA oxidation independent of total fat mass. In conclusion, greater FA oxidation in obesity may reflect molecular processes that enhance FA oxidation capacity at the mitochondrial level.
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http://dx.doi.org/10.1155/2017/7832057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5674507PMC
October 2017

Fingernail and toenail clippings as a non-invasive measure of chronic cortisol levels in adult cancer survivors.

Cancer Causes Control 2018 01 23;29(1):185-191. Epub 2017 Nov 23.

Department of Nutrition Sciences, University of Alabama at Birmingham (UAB), WTI 102V, 1824 6th Ave S, Birmingham, AL, 35294, USA.

Purpose: Cancer survivors are at greater risk of comorbidities and functional decline due to physiological and psychological stress which can be measured by salivary cortisol. If saliva is used, multiple samples must be collected to accurately quantify long-term stress; however, fingernail (FN) and toenail (TN) clippings offer an opportunity to measure retrospective cortisol levels in a non-invasive manner.

Methods: Three sets of FN and TN clippings were collected at 12-month intervals in conjunction with saliva samples from cancer survivors (n = 109) participating in two clinical trials. FN and TN samples were stored at room temperature (RT); a subset underwent additional processing and freezing before analysis. Cortisol levels were determined via enzyme immunoassay, and correlation coefficients were generated to determine overall correspondence of the individual measures.

Results: Matched RT and frozen samples were highly correlated for TN (r = 0.950, p = 5.44 × 10) and FN (r = 0.784, p = 1.05 × 10). Correlations between RT FN and TN were statistically significant (r = 0.621, p = 3.61 × 10), as were frozen FN and TN (r = 0.310, p = 0.0283). RT, but not frozen TN and FN correlated with salivary cortisol (r = 0.580, p = 1.65 × 10 and r = 0.287, p = 0.00042 for TN and FN, respectively).

Conclusions: FN and TN cortisol levels correlate with salivary cortisol in adult cancer survivors and may offer a less invasive and convenient means for measuring chronic cortisol levels.
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http://dx.doi.org/10.1007/s10552-017-0989-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764195PMC
January 2018

Potential Causes of Elevated REE after High-Intensity Exercise.

Med Sci Sports Exerc 2017 Dec;49(12):2414-2421

1Department of Human Studies, University of Alabama at Birmingham, Birmingham, AL; 2Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL; 3Diabetes Research Center Bioanalytical Redox Biology (BARB) Core, University of Alabama at Birmingham, Birmingham, AL; 4Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL; and 5Department of Kinesiology, Recreation, and Sport Studies, University of Tennessee, Knoxville, TN.

Introduction: Resting energy expenditure (REE) increases after an intense exercise; however, little is known concerning mechanisms.

Purpose: The purpose of this study was to determine effects of a single bout of moderate-intensity continuous (MIC) aerobic exercise, or high-intensity interval (HII) exercise on REE under energy balance conditions.

Methods: Thirty-three untrained premenopausal women were evaluated at baseline, after 8-16 wk of training, 22 h after either MIC (50% peak V˙O2) or HII (84% peak V˙O2). Participants were in a room calorimeter during and after the exercise challenge. Food intake was adjusted to obtain energy balance across 23 h. REE was measured after 22 h after all conditions. Twenty-three-hour urine norepinephrine concentration and serum creatine kinase activity (CrKact) were obtained. Muscle biopsies were obtained in a subset of 15 participants to examine muscle mitochondrial state 2, 3, and 4 fat oxidation.

Results: REE was increased 22 h after MIC (64 ± 119 kcal) and HII (103 ± 137 kcal). Markers of muscle damage (CrKact) increased after HII (9.6 ± 25.5 U·L) and MIC (22.2 ± 22.8 U·L), whereas sympathetic tone (urine norepinephrine) increased after HII (1.1 ± 10.6 ng·mg). Uncoupled phosphorylation (states 2 and 4) fat oxidation were related to REE (r = 0.65 and r = 0.55, respectively); however, neither state 2 nor state 4 fat oxidation increased after MIC or HII. REE was not increased after 8 wk of aerobic training when exercise was restrained for 60 h.

Conclusions: Under energy balance conditions, REE increased 22 h after both moderate-intensity and high-intensity exercise. Exercise-induced muscle damage/repair and increased sympathetic tone may contribute to increased REE, whereas uncoupled phosphorylation does not. These results suggest that moderate- to high-intensity exercise may be valuable for increasing energy expenditure for at least 22 h after the exercise.
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http://dx.doi.org/10.1249/MSS.0000000000001386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5688014PMC
December 2017

Identification of Small Molecule Inhibitors of Human Cytochrome c Oxidase That Target Chemoresistant Glioma Cells.

J Biol Chem 2016 Nov 27;291(46):24188-24199. Epub 2016 Sep 27.

From the Department of Neurosurgery,

The enzyme cytochrome c oxidase (CcO) or complex IV (EC 1.9.3.1) is a large transmembrane protein complex that serves as the last enzyme in the respiratory electron transport chain of eukaryotic mitochondria. CcO promotes the switch from glycolytic to oxidative phosphorylation (OXPHOS) metabolism and has been associated with increased self-renewal characteristics in gliomas. Increased CcO activity in tumors has been associated with tumor progression after chemotherapy failure, and patients with primary glioblastoma multiforme and high tumor CcO activity have worse clinical outcomes than those with low tumor CcO activity. Therefore, CcO is an attractive target for cancer therapy. We report here the characterization of a CcO inhibitor (ADDA 5) that was identified using a high throughput screening paradigm. ADDA 5 demonstrated specificity for CcO, with no inhibition of other mitochondrial complexes or other relevant enzymes, and biochemical characterization showed that this compound is a non-competitive inhibitor of cytochrome c When tested in cellular assays, ADDA 5 dose-dependently inhibited the proliferation of chemosensitive and chemoresistant glioma cells but did not display toxicity against non-cancer cells. Furthermore, treatment with ADDA 5 led to significant inhibition of tumor growth in flank xenograft mouse models. Importantly, ADDA 5 inhibited CcO activity and blocked cell proliferation and neurosphere formation in cultures of glioma stem cells, the cells implicated in tumor recurrence and resistance to therapy in patients with glioblastoma. In summary, we have identified ADDA 5 as a lead CcO inhibitor for further optimization as a novel approach for the treatment of glioblastoma and related cancers.
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http://dx.doi.org/10.1074/jbc.M116.749978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104942PMC
November 2016

Detailed methods of two home-based vegetable gardening intervention trials to improve diet, physical activity, and quality of life in two different populations of cancer survivors.

Contemp Clin Trials 2016 09 23;50:201-12. Epub 2016 Aug 23.

Department of Nutrition Sciences, School of Health Professions, University of Alabama at Birmingham, 1675 University Boulevard, Webb Building 346, Birmingham, AL 35294, United States.

Background: Cancer survivors suffer from long-term adverse effects that reduce health-related quality of life (QOL) and physical functioning, creating an urgent need to develop effective, durable, and disseminable interventions. Harvest for Health, a home-based vegetable gardening intervention, holds promise for these domains.

Methods: This report describes the methods and recruitment experiences from two randomized controlled feasibility trials that employ a waitlist-controlled design. Delivered in partnership with Cooperative Extension Master Gardeners, this intervention provides one-on-one mentorship of cancer survivors in planning and maintaining three seasonal vegetable gardens over 12months. The primary aim is to determine intervention feasibility and acceptability; secondary aims are to explore effects on objective and subjective measures of diet, physical activity and function, and QOL and examine participant factors associated with potential effects. One trial is conducted exclusively among 82 female breast cancer survivors residing in the Birmingham, AL metropolitan area (BBCS); another broadly throughout Alabama among 46 older cancer survivors aged >60 (ASCS).

Results: Response rates were 32.6% (BBCS) and 52.3% (ASCS). Both trials exceeded 80% of their accrual target. Leading reasons for ineligibility were removal of >10 lymph nodes (lymphedema risk factor), lack of physician approval, and unwillingness to be randomized to the waitlist.

Conclusion: To date, recruitment and implementation of Harvest for Health appears feasible.

Discussion: Although both studies encountered recruitment challenges, lessons learned can inform future larger-scale studies. Vegetable gardening interventions are of interest to cancer survivors and may provide opportunities to gain life skills leading to improvements in overall health and QOL.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055381PMC
http://dx.doi.org/10.1016/j.cct.2016.08.014DOI Listing
September 2016

Endothelial Cell Bioenergetics and Mitochondrial DNA Damage Differ in Humans Having African or West Eurasian Maternal Ancestry.

Circ Cardiovasc Genet 2016 Feb 19;9(1):26-36. Epub 2016 Jan 19.

From the Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport (D.M.K.); Department of Nutrition Sciences (D.R.M.), Center for Free Radical Biology and Medicine (D.R.M., D.G.W., K.J.D.-S., J.B., A.W.B., K.P.F., M.J.S., M.R.S., L.D., S.W.B.), Division of Molecular and Cellular Pathology, Department of Pathology (D.G.W., J.B., A.W.B., K.P.F., M.J.S., M.R.S., S.W.B.), Department of Pediatrics (N.A.), Department of Medicine (D.C., L.D.), University of Alabama at Birmingham; Department of Medicine, Queen's University, Kingston, Ontario, Canada (K.J.D.-S.); Department of Anthropology, University of Pennsylvania, Philadelphia (T.G.S.); and Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (J.A.V.).

Background: We hypothesized that endothelial cells having distinct mitochondrial genetic backgrounds would show variation in mitochondrial function and oxidative stress markers concordant with known differential cardiovascular disease susceptibilities. To test this hypothesis, mitochondrial bioenergetics were determined in endothelial cells from healthy individuals with African versus European maternal ancestries.

Methods And Results: Bioenergetics and mitochondrial DNA (mtDNA) damage were assessed in single-donor human umbilical vein endothelial cells belonging to mtDNA haplogroups H and L, representing West Eurasian and African maternal ancestries, respectively. Human umbilical vein endothelial cells from haplogroup L used less oxygen for ATP production and had increased levels of mtDNA damage compared with those in haplogroup H. Differences in bioenergetic capacity were also observed in that human umbilical vein endothelial cells belonging to haplogroup L had decreased maximal bioenergetic capacities compared with haplogroup H. Analysis of peripheral blood mononuclear cells from age-matched healthy controls with West Eurasian or African maternal ancestries showed that haplogroups sharing an A to G mtDNA mutation at nucleotide pair 10398 had increased mtDNA damage compared with those lacking this mutation. Further study of angiographically proven patients with coronary artery disease and age-matched healthy controls revealed that mtDNA damage was associated with vascular function and remodeling and that age of disease onset was later in individuals from haplogroups lacking the A to G mutation at nucleotide pair 10398.

Conclusions: Differences in mitochondrial bioenergetics and mtDNA damage associated with maternal ancestry may contribute to endothelial dysfunction and vascular disease.
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http://dx.doi.org/10.1161/CIRCGENETICS.115.001308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758889PMC
February 2016

Pyruvate dehydrogenase kinase 1 participates in macrophage polarization via regulating glucose metabolism.

J Immunol 2015 Jun 11;194(12):6082-9. Epub 2015 May 11.

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294;

The M1 and M2 polarized phenotypes dictate distinctive roles for macrophages as they participate in inflammatory disorders. There has been growing interest in the role of cellular metabolism in macrophage polarization. However, it is currently unclear whether different aspects of a specific metabolic program coordinately regulate this cellular process. In this study, we found that pyruvate dehydrogenase kinase 1 (PDK1), a key regulatory enzyme in glucose metabolism, plays an important role in the differential activation of macrophages. Knockdown of PDK1 diminished M1, whereas it enhanced M2 activation of macrophages. Mechanistically, PDK1 knockdown led to diminished aerobic glycolysis in M1 macrophages, which likely accounts for the attenuated inflammatory response in these cells. Furthermore, we found that mitochondrial respiration is enhanced during and required by the early activation of M2 macrophages. Suppression of glucose oxidation, but not that of fatty acids, inhibits this process. Consistent with its inhibitory role in early M2 activation, knockdown of PDK1 enhanced mitochondrial respiration in macrophages. Our data suggest that two arms of the glucose metabolism synergistically regulate the differential activation of macrophages. Our findings also highlight the central role of PDK1 in this event via controlling glycolysis and glucose oxidation.
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http://dx.doi.org/10.4049/jimmunol.1402469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458459PMC
June 2015

Use of HbA1c for diagnoses of diabetes and prediabetes: comparison with diagnoses based on fasting and 2-hr glucose values and effects of gender, race, and age.

Metab Syndr Relat Disord 2014 Jun 10;12(5):258-68. Epub 2014 Feb 10.

1 Department of Nutrition Sciences, University of Alabama at Birmingham , Birmingham, Alabama.

Background: Glycated hemoglobin (HbA1c) has been advocated for the diagnosis of diabetes and prediabetes. Its performance has been commonly assessed in corroboration with elevated fasting plasma glucose (FPG), but not the combination of FPG and 2-hr glucose values. This study assesses receiver operating characteristics (ROC) curves of HbA1c pertaining to the diagnoses of prediabetes and diabetes by FPG and/or 2-hr glucose, and the effects of age, gender, and race.

Methods: We assessed the utility of HbA1c for diagnosing diabetes and prediabetes among 5395 adults without known diabetes from the National Health and Nutrition Examination Survey (NHANES) 2005-2010.

Results: Current cutoffs of HbA1c for diabetes (6.5%) or prediabetes (5.7%) exhibited low sensitivity (0.249 and 0.354, respectively) and high specificity in identifying patients diagnosed using both FPG and 2-hr glucose, resulting in large false-negative rates (75.1% and 64.9%). Misdiagnosis rates increased with age and in non-Hispanic whites and Mexican Americans. When HbA1c was combined with FPG for diagnoses, the false-negative rate remained high for diabetes (45.7%), but was reduced for prediabetes (9.2%).

Conclusions: When assessed against diagnoses using both FPG and 2-hr glucose, HbA1c had low sensitivity and high specificity for identifying diabetes and prediabetes, which varied as a function of age and race. Regarding recently released American Diabetes Association (ADA) and joint European guidelines, it is important to consider that HbA1c values below 6.5% and 5.7% do not reliably exclude the presence of diabetes and prediabetes, respectively. Overall, the data argue for greater use of oral glucose tolerance tests (OGTTs) and both FPG and 2-hr glucose values for diagnosis of diabetes and prediabetes.
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http://dx.doi.org/10.1089/met.2013.0128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4088353PMC
June 2014

Novel, high-intensity exercise prescription improves muscle mass, mitochondrial function, and physical capacity in individuals with Parkinson's disease.

J Appl Physiol (1985) 2014 Mar 9;116(5):582-92. Epub 2014 Jan 9.

UAB Center for Exercise Medicine, University of Alabama at Birmingham, Birmingham, Alabama;

We conducted, in persons with Parkinson's disease (PD), a thorough assessment of neuromotor function and performance in conjunction with phenotypic analyses of skeletal muscle tissue, and further tested the adaptability of PD muscle to high-intensity exercise training. Fifteen participants with PD (Hoehn and Yahr stage 2-3) completed 16 wk of high-intensity exercise training designed to simultaneously challenge strength, power, endurance, balance, and mobility function. Skeletal muscle adaptations (P < 0.05) to exercise training in PD included myofiber hypertrophy (type I: +14%, type II: +36%), shift to less fatigable myofiber type profile, and increased mitochondrial complex activity in both subsarcolemmal and intermyofibrillar fractions (I: +45-56%, IV: +39-54%). These adaptations were accompanied by a host of functional and clinical improvements (P < 0.05): total body strength (+30-56%); leg power (+42%); single leg balance (+34%); sit-to-stand motor unit activation requirement (-30%); 6-min walk (+43 m), Parkinson's Disease Quality of Life Scale (PDQ-39, -7.8pts); Unified Parkinson's Disease Rating Scale (UPDRS) total (-5.7 pts) and motor (-2.7 pts); and fatigue severity (-17%). Additionally, PD subjects in the pretraining state were compared with a group of matched, non-PD controls (CON; did not exercise). A combined assessment of muscle tissue phenotype and neuromuscular function revealed a higher distribution and larger cross-sectional area of type I myofibers and greater type II myofiber size heterogeneity in PD vs. CON (P < 0.05). In conclusion, persons with moderately advanced PD adapt to high-intensity exercise training with favorable changes in skeletal muscle at the cellular and subcellular levels that are associated with improvements in motor function, physical capacity, and fatigue perception.
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http://dx.doi.org/10.1152/japplphysiol.01277.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073951PMC
March 2014

Mitochondrial genetic background modulates bioenergetics and susceptibility to acute cardiac volume overload.

Biochem J 2013 Oct;455(2):157-67

‡Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.

Dysfunctional bioenergetics has emerged as a key feature in many chronic pathologies such as diabetes and cardiovascular disease. This has led to the mitochondrial paradigm in which it has been proposed that mtDNA sequence variation contributes to disease susceptibility. In the present study we show a novel animal model of mtDNA polymorphisms, the MNX (mitochondrial-nuclear exchange) mouse, in which the mtDNA from the C3H/HeN mouse has been inserted on to the C57/BL6 nuclear background and vice versa to test this concept. Our data show a major contribution of the C57/BL6 mtDNA to the susceptibility to the pathological stress of cardiac volume overload which is independent of the nuclear background. Mitochondria harbouring the C57/BL6J mtDNA generate more ROS (reactive oxygen species) and have a higher mitochondrial membrane potential relative to those with C3H/HeN mtDNA, independent of nuclear background. We propose this is the primary mechanism associated with increased bioenergetic dysfunction in response to volume overload. In summary, these studies support the 'mitochondrial paradigm' for the development of disease susceptibility, and show that the mtDNA modulates cellular bioenergetics, mitochondrial ROS generation and susceptibility to cardiac stress.
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http://dx.doi.org/10.1042/BJ20130029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807257PMC
October 2013

The progression of cardiometabolic disease: validation of a new cardiometabolic disease staging system applicable to obesity.

Obesity (Silver Spring) 2014 Jan 5;22(1):110-8. Epub 2013 Sep 5.

Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Objective: To validate a Cardiometabolic Disease Staging (CMDS) system for assigning risk level for diabetes, and all-cause and cardiovascular disease (CVD) mortality.

Design And Methods: Two large national cohorts, CARDIA and NHANES III, were used to validate CMDS. CMDS: Stage 0: metabolically healthy; Stage 1: one or two metabolic syndrome risk factors [other than impaired fasting glucose (IFG)]; Stage 2: IFG or impaired glucose tolerance (IGT) or metabolic syndrome (without IFG); Stage 3: two of three (IFG, IGT, and/or metabolic syndrome); and Stage 4: type 2 diabetes mellitus/CVD.

Results: In the CARDIA study, compared with Stage 0 metabolically healthy subjects, adjusted risk for diabetes exponentially increased from Stage 1 [hazard ratio (HR) 2.83, 95% confidence interval (CI): 1.76-4.55], to Stage 2 (HR 8.06, 95% CI 4.91-13.2), to Stage 3 (HR 23.5, 95% CI 13.7-40.1) (P for trend <0.001). In NHANES III, both cumulative incidence and multivariable adjusted HRs markedly increased for both all-cause and CVD mortality with advancement of the risk stage from Stages 0 to 4. Adjustment for body mass index (BMI) minimally affected the risks for diabetes and all-cause/CVD mortality using CMDS.

Conclusion: CMDS can discriminate a wide range of risk for diabetes, CVD mortality, and all-cause mortality independent of BMI, and should be studied as a risk assessment tool to guide interventions that prevent and treat cardiometabolic disease.
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http://dx.doi.org/10.1002/oby.20585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866217PMC
January 2014

Nuclear genomic control of naturally occurring variation in mitochondrial function in Drosophila melanogaster.

BMC Genomics 2012 Nov 22;13:659. Epub 2012 Nov 22.

Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Background: Mitochondria are organelles found in nearly all eukaryotic cells that play a crucial role in cellular survival and function. Mitochondrial function is under the control of nuclear and mitochondrial genomes. While the latter has been the focus of most genetic research, we remain largely ignorant about the nuclear-encoded genomic control of inter-individual variability in mitochondrial function. Here, we used Drosophila melanogaster as our model organism to address this question.

Results: We quantified mitochondrial state 3 and state 4 respiration rates and P:O ratio in mitochondria isolated from the thoraces of 40 sequenced inbred lines of the Drosophila Genetic Reference Panel. We found significant within-population genetic variability for all mitochondrial traits. Hence, we performed genome-wide association mapping and identified 141 single nucleotide polymorphisms (SNPs) associated with differences in mitochondrial respiration and efficiency (P ≤1 × 10-5). Gene-centered regression models showed that 2-3 SNPs can explain 31, 13, and 18% of the phenotypic variation in state 3, state 4, and P:O ratio, respectively. Most of the genes tagged by the SNPs are involved in organ development, second messenger-mediated signaling pathways, and cytoskeleton remodeling. One of these genes, sallimus (sls), encodes a component of the muscle sarcomere. We confirmed the direct effect of sls on mitochondrial respiration using two viable mutants and their coisogenic wild-type strain. Furthermore, correlation network analysis revealed that sls functions as a transcriptional hub in a co-regulated module associated with mitochondrial respiration and is connected to CG7834, which is predicted to encode a protein with mitochondrial electron transfer flavoprotein activity. This latter finding was also verified in the sls mutants.

Conclusions: Our results provide novel insights into the genetic factors regulating natural variation in mitochondrial function in D. melanogaster. The integrative genomic approach used in our study allowed us to identify sls as a novel hub gene responsible for the regulation of mitochondrial respiration in muscle sarcomere and to provide evidence that sls might act via the electron transfer flavoprotein/ubiquinone oxidoreductase complex.
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http://dx.doi.org/10.1186/1471-2164-13-659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526424PMC
November 2012

Role of TRIB3 in regulation of insulin sensitivity and nutrient metabolism during short-term fasting and nutrient excess.

Am J Physiol Endocrinol Metab 2012 Oct 31;303(7):E908-16. Epub 2012 Jul 31.

Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294-3360, USA.

We have suggested previously that Tribbles homolog 3 (TRIB3), a negative regulator of Akt activity in insulin-sensitive tissues, could mediate glucose-induced insulin resistance in muscle under conditions of chronic hyperglycemia (Liu J, Wu X, Franklin JL, Messina JL, Hill HS, Moellering DR, Walton RG, Martin M, Garvey WT. Am J Physiol Endocrinol Metab 298: E565-E576, 2010). In the current study, we have assessed short-term physiological regulation of TRIB3 in skeletal muscle and adipose tissues by nutrient excess and fasting as well as TRIB3's ability to modulate glucose transport and mitochondrial oxidation. In Sprague-Dawley rats, we found that short-term fasting enhanced insulin sensitivity concomitantly with decrements in TRIB3 mRNA (66%, P < 0.05) and protein (81%, P < 0.05) in muscle and increments in TRIB3 mRNA (96%, P < 0.05) and protein (~10-fold, P < 0.05) in adipose tissue compared with nonfasted controls. On the other hand, rats fed a Western diet for 7 days became insulin resistant concomitantly with increments in TRIB3 mRNA (155%, P < 0.05) and protein (69%, P = 0.0567) in muscle and a decrease in the mRNA (76%, P < 0.05) and protein (70%, P < 0.05) in adipose. In glucose transport and mitochondria oxidation studies using skeletal muscle cells, we found that stable TRIB3 overexpression impaired insulin-stimulated glucose uptake without affecting basal glucose transport and increased both basal glucose oxidation and the maximal uncoupled oxygen consumption rate. With stable knockdown of TRIB3, basal and insulin-stimulated glucose transport rates were increased, whereas basal glucose oxidation and the maximal uncoupled oxygen consumption rate were decreased. In conclusion, TRIB3 impacts glucose uptake and oxidation oppositely in muscle and fat according to levels of nutrient availability. The above data for the first time implicate TRIB3 as a potent physiological regulator of insulin sensitivity and mitochondrial glucose oxidation under conditions of nutrient deprivation and excess.
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http://dx.doi.org/10.1152/ajpendo.00663.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3469620PMC
October 2012

Skeletal muscle lipid peroxidation and insulin resistance in humans.

J Clin Endocrinol Metab 2012 Jul 11;97(7):E1182-6. Epub 2012 Apr 11.

Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama 35294-3360, USA.

Objective: The relationships among skeletal muscle lipid peroxidation, intramyocellular lipid content (IMCL), and insulin sensitivity were evaluated in nine insulin-sensitive (IS), 13 insulin-resistant (IR), and 10 adults with type 2 diabetes (T2DM).

Design: Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp [glucose disposal rate (GDR)]. Lipid peroxidation was assessed by 4-hydroxynonenal (HNE)-protein adducts and general oxidative stress by protein carbonyl content. All patients were sedentary.

Results: Protein-HNE adducts were elevated 1.6-fold in T2DM compared with IS adults, whereas IR showed intermediate levels of HNE-modified proteins. Protein-HNE adducts correlated with GDR, waist circumference, and body mass index. IMCL was increased by 4.0- and 1.9-fold in T2DM and IR patients, respectively, compared with IS, and was correlated with GDR and waist circumference but not BMI. Protein carbonyls were not different among groups and did not correlate with any of the measured variables. Correlations were detected between IMCL and protein-HNE.

Conclusion: Our data show for the first time that skeletal muscle protein-HNE adducts are related to the severity of insulin resistance in sedentary adults. These results suggest that muscle lipid peroxidation could be involved in the development of insulin resistance.
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http://dx.doi.org/10.1210/jc.2011-2963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387404PMC
July 2012

Ambient Temperature and Obesity.

Curr Obes Rep 2012 Mar;1(1):26-34

Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA ; Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL, USA.

Homeotherms maintain an optimal body temperature that is most often above their environment or ambient temperature. As ambient temperature decreases, energy expenditure (and energy intake) must increase to maintain thermal homeostasis. With the wide spread adoption of climate control, humans in modern society are buffered from temperature extremes and spend an increasing amount of time in a thermally comfortable state where energetic demands are minimized. This is hypothesized to contribute to the contemporary increase in obesity rates. Studies reporting exposures of animals and humans to different ambient temperatures are discussed. Additional consideration is given to the potentially altered metabolic and physiologic responses in obese versus lean subjects at a given temperature. The data suggest that ambient temperature is a significant contributor to both energy intake and energy expenditure, and that this variable should be more thoroughly explored in future studies as a potential contributor to obesity susceptibility.
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http://dx.doi.org/10.1007/s13679-011-0002-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975627PMC
March 2012

Acquisition of chemoresistance in gliomas is associated with increased mitochondrial coupling and decreased ROS production.

PLoS One 2011 9;6(9):e24665. Epub 2011 Sep 9.

Division of Neurosurgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

Temozolomide (TMZ) is an alkylating agent used for treating gliomas. Chemoresistance is a severe limitation to TMZ therapy; there is a critical need to understand the underlying mechanisms that determine tumor response to TMZ. We recently reported that chemoresistance to TMZ is related to a remodeling of the entire electron transport chain, with significant increases in the activity of complexes II/III and cytochrome c oxidase (CcO). Moreover, pharmacologic and genetic manipulation of CcO reverses chemoresistance. Therefore, to test the hypothesis that TMZ-resistance arises from tighter mitochondrial coupling and decreased production of reactive oxygen species (ROS), we have assessed mitochondrial function in TMZ-sensitive and -resistant glioma cells, and in TMZ-resistant glioblastoma multiform (GBM) xenograft lines (xenolines). Maximum ADP-stimulated (state 3) rates of mitochondrial oxygen consumption were greater in TMZ-resistant cells and xenolines, and basal respiration (state 2), proton leak (state 4), and mitochondrial ROS production were significantly lower in TMZ-resistant cells. Furthermore, TMZ-resistant cells consumed less glucose and produced less lactic acid. Chemoresistant cells were insensitive to the oxidative stress induced by TMZ and hydrogen peroxide challenges, but treatment with the oxidant L-buthionine-S,R-sulfoximine increased TMZ-dependent ROS generation and reversed chemoresistance. Importantly, treatment with the antioxidant N-acetyl-cysteine inhibited TMZ-dependent ROS generation in chemosensitive cells, preventing TMZ toxicity. Finally, we found that mitochondrial DNA-depleted cells (ρ°) were resistant to TMZ and had lower intracellular ROS levels after TMZ exposure compared with parental cells. Repopulation of ρ° cells with mitochondria restored ROS production and sensitivity to TMZ. Taken together, our results indicate that chemoresistance to TMZ is linked to tighter mitochondrial coupling and low ROS production, and suggest a novel mitochondrial ROS-dependent mechanism underlying TMZ-chemoresistance in glioma. Thus, perturbation of mitochondrial functions and changes in redox status might constitute a novel strategy for sensitizing glioma cells to therapeutic approaches.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024665PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170372PMC
February 2012

The mitochondrial paradigm for cardiovascular disease susceptibility and cellular function: a complementary concept to Mendelian genetics.

Lab Invest 2011 Aug 6;91(8):1122-35. Epub 2011 Jun 6.

Division of Molecular and Cellular Pathology, Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA.

While there is general agreement that cardiovascular disease (CVD) development is influenced by a combination of genetic, environmental, and behavioral contributors, the actual mechanistic basis of how these factors initiate or promote CVD development in some individuals while others with identical risk profiles do not, is not clearly understood. This review considers the potential role for mitochondrial genetics and function in determining CVD susceptibility from the standpoint that the original features that molded cellular function were based upon mitochondrial-nuclear relationships established millions of years ago and were likely refined during prehistoric environmental selection events that today, are largely absent. Consequently, contemporary risk factors that influence our susceptibility to a variety of age-related diseases, including CVD were probably not part of the dynamics that defined the processes of mitochondrial-nuclear interaction, and thus, cell function. In this regard, the selective conditions that contributed to cellular functionality and evolution should be given more consideration when interpreting and designing experimental data and strategies. Finally, future studies that probe beyond epidemiologic associations are required. These studies will serve as the initial steps for addressing the provocative concept that contemporary human disease susceptibility is the result of selection events for mitochondrial function that increased chances for prehistoric human survival and reproductive success.
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http://dx.doi.org/10.1038/labinvest.2011.95DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654682PMC
August 2011

Mammalian Tribbles homolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance.

Am J Physiol Endocrinol Metab 2010 Mar 8;298(3):E565-76. Epub 2009 Dec 8.

Dept. of Nutrition Sciences, Univ. of Alabama at Birmingham, 35294-3360, USA.

Tribbles homolog 3 (TRIB3) was found to inhibit insulin-stimulated Akt phosphorylation and modulate gluconeogenesis in rodent liver. Currently, we examined a role for TRIB3 in skeletal muscle insulin resistance. Ten insulin-sensitive, ten insulin-resistant, and ten untreated type 2 diabetic (T2DM) patients were metabolically characterized by hyperinsulinemic euglycemic glucose clamps, and biopsies of vastus lateralis were obtained. Skeletal muscle samples were also collected from rodent models including streptozotocin (STZ)-induced diabetic rats, db/db mice, and Zucker fatty rats. Finally, L6 muscle cells were used to examine regulation of TRIB3 by glucose, and stable cell lines hyperexpressing TRIB3 were generated to identify mechanisms underlying TRIB3-induced insulin resistance. We found that 1) skeletal muscle TRIB3 protein levels are significantly elevated in T2DM patients; 2) muscle TRIB3 protein content is inversely correlated with glucose disposal rates and positively correlated with fasting glucose; 3) skeletal muscle TRIB3 protein levels are increased in STZ-diabetic rats, db/db mice, and Zucker fatty rats; 4) stable TRIB3 hyperexpression in muscle cells blocks insulin-stimulated glucose transport and glucose transporter 4 (GLUT4) translocation and impairs phosphorylation of Akt, ERK, and insulin receptor substrate-1 in insulin signal transduction; and 5) TRIB3 mRNA and protein levels are increased by high glucose concentrations, as well as by glucose deprivation in muscle cells. These data identify TRIB3 induction as a novel molecular mechanism in human insulin resistance and diabetes. TRIB3 acts as a nutrient sensor and could mediate the component of insulin resistance attributable to hyperglycemia (i.e., glucose toxicity) in diabetes.
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http://dx.doi.org/10.1152/ajpendo.00467.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2838520PMC
March 2010

Effect of exercise and calorie restriction on biomarkers of aging in mice.

Am J Physiol Regul Integr Comp Physiol 2008 May 5;294(5):R1618-27. Epub 2008 Mar 5.

Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.

Unlike calorie restriction, exercise fails to extend maximum life span, but the mechanisms that explain this disparate effect are unknown. We used a 24-wk protocol of treadmill running, weight matching, and pair feeding to compare the effects of exercise and calorie restriction on biomarkers related to aging. This study consisted of young controls, an ad libitum-fed sedentary group, two groups that were weight matched by exercise or 9% calorie restriction, and two groups that were weight matched by 9% calorie restriction + exercise or 18% calorie restriction. After 24 wk, ad libitum-fed sedentary mice were the heaviest and fattest. When weight-matched groups were compared, mice that exercised were leaner than calorie-restricted mice. Ad libitum-fed exercise mice tended to have lower serum IGF-1 than fully-fed controls, but no difference in fasting insulin. Mice that underwent 9% calorie restriction or 9% calorie restriction + exercise, had lower insulin levels; the lowest concentrations of serum insulin and IGF-1 were observed in 18% calorie-restricted mice. Exercise resulted in elevated levels of tissue heat shock proteins, but did not accelerate the accumulation of oxidative damage. Thus, failure of exercise to slow aging in previous studies is not likely the result of increased accrual of oxidative damage and may instead be due to an inability to fully mimic the hormonal and/or metabolic response to calorie restriction.
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http://dx.doi.org/10.1152/ajpregu.00890.2007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332519PMC
May 2008

Atypical antipsychotic drugs directly impair insulin action in adipocytes: effects on glucose transport, lipogenesis, and antilipolysis.

Neuropsychopharmacology 2007 Apr 28;32(4):765-72. Epub 2006 Jun 28.

Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294-3360, USA.

Treatment with second-generation antipsychotics (SGAs) has been associated with weight gain and the development of diabetes mellitus, although the mechanisms are unknown. We tested the hypothesis that SGAs exert direct cellular effects on insulin action and substrate metabolism in adipocytes. We utilized two cultured cell models including 3T3-L1 adipocytes and primary cultured rat adipocytes, and tested for effects of SGAs risperidone (RISP), clozapine (CLZ), olanzapine (OLZ), and quetiapine (QUE), together with conventional antipsychotic drugs butyrophenone (BUTY), and trifluoperazine (TFP), over a wide concentration range from 1 to 500 microM. The effects of antipsychotic drugs on basal and insulin-stimulated rates of glucose transport were studied at 3 h, 15 h, and 3 days. Both CLZ and OLZ (but not RISP) at doses as low as 5 microM were able to significantly decrease the maximal insulin-stimulated glucose transport rate by approximately 40% in 3T3-L1 cells, whereas CLZ and RISP reduced insulin-stimulated glucose transport rates in primary cultured rat adipocytes by approximately 50-70%. Conventional drugs (BUTY and TFP) did not affect glucose transport rates. Regarding intracellular glucose metabolism, both SGAs (OLZ, QUE, RISP) and conventional drugs (BUTY and TFP) increased basal and/or insulin-stimulated glucose oxidation rates, whereas rates of lipogenesis were increased by CLZ, OLZ, QUE, and BUTY. Finally, rates of lipolysis in response to isoproterenol were reduced by the SGAs (CLZ, OLZ, QUE, RISP), but not by BUTY or TFP. These experiments demonstrate that antipsychotic drugs can differentially affect insulin action and metabolism through direct cellular effects in adipocytes. However, only SGAs were able to impair the insulin-responsive glucose transport system and to impair lipolysis in adipocytes. Thus, SGAs directly induce insulin resistance and alter lipogenesis and lipolysis in favor of progressive lipid accumulation and adipocyte enlargement. These effects of SGAs on adipocytes could explain, in part, the association of SGAs with weight gain and diabetes.
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http://dx.doi.org/10.1038/sj.npp.1301142DOI Listing
April 2007

Oxidized LDL induces mitochondrially associated reactive oxygen/nitrogen species formation in endothelial cells.

Am J Physiol Heart Circ Physiol 2005 Aug 1;289(2):H852-61. Epub 2005 Apr 1.

Center for Free Radical Biology, Univ. of Alabama at Birmingham, Biomedical Research Bldg. II, 901 19th St. South, Birmingham, AL 35294, USA.

Exposure of cells to complex mixtures of oxidized lipids such as those found in oxidized low-density lipoprotein (oxLDL) induce reactive oxygen and nitrogen species (ROS/RNS) formation. The source of the ROS/RNS within cells is unknown; it is thought they may be involved in redox cell signaling. Although this possibility was initially overlooked, it is becoming clear that mitochondria, which are a source of superoxide and hydrogen peroxide, may play a critical role in the response of cells on exposure to oxidized lipids. In this study, we tested the possibility that mitochondria are a potential source of oxLDL-dependent formation of ROS/RNS in endothelial cells. Using confocal microscopy, we demonstrated that a significant proportion of oxLDL-dependent dichlorodihydrofluorescein (DCF) fluorescence is colocalized to mitochondria. In support of this concept, rho0 endothelial cells showed a substantial decrease in ROS/RNS formation stimulated by oxLDL. In contrast, mostly nonmitochondrial DCF fluorescence was detected in cells exposed to an extracellular source of hydrogen peroxide. The exposure of cells to a nitric oxide synthase inhibitor and urate resulted in a decrease in oxLDL-induced DCF fluorescence that was restored by addition of nitric oxide donors to the medium. Taken together, these results suggest that oxLDL-dependent DCF fluorescence is mitochondrially associated and may be due to the formation of peroxynitrite.
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http://dx.doi.org/10.1152/ajpheart.00015.2005DOI Listing
August 2005

Human glutamate cysteine ligase gene regulation through the electrophile response element.

Free Radic Biol Med 2004 Oct;37(8):1152-9

Department of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Glutathione (GSH) is the primary nonprotein thiol in the cell. It has many important roles in cell function, including regulating redox-dependent signal transduction pathways. The content of GSH within the cell varies with stress. In many cases, a process involving GSH synthesis results in adaptation to subsequent stressors. Sustained increases in GSH content are controlled primarily through induction of two genes, Gclc and Gclm, leading to the synthesis of the rate-limiting enzyme for GSH synthesis, glutamate cysteine ligase. Each of these genes in humans has a number of putative enhancer elements in their promoters. Overall, the most important element in both Gclc and Gclm expression is the electrophile response element. We review the evidence that has led to this conclusion and the implications for the redox-dependent regulation of this critical intracellular antioxidant.
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http://dx.doi.org/10.1016/j.freeradbiomed.2004.06.011DOI Listing
October 2004

Cytoprotection against oxidative stress and the regulation of glutathione synthesis.

Biol Chem 2003 Apr;384(4):527-37

Center for Free Radical Biology and Department of Environmental Health Sciences, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294-0022, USA.

Adaptation to oxidative and nitrosative stress occurs in cells first exposed to a nontoxic stress, resulting in the ability to tolerate a toxic challenge of the same or a related oxidant. Adaptation is observed in a wide variety of cells including endothelial cells on exposure to nitric oxide or oxidized lipids, and lung epithelial cells exposed to air-borne pollutants and toxicants. This acquired characteristic has been related to the regulation of a family of stress responding proteins including those that control the synthesis of the intracellular antioxidant glutathione. The focus of this article, which includes a review of recent results along with new data, is the regulation and signaling of glutathione biosynthesis, especially those relating to adaptive mechanisms. These concepts are illustrated with examples using nitric oxide and oxidized low density lipoprotein mediated adaptation to oxidative stress. These data are discussed in the context of other adaptive mechanisms relating to glutathione synthesis including those from dietary constituents such as curcumin.
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http://dx.doi.org/10.1515/BC.2003.061DOI Listing
April 2003

Inhibition of mitochondrial protein synthesis results in increased endothelial cell susceptibility to nitric oxide-induced apoptosis.

Proc Natl Acad Sci U S A 2002 May;99(10):6643-8

Department of Pathology, University of Alabama, Birmingham, AL 35294, USA.

Mutations in mitochondrial DNA, affecting the activity of respiratory complexes, have been implicated in many chronic degenerative diseases. Mitochondrial proteins coded for by both the mitochondrial and nuclear genes are known to have important signaling roles in apoptosis. However, the impact of the inhibition of mitochondrial protein synthesis on apoptosis is largely unknown. This inhibition is particularly important in NO-dependent cytotoxicity, which is believed to have a significant mitochondrial component and depend on other factors such as glycolysis. In this study we have examined whether the inhibition of mitochondrial protein synthesis by chloramphenicol increases the susceptibility of endothelial cells to undergo NO-dependent apoptosis in glucose-free media. Bovine aortic endothelial cells were treated with chloramphenicol, which resulted in a decreased ratio of mitochondrial complex IV to cytochrome c and increased oxidant production in the cell. Inhibition of mitochondrial protein synthesis was associated with a greater susceptibility of the cells to apoptosis induced by NO in glucose-free medium.
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http://dx.doi.org/10.1073/pnas.102019899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC124456PMC
May 2002