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Okamura T, Hamaguchi M, Bamba R, Nakajima H, Yoshimura Y, Kimura T, Hashimoto Y, Majima S, Senmaru T, Ushigome E, Nakanishi N, Asano M, Yamazaki M, Nishimoto Y, Yamada T, Fujikura C, Asama T, Okumura N, Takakuwa H, Sasano R, Fukui M. Brazilian green propolis improves gut microbiota dysbiosis and protects against sarcopenic obesity. J Cachexia Sarcopenia Muscle 2022; 13:3028-3047. [PMID: 36162824 PMCID: PMC9745478 DOI: 10.1002/jcsm.13076] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 06/26/2022] [Accepted: 07/27/2022] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Brazilian green propolis is an important honeybee product that is considered beneficial for health. Here, we examined the therapeutic potential of dietary supplementation with propolis against sarcopenic obesity using Db/Db mice. METHODS Db/m mice fed a normal diet alone and Db/Db mice fed normal diet alone, or supplemented with different amounts of propolis (0.08, 0.4 and 2%), were examined for effects on sarcopenic obesity. RESULTS Propolis improved the glucose tolerance (P < 0.001), increased the grip strength (P < 0.001) and the weight of soleus (P = 0.006) and plantaris muscles (P = 0.008). Moreover, propolis improved the non-alcoholic fatty liver disease activity score (P < 0.001) and decreased the expression of genes related to inflammation, liver fibrosis and fatty acid metabolism. Propolis decreased the accumulation of saturated fatty acids in the liver and increased their excretion in faeces. With regard to the innate immunity, propolis decreased the ratio of M1 macrophages (P = 0.008) and Type 1 and 3 innate lymphoid cells to CD45-positive cells (P < 0.001) and increased the ratio of M2 macrophages (P = 0.002) and ILC2s (P = 0.007) in the liver. Additionally, propolis decreased the expression of genes related to muscle atrophy and inflammation and the concentration of saturated fatty acids in the soleus muscle. 16S rRNA phylogenetic sequencing revealed that propolis increased the Bacteroidetes/Firmicutes ratio, and the abundance of Butyricicoccus and Acetivibrio genera. Gut microbiota related to the pentose phosphatase pathway and glycerolipid metabolism was more prevalent after the administration of propolis. CONCLUSIONS This is the first study to demonstrate that propolis can improve sarcopenic obesity by improving dysbiosis due to overeating and provides new insights into diet-microbiota interactions during sarcopenic obesity.
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Affiliation(s)
- Takuro Okamura
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Masahide Hamaguchi
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Ryo Bamba
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hanako Nakajima
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yuta Yoshimura
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tomonori Kimura
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshitaka Hashimoto
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Saori Majima
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takafumi Senmaru
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Emi Ushigome
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Naoko Nakanishi
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Mai Asano
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Masahiro Yamazaki
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | | | - Takuji Yamada
- Metabologenomics Inc., Tsuruoka, Yamagata, Japan.,Department of Life Science and Technology, Tokyo Institute of Technology, Tokyo, Japan
| | - Chizuru Fujikura
- Institute for Bee Products and Health Science, R&D Department, Yamada Bee Company, Inc, Okayama, Japan
| | - Takashi Asama
- Institute for Bee Products and Health Science, R&D Department, Yamada Bee Company, Inc, Okayama, Japan
| | - Nobuaki Okumura
- Institute for Bee Products and Health Science, R&D Department, Yamada Bee Company, Inc, Okayama, Japan
| | - Hiroshi Takakuwa
- Agilent Technologies, Chromatography Mass Spectrometry Sales Department, Life Science and Applied Markets Group, Tokyo, Japan
| | | | - Michiaki Fukui
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Berteli TS, Vireque AA, Da Luz CM, Borges ED, Ferreira CR, Navarro PA. Equilibration solution composition and extended exposure to equilibration phase affect embryo development and lipid profile of mouse oocytes. Reprod Biomed Online 2022; 44:961-975. [DOI: 10.1016/j.rbmo.2022.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 11/25/2021] [Accepted: 01/13/2022] [Indexed: 10/19/2022]
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Presby DM, Rudolph MC, Sherk VD, Jackman MR, Foright RM, Jones KL, Houck JA, Johnson GC, Higgins JA, Neufer PD, Eckel RH, MacLean PS. Lipoprotein Lipase Overexpression in Skeletal Muscle Attenuates Weight Regain by Potentiating Energy Expenditure. Diabetes 2021; 70:867-877. [PMID: 33536195 PMCID: PMC7980196 DOI: 10.2337/db20-0763] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 01/27/2021] [Indexed: 11/13/2022]
Abstract
Moderate weight loss improves numerous risk factors for cardiometabolic disease; however, long-term weight loss maintenance (WLM) is often thwarted by metabolic adaptations that suppress energy expenditure and facilitate weight regain. Skeletal muscle has a prominent role in energy homeostasis; therefore, we investigated the effect of WLM and weight regain on skeletal muscle in rodents. In skeletal muscle of obesity-prone rats, WLM reduced fat oxidative capacity and downregulated genes involved in fat metabolism. Interestingly, even after weight was regained, genes involved in fat metabolism were also reduced. We then subjected mice with skeletal muscle lipoprotein lipase overexpression (mCK-hLPL), which augments fat metabolism, to WLM and weight regain and found that mCK-hLPL attenuates weight regain by potentiating energy expenditure. Irrespective of genotype, weight regain suppressed dietary fat oxidation and downregulated genes involved in fat metabolism in skeletal muscle. However, mCK-hLPL mice oxidized more fat throughout weight regain and had greater expression of genes involved in fat metabolism and lower expression of genes involved in carbohydrate metabolism during WLM and regain. In summary, these results suggest that skeletal muscle fat oxidation is reduced during WLM and regain, and therapies that improve skeletal muscle fat metabolism may attenuate rapid weight regain.
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Affiliation(s)
- David M Presby
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Michael C Rudolph
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Vanessa D Sherk
- Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Matthew R Jackman
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Rebecca M Foright
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS
| | - Kenneth L Jones
- Department of Pediatrics, University of Colorado Denver Anschutz Medical Campus, Aurora, CO
| | - Julie A Houck
- Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Ginger C Johnson
- Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Janine A Higgins
- Department of Pediatrics, University of Colorado Denver Anschutz Medical Campus, Aurora, CO
| | - P Darrell Neufer
- East Carolina Diabetes and Obesity Institute and the Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC
| | - Robert H Eckel
- Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Paul S MacLean
- Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
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Ehara A, Taguchi D, Nakadate K, Ueda S. Attractin deficiency causes metabolic and morphological abnormalities in slow-twitch muscle. Cell Tissue Res 2021; 384:745-756. [PMID: 33660050 DOI: 10.1007/s00441-021-03423-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 01/24/2021] [Indexed: 11/25/2022]
Abstract
Skeletal muscle fibers are classified as slow-twitch and fast-twitch fibers, which have different reactive oxygen species (ROS) metabolism and mitochondrial biogenesis. Recently, Attractin (Atrn), which encodes secreted (sAtrn) and transmembrane (mAtrn)-type proteins, has been shown to be involved in free radical scavenging. Although Atrn has been found in skeletal muscle, little is known about the expression levels and function of Atrn in each muscle fiber type. Therefore, we investigate sAtrn and mAtrn expression levels in the slow-twitch soleus (sol) and fast-twitch extensor digitorum longus (EDL) muscles as well as the morphology and expression levels of antioxidant enzymes and functional mitochondrial markers using Atrn-deficient muscles. Both types of Atrn were expressed in the sol and EDL. mAtrn was mainly expressed in the adult sol, whereas sAtrn expression levels did not differ between muscle types. Moreover, mAtrn in the sol was abundantly localized in the subsarcolemmal area, especially in the myoplasm near mitochondria. Atrn-deficient Zitter rats showed muscle fiber atrophy, myofibril misalignment, mitochondrial swelling and vacuolation in the sol but not EDL. Furthermore, the Atrn-deficient sol exhibited a marked reduction in antioxidant enzyme SOD1, GPx1, catalase and Prx6 and mitochondrial functional protein, UCP2, expression. Even Atrn-deficient EDL showed a significant reduction in Prx3, Prx6, UCP2 and UCP3 expression. These data indicate that Atrn-deficiency disturbs ROS metabolism in skeletal muscles. In particular, mAtrn is involved in metabolism in the slow-twitch sol muscle and mAtrn-deficiency may cause ROS imbalance, resulting in morphological abnormalities in the muscle.
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Affiliation(s)
- Ayuka Ehara
- Department of Histology and Neurobiology, Dokkyo Medical University School of Medicine, 880 Kita-Kobayashi, Mibu, 321-0293, Tochigi, Japan.
| | - Daisuke Taguchi
- Department of Histology and Neurobiology, Dokkyo Medical University School of Medicine, 880 Kita-Kobayashi, Mibu, 321-0293, Tochigi, Japan
- Department of Judo Therapy, Faculty of Medical Technology, Teikyo University, 1-1 Toyosatodai, Utsunomiya-shi, 320-8551, Tochigi, Japan
| | - Kazuhiko Nakadate
- Department of Basic Science, Educational and Research Center for Pharmacy , Meiji Pharmaceutical University , 2-522-1 Noshio, Kiyose-shi, 204- 8588, Tokyo, Japan
| | - Shuichi Ueda
- Department of Histology and Neurobiology, Dokkyo Medical University School of Medicine, 880 Kita-Kobayashi, Mibu, 321-0293, Tochigi, Japan
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Enhanced Biofilm Eradication and Reduced Cytotoxicity of a Novel Polygalacturonic and Caprylic Acid Wound Ointment Compared with Common Antiseptic Ointments. BIOMED RESEARCH INTERNATIONAL 2021; 2021:2710484. [PMID: 33708989 PMCID: PMC7932769 DOI: 10.1155/2021/2710484] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 12/11/2020] [Accepted: 02/11/2021] [Indexed: 11/23/2022]
Abstract
Antiseptic wound ointments are widely used to treat dermal wounds that are microbially contaminated. Polygalacturonic acid (PG)+caprylic acid (CAP) is a novel combination that has been shown to eradicate biofilms. We developed a novel PG+CAP ointment and compared the biofilm eradication capability and cytotoxicity of PG+CAP with that of commercially available antiseptic wound ointments. We used a well-established biofilm model to quantitatively assess the eradication of organisms following exposure to the wound ointments for 2 hours. PG+CAP ointment completely eradicated Candida albicans, multidrug-resistant Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus biofilms, whereas MediHoney, polyhexamethylene biguanide (PHMB), and benzalkonium chloride (BZK) ointments failed to eradicate all biofilms within 2 hours. We assessed cytotoxicity by exposing L-929 fibroblasts to extracts of each ointment; Trypan blue exclusion was used to assess cell viability, and Alamar blue conversion was used to assess metabolic function. After exposure to PG+CAP and MediHoney, fibroblast viability was 96.23% and 95.23%, respectively (Trypan blue), and was comparable to untreated cells (98.77%). PHMB and BZK showed reduced viability (83.25% and 77.83%, respectively, p < 0.05). Metabolic activity results followed a similar pattern. Cytotoxicity of PG+CAP ointment towards erythrocytes was comparable to saline. PG+CAP ointment seems to be safe and can rapidly eradicate microbial biofilm; thus, PG+CAP ointment merits further in vivo testing as a potential antimicrobial wound ointment.
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Abboud KY, Reis SK, Martelli ME, Zordão OP, Tannihão F, de Souza AZZ, Assalin HB, Guadagnini D, Rocha GZ, Saad MJA, Prada PO. Oral Glutamine Supplementation Reduces Obesity, Pro-Inflammatory Markers, and Improves Insulin Sensitivity in DIO Wistar Rats and Reduces Waist Circumference in Overweight and Obese Humans. Nutrients 2019; 11:nu11030536. [PMID: 30832230 PMCID: PMC6471297 DOI: 10.3390/nu11030536] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 02/18/2019] [Accepted: 02/24/2019] [Indexed: 12/16/2022] Open
Abstract
In the present study, we aimed to investigate whether chronic oral glutamine (Gln) supplementation may alter metabolic parameters and the inflammatory profile in overweight and obese humans as well as whether Gln may modulate molecular pathways in key tissues linked to the insulin action in rats. Thirty-nine overweight/obese volunteers received 30 g of Gln or alanine (Ala-control) for 14 days. Body weight (BW), waist circumference (WC), hormones, and pro-inflammatory markers were evaluated. To investigate molecular mechanisms, Gln or Ala was given to Wistar rats on a high-fat diet (HFD), and metabolic parameters, euglycemic hyperinsulinemic clamp with tracers, and Western blot were done. Gln reduced WC and serum lipopolysaccharide (LPS) in overweight volunteers. In the obese group, Gln diminished WC and serum insulin. There was a positive correlation between the reduction on WC and LPS. In rats on HFD, Gln reduced adiposity, improved insulin action and signaling, and reversed both defects in glucose metabolism in the liver and muscle. Gln supplementation increased muscle glucose uptake and reversed the increased hepatic glucose production, in parallel with a reduced glucose uptake in adipose tissue. This insulin resistance in AT was accompanied by enhanced IRS1 O-linked-glycosamine association in this tissue, but not in the liver and muscle. These data suggest that Gln supplementation leads to insulin resistance specifically in adipose tissue via the hexosamine pathway and reduces adipose mass, which is associated with improvement in the systemic insulin action. Thus, further investigation with Gln supplementation should be performed for longer periods in humans before prescribing as a beneficial therapeutic approach for individuals who are overweight and obese.
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Affiliation(s)
- Kahlile Youssef Abboud
- School of Applied Sciences, State University of Campinas (UNICAMP), Limeira 13484-350 SP, Brazil.
| | - Sabrina Karen Reis
- School of Applied Sciences, State University of Campinas (UNICAMP), Limeira 13484-350 SP, Brazil.
| | - Maria Eduarda Martelli
- School of Applied Sciences, State University of Campinas (UNICAMP), Limeira 13484-350 SP, Brazil.
| | - Olivia Pizetta Zordão
- Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas 13083-887 SP, Brazil.
| | - Fabiana Tannihão
- School of Applied Sciences, State University of Campinas (UNICAMP), Limeira 13484-350 SP, Brazil.
| | | | - Heloisa Balan Assalin
- Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas 13083-887 SP, Brazil.
| | - Dioze Guadagnini
- Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas 13083-887 SP, Brazil.
| | - Guilherme Zweig Rocha
- Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas 13083-887 SP, Brazil.
| | - Mario Jose Abdalla Saad
- Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas 13083-887 SP, Brazil.
| | - Patricia Oliveira Prada
- School of Applied Sciences, State University of Campinas (UNICAMP), Limeira 13484-350 SP, Brazil.
- Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas 13083-887 SP, Brazil.
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Royal jelly supplementation reduces skeletal muscle lipotoxicity and insulin resistance in aged obese rats. ACTA ACUST UNITED AC 2018; 25:307-315. [PMID: 29960833 DOI: 10.1016/j.pathophys.2018.05.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 04/28/2018] [Accepted: 05/03/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Consumption of a high-fat diet (HFD) in aged rats is associated with several metabolic disorders. The mechanism of skeletal muscle lipotoxicity and insulin resistance (IR) is multi-factorial, but the exact mechanism of how aging affects these processes unknown. Royal jelly (RJ) is a dietary supplement with many physiological and pharmacological properties. No previous studies have demonstrated the protective effects and mechanism of RJ in aged obese rats. OBJECTIVES The study was carried to investigate the effects of aging and HFD on skeletal muscles, and adipose tissue metabolism and inflammation, in aged rats, and whether RJ could combat such adverse effects. METHODOLOGY A total of 40 male rats were divided into5 groups; young rats fed a standard diet, aged rats fed a standard diet, aged rats fed RJ, aged rats fed a HFD, and aged rats fed both a HFD and RJ for 8 weeks. We investigated changes in body weights (BW), abdominal fat weights, total cholesterol, triglycerides (TG), low density lipoprotein-cholesterol (LDL-c), high density lipoprotein-cholesterol (HDL-c), muscle TG, and IR levels. Also, concentrations of TNF-α receptor 1(TNFR1) were estimated in the serum and adipose tissues. RESULTS Aged, obese rats showed increased BW, adipose weights, IR, and disturbed serum and muscle lipids. Also, TNFR1 was increased. Rats fed RJ showed decreased adiposity, improved lipids' profiles, improved IR, and decreased TNFR1. CONCLUSION Aging and HFD were associated with disturbed metabolism, and muscle lipotoxicity and inflammation, while RJ could counteract muscle lipotoxicity in rats and reduce IR, most likely due to an anti-inflammatory effect.
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Fiamoncini J, Rundle M, Gibbons H, Thomas EL, Geillinger-Kästle K, Bunzel D, Trezzi JP, Kiselova-Kaneva Y, Wopereis S, Wahrheit J, Kulling SE, Hiller K, Sonntag D, Ivanova D, van Ommen B, Frost G, Brennan L, Bell J, Daniel H. Plasma metabolome analysis identifies distinct human metabotypes in the postprandial state with different susceptibility to weight loss-mediated metabolic improvements. FASEB J 2018; 32:5447-5458. [PMID: 29718708 DOI: 10.1096/fj.201800330r] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Health has been defined as the capability of the organism to adapt to challenges. In this study, we tested to what extent comprehensively phenotyped individuals reveal differences in metabolic responses to a standardized mixed meal tolerance test (MMTT) and how these responses change when individuals experience moderate weight loss. Metabolome analysis was used in 70 healthy individuals. with profiling of ∼300 plasma metabolites during an MMTT over 8 h. Multivariate analysis of plasma markers of fatty acid catabolism identified 2 distinct metabotype clusters (A and B). Individuals from metabotype B showed slower glucose clearance, had increased intra-abdominal adipose tissue mass and higher hepatic lipid levels when compared with individuals from metabotype A. An NMR-based urine analysis revealed that these individuals also to have a less healthy dietary pattern. After a weight loss of ∼5.6 kg over 12 wk, only the subjects from metabotype B showed positive changes in the glycemic response during the MMTT and in markers of metabolic diseases. Our study in healthy individuals demonstrates that more comprehensive phenotyping can reveal discrete metabotypes with different outcomes in a dietary intervention and that markers of lipid catabolism in plasma could allow early detection of the metabolic syndrome.-Fiamoncini, J., Rundle, M., Gibbons, H., Thomas, E. L., Geillinger-Kästle, K., Bunzel, D., Trezzi, J.-P., Kiselova-Kaneva, Y., Wopereis, S., Wahrheit, J., Kulling, S. E., Hiller, K., Sonntag, D., Ivanova, D., van Ommen, B., Frost, G., Brennan, L., Bell, J. Daniel, H. Plasma metabolome analysis identifies distinct human metabotypes in the postprandial state with different susceptibility to weight loss-mediated metabolic improvements.
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Affiliation(s)
- Jarlei Fiamoncini
- Department of Food and Nutrition, Technische Universität München, Freising-Weihenstephan, Germany
| | - Milena Rundle
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom
| | - Helena Gibbons
- University College Dublin (UCD) School of Agriculture and Food Science, Institute of Food and Health, Dublin, Ireland
| | - E Louise Thomas
- Research Centre for Optimal Health, Department of Life Sciences, University of Westminster, London, United Kingdom
| | | | - Diana Bunzel
- Department of Safety and Quality of Fruit and Vegetables, Max Rubner Institut, Karlsruhe, Germany
| | - Jean-Pierre Trezzi
- Integrated Biobank of Luxembourg, Dudelange, Luxembourg.,Centre for Systems Biomedicine, Esch-sur-Alzette, Luxembourg
| | - Yoana Kiselova-Kaneva
- Department of Biochemistry, Molecular Medicine, and Nutrigenomics, Medical University-Varna, Varna, Bulgaria
| | - Suzan Wopereis
- Department of Microbiology and Systems Biology, Netherlands Organization for Applied Scientific Research (TNO), Zeist, The Netherlands
| | | | - Sabine E Kulling
- Department of Safety and Quality of Fruit and Vegetables, Max Rubner Institut, Karlsruhe, Germany
| | - Karsten Hiller
- Braunschweig Integrated Centre of Systems Biology, University of Braunschweig, Braunschweig, Germany.,Department of Computational Biology of Infection Research, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Denise Sonntag
- Department of Microbiology and Systems Biology, Netherlands Organization for Applied Scientific Research (TNO), Zeist, The Netherlands
| | - Diana Ivanova
- Department of Biochemistry, Molecular Medicine, and Nutrigenomics, Medical University-Varna, Varna, Bulgaria
| | - Ben van Ommen
- Department of Microbiology and Systems Biology, Netherlands Organization for Applied Scientific Research (TNO), Zeist, The Netherlands
| | - Gary Frost
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom
| | - Lorraine Brennan
- University College Dublin (UCD) School of Agriculture and Food Science, Institute of Food and Health, Dublin, Ireland
| | - Jimmy Bell
- Research Centre for Optimal Health, Department of Life Sciences, University of Westminster, London, United Kingdom
| | - Hannelore Daniel
- Department of Food and Nutrition, Technische Universität München, Freising-Weihenstephan, Germany
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Abstract
The most common cause of death among adults with diabetes is cardiovascular disease (CVD). In this concise review on pathogenesis of CVD in diabetes, the 4 common conditions, atherosclerosis, microangiopathy, diabetic cardiomyopathy, and cardiac autonomic neuropathy, are explored and illustrated to be caused by interrelated pathogenetic factors. Each of these diagnoses can present alone or, commonly, along with others due to overlapping pathophysiology. Although the spectrum of physiologic abnormalities that characterize the diabetes milieu is broad and go beyond hyperglycemia, the authors highlight the most relevant evidence supporting the current knowledge of potent factors that contribute to CVD in diabetes.
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Affiliation(s)
- Andrea V Haas
- Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA
| | - Marie E McDonnell
- Diabetes Section, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Room 381, Boston, MA 02115, USA.
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Short-term treatment with metformin reduces hepatic lipid accumulation but induces liver inflammation in obese mice. Inflammopharmacology 2018; 26:1103-1115. [PMID: 29450671 DOI: 10.1007/s10787-018-0443-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 01/12/2018] [Indexed: 12/11/2022]
Abstract
The study aimed to evaluate the metabolic and inflammatory effects of short-term treatments (10 days) with metformin (MET) on the NAFLD caused by a high-fat diet (HFD) in C57BL/6 mice. After the treatment, histological liver slices were obtained, hepatocytes and macrophages were extracted and cultured with phosphate buffered saline, LPS (2.5 µg/mL) and MET (1 µM) for 24 h. Cytokine levels were determined by ELISA. NAFLD caused by the HFD was partially reduced by MET. The lipid accumulation induced by the HFD was not associated with liver inflammation; however, MET seemed to promote pro-inflammatory effects in liver, since it increased hepatic concentration of IL-1β, TNF-α, IL-6, MCP-1 and IFN-γ. Similarly, MET increased the concentration of IL-1β, IL-6 in hepatocyte cultures. However, in macrophages culture, MET lowered levels of IL-1β, IL-6 and TNF-α stimulated by LPS. Overall, MET reduced liver NAFLD but promoted hepatocyte increase in pro-inflammatory cytokines, thus, leading to liver inflammation.
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Kuwabara WMT, Panveloski-Costa AC, Yokota CNF, Pereira JNB, Filho JM, Torres RP, Hirabara SM, Curi R, Alba-Loureiro TC. Comparison of Goto-Kakizaki rats and high fat diet-induced obese rats: Are they reliable models to study Type 2 Diabetes mellitus? PLoS One 2017; 12:e0189622. [PMID: 29220408 PMCID: PMC5722336 DOI: 10.1371/journal.pone.0189622] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 11/29/2017] [Indexed: 02/07/2023] Open
Abstract
Type 2 Diabetes mellitus (T2DM) is an evident growing disease that affects different cultures throughout the world. T2DM occurs under the influence of three main factors: the genetic background, environmental and behavioral components. Obesity is strongly associated to the development of T2DM in the occident, while in the orient most of the diabetic patients are considered lean. Genetics may be a key factor in the development of T2DM in societies where obesity is not a recurrent public health problem. Herein, two different models of rats were used to understand their differences and reliability as experimental models to study the pathophysiology of T2DM, in two different approaches: the genetic (GK rats) and the environmental (HFD-induced obese rats) influences. GK rats were resistant to weight gain even though food/energy consumption (relative to body weight) was higher in this group. HFD, on the other hand, induced obesity in Wistar rats. White adipose tissue (WAT) expansion in this group was accompanied by immune cells infiltration, inflammation and insulin resistance. GK rats also presented WAT inflammation and insulin resistance; however, no immune cells infiltration was observed in the WAT of this group. Liver of HFD group presented fat accumulation without differences in inflammatory cytokines content, while liver of GK rats didn't present fat accumulation, but showed an increase of IL-6 and IL-10 content and glycogen. Also, GK rats showed increased plasma GOT and GPT. Soleus muscle of HFD presented normal insulin signaling, contrary to GK rats, which presented higher content of basal phosphorylation of GSK-3β. Our results demonstrated that HFD developed a mild insulin resistance in Wistar rats, but was not sufficient to develop T2DM. In contrast, GK rats presented all the typical hallmarks of T2DM, such as insulin resistance, defective insulin production, fasting hyperglycemia/hyperinsulinemia and lipid plasma alteration. Thus, on the given time point of this study, we may conclude that only GK rats shown to be a reliable model to study T2DM.
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Affiliation(s)
| | - Ana Carolina Panveloski-Costa
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | | | - Joice Naiara Bertaglia Pereira
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
- Cruzeiro do Sul University, São Paulo, Brazil
| | - Jorge Mancini Filho
- Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | | | | | - Rui Curi
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
- Cruzeiro do Sul University, São Paulo, Brazil
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12
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Loureiro R, Mesquita KA, Magalhães-Novais S, Oliveira PJ, Vega-Naredo I. Mitochondrial biology in cancer stem cells. Semin Cancer Biol 2017; 47:18-28. [DOI: 10.1016/j.semcancer.2017.06.012] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Revised: 06/24/2017] [Accepted: 06/27/2017] [Indexed: 02/06/2023]
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13
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Theunissen TEJ, Gerards M, Hellebrekers DMEI, van Tienen FH, Kamps R, Sallevelt SCEH, Hartog ENMMD, Scholte HR, Verdijk RM, Schoonderwoerd K, de Coo IFM, Szklarczyk R, Smeets HJM. Selection and Characterization of Palmitic Acid Responsive Patients with an OXPHOS Complex I Defect. Front Mol Neurosci 2017; 10:336. [PMID: 29093663 PMCID: PMC5651253 DOI: 10.3389/fnmol.2017.00336] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 10/03/2017] [Indexed: 12/19/2022] Open
Abstract
Mitochondrial disorders are genetically and clinically heterogeneous, mainly affecting high energy-demanding organs due to impaired oxidative phosphorylation (OXPHOS). Currently, effective treatments for OXPHOS defects, with complex I deficiency being the most prevalent, are not available. Yet, clinical practice has shown that some complex I deficient patients benefit from a high-fat or ketogenic diet, but it is unclear how these therapeutic diets influence mitochondrial function and more importantly, which complex I patients could benefit from such treatment. Dietary studies in a complex I deficient patient with exercise intolerance showed increased muscle endurance on a high-fat diet compared to a high-carbohydrate diet. We performed whole-exome sequencing to characterize the genetic defect. A pathogenic homozygous p.G212V missense mutation was identified in the TMEM126B gene, encoding an early assembly factor of complex I. A complementation study in fibroblasts confirmed that the p.G212V mutation caused the complex I deficiency. The mechanism turned out to be an incomplete assembly of the peripheral arm of complex I, leading to a decrease in the amount of mature complex I. The patient clinically improved on a high-fat diet, which was supported by the 25% increase in maximal OXPHOS capacity in TMEM126B defective fibroblast by the saturated fatty acid palmitic acid, whereas oleic acid did not have any effect in those fibroblasts. Fibroblasts of other patients with a characterized complex I gene defect were tested in the same way. Patient fibroblasts with complex I defects in NDUFS7 and NDUFAF5 responded to palmitic acid, whereas ACAD9, NDUFA12, and NDUFV2 defects were non-responding. Although the data are too limited to draw a definite conclusion on the mechanism, there is a tendency that protein defects involved in early assembly complexes, improve with palmitic acid, whereas proteins defects involved in late assembly, do not. Our data show at a clinical and biochemical level that a high fat diet can be beneficial for complex I patients and that our cell line assay will be an easy tool for the selection of patients, who might potentially benefit from this therapeutic diet.
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Affiliation(s)
- Tom E J Theunissen
- Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, Netherlands.,Department of Genetics and Cell Biology, School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Mike Gerards
- Maastricht Centre for Systems Biology, Maastricht University, Maastricht, Netherlands
| | | | - Florence H van Tienen
- Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Rick Kamps
- Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Suzanne C E H Sallevelt
- Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, Netherlands
| | | | - Hans R Scholte
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands
| | - Robert M Verdijk
- Department of Pathology, Erasmus Medical Center, Rotterdam, Netherlands
| | - Kees Schoonderwoerd
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands
| | | | - Radek Szklarczyk
- Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Hubert J M Smeets
- Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, Netherlands.,Department of Genetics and Cell Biology, School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, Netherlands.,Maastricht Centre for Systems Biology, Maastricht University, Maastricht, Netherlands
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14
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Rosenblatt J, Reitzel RA, Vargas-Cruz N, Chaftari AM, Hachem R, Raad I. Caprylic and Polygalacturonic Acid Combinations for Eradication of Microbial Organisms Embedded in Biofilm. Front Microbiol 2017; 8:1999. [PMID: 29093703 PMCID: PMC5651231 DOI: 10.3389/fmicb.2017.01999] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 09/28/2017] [Indexed: 12/29/2022] Open
Abstract
There is a need for non-antibiotic, antimicrobial compositions with low toxicity capable of broad-spectrum eradication of pathogenic biofilms in food preparation and healthcare settings. In this study we demonstrated complete biofilm eradication within 60 min with synergistic combinations of caprylic and polygalacturonic (PG) acids in an in vitro biofilm eradication model against representative hospital and foodborne infectious pathogen biofilms (methicillin-resistant Staphylococcus aureus, multidrug-resistant Pseudomonas aeruginosa, Candida albicans, Escherichia coli, and Salmonella enteritidis). Antimicrobial synergy against biofilms was demonstrated by quantifying viable organisms remaining in biofilms exposed to caprylic acid alone, PG acid alone, or combinations of the two. The combinations also synergistically inhibited growth of planktonic organisms. Toxicity of the combination was assessed in vitro on L929 fibroblasts incubated with extracts of caprylic and PG acid combinations using the Alamar Blue metabolic activity assay and the Trypan Blue exclusion cell viability assay. The extracts did not produce cytotoxic responses relative to untreated control fibroblasts.
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Affiliation(s)
- Joel Rosenblatt
- Department of Infectious Diseases, Infection Control & Employee Health, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ruth A Reitzel
- Department of Infectious Diseases, Infection Control & Employee Health, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Nylev Vargas-Cruz
- Department of Infectious Diseases, Infection Control & Employee Health, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Anne-Marie Chaftari
- Department of Infectious Diseases, Infection Control & Employee Health, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ray Hachem
- Department of Infectious Diseases, Infection Control & Employee Health, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Issam Raad
- Department of Infectious Diseases, Infection Control & Employee Health, University of Texas MD Anderson Cancer Center, Houston, TX, United States
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Oleate Prevents Palmitate-Induced Atrophy via Modulation of Mitochondrial ROS Production in Skeletal Myotubes. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:2739721. [PMID: 28947926 PMCID: PMC5602654 DOI: 10.1155/2017/2739721] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 07/26/2017] [Accepted: 08/08/2017] [Indexed: 12/25/2022]
Abstract
Accumulation of saturated fatty acids contributes to lipotoxicity-related insulin resistance and atrophy in skeletal muscle. Conversely, unsaturated fatty acids like docosahexaenoic acid were proven to preserve muscle mass. However, it is not known if the most common unsaturated oleate will protect skeletal myotubes against palmitate-mediated atrophy, and its specific mechanism remains to be elucidated. Therefore, we investigated the effects of oleate on atrophy-related factors in palmitate-conditioned myotubes. Exposure of myotubes to palmitate, but not to oleate, led to an induction of fragmented nuclei, myotube loss, atrophy, and mitochondrial superoxide in a dose-dependent manner. Treatment of oleate to myotubes attenuated production of palmitate-induced mitochondrial superoxide in a dose-dependent manner. The treatment of oleate or MitoTEMPO to palmitate-conditioned myotubes led to inhibition of palmitate-induced mRNA expression of proinflammatory (TNF-α and IL6), mitochondrial fission (Drp1 and Fis1), and atrophy markers (myostatin and atrogin1). In accordance with the gene expression data, our immunocytochemistry experiment demonstrated that oleate and MitoTEMPO prevented or attenuated palmitate-mediated myotube shrinkage. These results provide a mechanism indicating that oleate prevents palmitate-mediated atrophy via at least partial modulation of mitochondrial superoxide production.
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Novohradsky V, Zanellato I, Marzano C, Pracharova J, Kasparkova J, Gibson D, Gandin V, Osella D, Brabec V. Epigenetic and antitumor effects of platinum(IV)-octanoato conjugates. Sci Rep 2017. [PMID: 28623355 PMCID: PMC5473904 DOI: 10.1038/s41598-017-03864-w] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
We present the anticancer properties of cis, cis, trans-[Pt(IV)(NH3)2Cl2(OA)2] [Pt(IV)diOA] (OA = octanoato), Pt(IV) derivative of cisplatin containing two OA units appended to the axial positions of a six-coordinate Pt(IV) center. Our results demonstrate that Pt(IV)diOA is a potent cytotoxic agent against many cancer cell lines (the IC50 values are approximately two orders of magnitude lower than those of clinically used cisplatin or Pt(IV) derivatives with biologically inactive axial ligands). Importantly, Pt(IV)diOA overcomes resistance to cisplatin, is significantly more potent than its branched Pt(IV) valproato isomer and exhibits promising in vivo antitumor activity. The potency of Pt(IV)diOA is a consequence of several factors including enhanced cellular accumulation correlating with enhanced DNA platination and cytotoxicity. Pt(IV)diOA induces DNA hypermethylation and reduces mitochondrial membrane potential in cancer cells at levels markedly lower than the IC50 value of free OA suggesting the synergistic action of platinum and OA moieties. Collectively, the remarkable antitumor effects of Pt(IV)diOA are a consequence of the enhanced cellular uptake which makes it possible to simultaneously accumulate high levels of both cisplatin and OA in cells. The simultaneous dual action of cisplatin and OA by different mechanisms in tumor cells may result in a markedly enhanced and unique antitumor effects of Pt(IV) prodrugs.
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Affiliation(s)
- Vojtech Novohradsky
- Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265, Brno, Czech Republic
| | - Ilaria Zanellato
- Dipartimento di Scienze e Innovazione Tecnologica, Universita del Piemonte Orientale, "A. Avogadro"Viale T. Michel 11, 15121, Alessandria, Italy
| | - Cristina Marzano
- Dipartimento di Scienze del Farmaco, Universita di Padova, Via Marzolo 5, 35131, Padova, Italy
| | - Jitka Pracharova
- Department of Biophysics, Centre of the Region Hana for Biotechnological Agricultural Research, Faculty of Science, Palacky University, 17. listopadu 12, CZ-77146, Olomouc, Czech Republic
| | - Jana Kasparkova
- Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265, Brno, Czech Republic
| | - Dan Gibson
- Institute for Drug Research, School of Pharmacy, The Hebrew University, Jerusalem, 91120, Israel
| | - Valentina Gandin
- Dipartimento di Scienze del Farmaco, Universita di Padova, Via Marzolo 5, 35131, Padova, Italy
| | - Domenico Osella
- Dipartimento di Scienze e Innovazione Tecnologica, Universita del Piemonte Orientale, "A. Avogadro"Viale T. Michel 11, 15121, Alessandria, Italy.
| | - Viktor Brabec
- Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265, Brno, Czech Republic.
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17
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de Brito Alves JL, Toscano AE, da Costa-Silva JH, Vidal H, Leandro CG, Pirola L. Transcriptional response of skeletal muscle to a low protein perinatal diet in rat offspring at different ages: The role of key enzymes of glucose-fatty acid oxidation. J Nutr Biochem 2016; 41:117-123. [PMID: 28088654 DOI: 10.1016/j.jnutbio.2016.12.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 10/29/2016] [Accepted: 12/09/2016] [Indexed: 10/20/2022]
Abstract
Skeletal muscle is a plastic tissue during development with distinctive acute and chronic response to maternal protein restriction. This study evaluated gene and protein expression of key-enzymes of glycolytic pathway (HK2, PFK, PDK4 and CS), and fatty acid oxidation (CPT1 and β-HAD) of two different types of skeletal muscle [soleus and extensor digitorium longus (EDL)] from offspring rats at 30 and 90 days of age, exposed to maternal isoenergetic low protein diet throughout gestation and lactation. Pups from dams fed 17% protein diet (n=5, normal protein, Np), and low protein pups from dams fed 8% casein diet (low protein, Lp, n=5) were evaluated. Offspring were sacrificed either 30 or 90 days old. Soleus and EDL were analyzed for mRNA and protein expression by quantitative PCR and western blotting, respectively. Soleus was more affected by Lp maternal diet at 90 days by down-regulation of key enzymes of glycolytic pathway, in particular HK2 and PDK4 with a concomitant reduction of β-HAD mRNA. For EDL, the effects of Lp maternal diet were more pronounced at 30 days, as the transcriptional key enzymes of glycolytic pathway were down-regulated. One important finding was that the observed acute (30 days) transcriptional changes did not remain in adult Lp rats (90 days), except for PDK4. The robust PDK4 mRNA down-regulation, observed in both soleus and EDL, and at both ages, and the consequent down-regulation of the PDK4 protein expression can be responsible for a state of reduced metabolic flexibility of skeletal muscle in response to maternal low protein diet.
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Affiliation(s)
- José Luiz de Brito Alves
- Department of Nutrition, Federal University of Paraiba, Brazil; Carmen (Cardiology, Metabolism and Nutrition) Laboratory; INSERM U1060; Lyon-1 University, South Lyon Medical Faculty; 69921, Oullins, France
| | - Ana Elisa Toscano
- Department of Physical Education and Sport Sciences, Federal University of Pernambuco, Vitoria de Santo Antão, - Pernambuco, 55608-680, Brazil
| | - João Henrique da Costa-Silva
- Department of Physical Education and Sport Sciences, Federal University of Pernambuco, Vitoria de Santo Antão, - Pernambuco, 55608-680, Brazil
| | - Hubert Vidal
- Carmen (Cardiology, Metabolism and Nutrition) Laboratory; INSERM U1060; Lyon-1 University, South Lyon Medical Faculty; 69921, Oullins, France
| | - Carol Góis Leandro
- Department of Physical Education and Sport Sciences, Federal University of Pernambuco, Vitoria de Santo Antão, - Pernambuco, 55608-680, Brazil.
| | - Luciano Pirola
- Carmen (Cardiology, Metabolism and Nutrition) Laboratory; INSERM U1060; Lyon-1 University, South Lyon Medical Faculty; 69921, Oullins, France
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18
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Rogers RS, Morris EM, Wheatley JL, Archer AE, McCoin CS, White KS, Wilson DR, Meers GME, Koch LG, Britton SL, Thyfault JP, Geiger PC. Deficiency in the Heat Stress Response Could Underlie Susceptibility to Metabolic Disease. Diabetes 2016; 65:3341-3351. [PMID: 27554472 PMCID: PMC5079638 DOI: 10.2337/db16-0292] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 08/16/2016] [Indexed: 12/18/2022]
Abstract
Heat treatment (HT) effectively prevents insulin resistance and glucose intolerance in rats fed a high-fat diet (HFD). The positive metabolic actions of heat shock protein 72 (HSP72), which include increased oxidative capacity and enhanced mitochondrial function, underlie the protective effects of HT. The purpose of this study was to test the ability of HSP72 induction to mitigate the effects of consumption of a short-term 3-day HFD in rats selectively bred to be low-capacity runners (LCRs) and high-capacity runners (HCRs)-selective breeding that results in disparate differences in intrinsic aerobic capacity. HCR and LCR rats were fed a chow or HFD for 3 days and received a single in vivo HT (41°C, for 20 min) or sham treatment (ST). Blood, skeletal muscles, liver, and adipose tissues were harvested 24 h after HT/ST. HT decreased blood glucose levels, adipocyte size, and triglyceride accumulation in liver and muscle and restored insulin sensitivity in glycolytic muscles from LCR rats. As expected, HCR rats were protected from the HFD. Importantly, HSP72 induction was decreased in LCR rats after only 3 days of eating the HFD. Deficiency in the highly conserved stress response mediated by HSPs could underlie susceptibility to metabolic disease with low aerobic capacity.
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Affiliation(s)
- Robert S Rogers
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS
| | - E Matthew Morris
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS
| | - Joshua L Wheatley
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS
| | - Ashley E Archer
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS
| | - Colin S McCoin
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS
| | - Kathleen S White
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS
| | - David R Wilson
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS
| | - Grace M E Meers
- Department of Medicine-Gastroenterology and Hepatology, University of Missouri, Columbia, MO
| | - Lauren G Koch
- Department of Anesthesiology, University of Michigan, Ann Arbor, MI
| | - Steven L Britton
- Department of Anesthesiology, University of Michigan, Ann Arbor, MI
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - John P Thyfault
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS
- Research Service, Kansas City VA Medical Center, Kansas City, MO
| | - Paige C Geiger
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS
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Tumova J, Malisova L, Andel M, Trnka J. Protective Effect of Unsaturated Fatty Acids on Palmitic Acid-Induced Toxicity in Skeletal Muscle Cells is not Mediated by PPARδ Activation. Lipids 2015; 50:955-64. [DOI: 10.1007/s11745-015-4058-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 07/22/2015] [Indexed: 11/28/2022]
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Grabiec K, Milewska M, Błaszczyk M, Gajewska M, Grzelkowska-Kowalczyk K. Palmitate exerts opposite effects on proliferation and differentiation of skeletal myoblasts. Cell Biol Int 2015; 39:1044-52. [PMID: 25857830 DOI: 10.1002/cbin.10477] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 03/31/2015] [Indexed: 12/27/2022]
Abstract
The purpose of the study was to examine mechanisms controlling cell cycle progression/arrest and differentiation of mouse C2C12 myoblasts exposed to long-chain saturated fatty acid salt, palmitate. Treatment of proliferating myoblasts with palmitate (0.1 mmol/l) markedly decreased myoblast number. Cyclin A and cyclin D1 levels decreased, whereas total p21 and p21 complexed with cyclin-dependent kinase-4 (cdk4) increased in myoblasts treated with palmitate. In cells induced to differentiation addition of palmitate augmented the level of cyclin D3, the early (myogenin) and late (α-actinin, myosin heavy chain) markers of myogenesis, and caused an increase of myotube diameter. In conclusion, exposure to palmitate inhibits proliferation of myoblasts through a decrease in cyclin A and cyclin D1 levels and an increase of p21-cdk4 complex formation; however, it promotes cell cycle exit, myogenic differentiation and myotube growth.
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Affiliation(s)
- Kamil Grabiec
- Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences (SGGW), Nowoursynowska 159, 02-776, Warsaw, Poland
| | - Marta Milewska
- Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences (SGGW), Nowoursynowska 159, 02-776, Warsaw, Poland
| | - Maciej Błaszczyk
- Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences (SGGW), Nowoursynowska 159, 02-776, Warsaw, Poland
| | - Małgorzata Gajewska
- Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences (SGGW), Nowoursynowska 159, 02-776, Warsaw, Poland
| | - Katarzyna Grzelkowska-Kowalczyk
- Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences (SGGW), Nowoursynowska 159, 02-776, Warsaw, Poland
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21
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Caprylic acid and glyceryl trinitrate combination for eradication of biofilm. Antimicrob Agents Chemother 2014; 59:1786-8. [PMID: 25534725 DOI: 10.1128/aac.04561-14] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
There is a growing need for biocompatible, broad-spectrum, nonantibiotic, antimicrobial treatments because of the frequent ineffectiveness of antibiotics against biofilms and the increasing incidence of antibiotic resistance. In this study, we demonstrate rapid and complete biofilm eradication in an in vitro model with synergistic combinations of glyceryl trinitrate and caprylic acid against resistant Gram-positive, Gram-negative, and fungal biofilms.
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Diet-induced obesity mediates a proinflammatory response in pancreatic β cell via toll-like receptor 4. Cent Eur J Immunol 2014; 39:306-15. [PMID: 26155140 PMCID: PMC4439999 DOI: 10.5114/ceji.2014.45940] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Accepted: 06/09/2014] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptor 4 has an important role in inflammation and immunity. Whether TLR4 signaling contributes to the link between insulin resistance and islet β cell dysfunction is an unanswered question. Here, we show that in the face of the same high-fat continuous stimulation for 24 weeks, in TLR4–/– HF mice, the weight, fraction of the liver, epididymal fat pad fraction, as well as blood glucose and insulin levels were lower than in the WT HF group. In TLR4–/– HF mice, the O2 consumption, CO2 production and activities were higher than in the WT HF group. Glucose tolerance test, insulin tolerance test and insulin release test suggest that the impaired insulin secretion was significantly improved in TLR4–/– HF mice, compared with the WT HF group. In TLR4–/– HF mice, islet β cell ultrastructure was not damaged in the face of the same high-fat continuous stimulation, compared to that in the WT HF group. By detecting glucose-stimulated insulin secretion in the primary islet, insulin secretion of TLR4–/– HF mice was better than that of the WT HF group, and in the TLR4–/– HF group, at the mRNA level, islet interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and monocyte chemotactic protein 1 (MCP-1) were significantly lower than in the WT HF group. There was the islet macrophage infiltration in the WT HF group, but no significant macrophage infiltration in the TLR4–/– HF group. These data suggest that the damaged islet functions of the high fat diet-induced obesity mice may be linked to the TLR4 expression level, and the recruitment of macrophages into the islets.
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Palmitic acid and oleic acid differentially regulate choline transporter-like 1 levels and glycerolipid metabolism in skeletal muscle cells. Lipids 2014; 49:731-44. [PMID: 24972900 DOI: 10.1007/s11745-014-3925-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Accepted: 06/16/2014] [Indexed: 12/20/2022]
Abstract
Choline is an essential nutrient required for the biosynthesis of membrane lipid phosphatidylcholine (PtdCho). Here we elucidate the mechanism of how palmitic acid (PAM) and oleic acid (OLA) regulate choline transporter-like protein 1 (CTL1/SLC44A1) function. We evaluated the mechanism of extracellular and intracellular transport of choline, and their contribution to PtdCho and other glycerolipid-diacylglycerol (DAG) and triacylglycerol (TAG) homeostasis in differentiated skeletal muscle cells. PAM reduces total and plasma membrane CTL1/SLC44A1 protein by lysosomal degradation, and limits the choline uptake while increasing DAG and TAG synthesis. OLA maintains total and plasma membrane CTL1/SLC44A1, but increases PtdCho synthesis more than PAM. OLA does not increase the rate of DAG synthesis, but does increase TAG content. Thus, the CTL1/SLC44A1 presence at the plasma membrane regulates choline requirements in accordance with the type of fatty acid. The increased PtdCho and TAG turnover by OLA stimulates cell growth and offers a specific protection mechanism from the excess of intracellular DAG and autophagy. This protection was present after OLA treatments, but not after PAM treatments. The mitochondrial choline uptake was reduced by both FA; however, the regulation is complex and guided not only by the presence of the mitochondrial CTL1/SLC44A1 protein but also by the membrane potential and general mitochondrial function.
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Dimitropoulos G, Tahrani AA, Stevens MJ. Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes 2014; 5:17-39. [PMID: 24567799 PMCID: PMC3932425 DOI: 10.4239/wjd.v5.i1.17] [Citation(s) in RCA: 188] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 12/02/2013] [Accepted: 12/12/2013] [Indexed: 02/05/2023] Open
Abstract
Cardiac autonomic neuropathy (CAN) is an often overlooked and common complication of diabetes mellitus. CAN is associated with increased cardiovascular morbidity and mortality. The pathogenesis of CAN is complex and involves a cascade of pathways activated by hyperglycaemia resulting in neuronal ischaemia and cellular death. In addition, autoimmune and genetic factors are involved in the development of CAN. CAN might be subclinical for several years until the patient develops resting tachycardia, exercise intolerance, postural hypotension, cardiac dysfunction and diabetic cardiomyopathy. During its sub-clinical phase, heart rate variability that is influenced by the balance between parasympathetic and sympathetic tones can help in detecting CAN before the disease is symptomatic. Newer imaging techniques (such as scintigraphy) have allowed earlier detection of CAN in the pre-clinical phase and allowed better assessment of the sympathetic nervous system. One of the main difficulties in CAN research is the lack of a universally accepted definition of CAN; however, the Toronto Consensus Panel on Diabetic Neuropathy has recently issued guidance for the diagnosis and staging of CAN, and also proposed screening for CAN in patients with diabetes mellitus. A major challenge, however, is the lack of specific treatment to slow the progression or prevent the development of CAN. Lifestyle changes, improved metabolic control might prevent or slow the progression of CAN. Reversal will require combination of these treatments with new targeted therapeutic approaches. The aim of this article is to review the latest evidence regarding the epidemiology, pathogenesis, manifestations, diagnosis and treatment for CAN.
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Cheon HG, Cho YS. Protection of palmitic acid-mediated lipotoxicity by arachidonic acid via channeling of palmitic acid into triglycerides in C2C12. J Biomed Sci 2014; 21:13. [PMID: 24521082 PMCID: PMC3926261 DOI: 10.1186/1423-0127-21-13] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Accepted: 02/10/2014] [Indexed: 01/22/2023] Open
Abstract
Background Excessive saturated fatty acids have been considered to be one of major contributing factors for the dysfunction of skeletal muscle cells as well as pancreatic beta cells, leading to the pathogenesis of type 2 diabetes. Results PA induced cell death in a dose dependent manner up to 1.5 mM, but AA protected substantially lipotoxicity caused by PA at even low concentration of 62 μM, at which monounsaturated fatty acids including palmitoleic acid (POA) and oleic acid (OA) did not protect as much as AA did. Induction of cell death by PA was resulted from mitochondrial membrane potential loss, and AA effectively blocked the progression of apoptosis. Furthermore, AA rescued significantly PA-impaired glucose uptake and -signal transduction of Akt in response to insulin. Based on the observations that polyunsaturated AA generated competently cellular droplets at low concentration within the cytosol of myotubes compared with other monounsaturated fatty acids, and AA-driven lipid droplets were also enhanced in the presence of PA, we hypothesized that incorporation of harmful PA into inert triglyceride (TG) may be responsible for the protective effects of AA against PA-induced lipotoxicity. To address this assumption, C2C12 myotubes were incubated with fluorescent probed-PA analogue 4, 4-difluoro-5, 7-dimethyl-4-boro-3a,4a-diaza-s-indacene-3-hexadecanoic acid (BODIPY FL C16) in the presence of AA and their subsequent lipid profiles were analyzed. The analyses of lipids on thin layer chromatograpy (TLC) showed that fluorescent PA analogue was rapidly channeled into AA-driven TG droplets. Conclusion Taken together, it is proposed that AA diverts PA into inert TG, therefore reducing the availability of harmful PA into intracellular target molecules.
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Affiliation(s)
| | - Young Sik Cho
- College of Pharmacy, Keimyung University, 1000 Sindang-dong, Dalseo-gu, Daegu 704-701, South Korea.
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Oxidative Stress and Cardiovascular Disease in Diabetes. OXIDATIVE STRESS IN APPLIED BASIC RESEARCH AND CLINICAL PRACTICE 2014. [DOI: 10.1007/978-1-4899-8035-9_11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Barbosa MR, Sampaio IH, Teodoro BG, Sousa TA, Zoppi CC, Queiroz AL, Passos MA, Alberici LC, Teixeira FR, Manfiolli AO, Batista TM, Cappelli APG, Reis RI, Frasson D, Kettelhut IC, Parreiras-e-Silva LT, Costa-Neto CM, Carneiro EM, Curi R, Silveira LR. Hydrogen peroxide production regulates the mitochondrial function in insulin resistant muscle cells: effect of catalase overexpression. Biochim Biophys Acta Mol Basis Dis 2013; 1832:1591-604. [PMID: 23643711 DOI: 10.1016/j.bbadis.2013.04.029] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2012] [Revised: 03/29/2013] [Accepted: 04/11/2013] [Indexed: 01/06/2023]
Abstract
The mitochondrial redox state plays a central role in the link between mitochondrial overloading and insulin resistance. However, the mechanism by which the ROS induce insulin resistance in skeletal muscle cells is not completely understood. We examined the association between mitochondrial function and H2O2 production in insulin resistant cells. Our hypothesis is that the low mitochondrial oxygen consumption leads to elevated ROS production by a mechanism associated with reduced PGC1α transcription and low content of phosphorylated CREB. The cells were transfected with either the encoded sequence for catalase overexpression or the specific siRNA for catalase inhibition. After transfection, myotubes were incubated with palmitic acid (500μM) and the insulin response, as well as mitochondrial function and fatty acid metabolism, was determined. The low mitochondrial oxygen consumption led to elevated ROS production by a mechanism associated with β-oxidation of fatty acids. Rotenone was observed to reduce the ratio of ROS production. The elevated H2O2 production markedly decreased the PGC1α transcription, an effect that was accompanied by a reduced phosphorylation of Akt and CREB. The catalase transfection prevented the reduction in the phosphorylated level of Akt and upregulated the levels of phosphorylated CREB. The mitochondrial function was elevated and H2O2 production reduced, thus increasing the insulin sensitivity. The catalase overexpression improved mitochondrial respiration protecting the cells from fatty acid-induced, insulin resistance. This effect indicates that control of hydrogen peroxide production regulates the mitochondrial respiration preventing the insulin resistance in skeletal muscle cells by a mechanism associated with CREB phosphorylation and β-oxidation of fatty acids.
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Affiliation(s)
- Marina R Barbosa
- Department of Biochemistry and Immunology, University of Sao Paulo, Ribeirão Preto, Brazil
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Hirabara SM, Folador A, Fiamoncini J, Lambertucci RH, Rodrigues CF, Rocha MS, Aikawa J, Yamazaki RK, Martins AR, Rodrigues AC, Carpinelli AR, Pithon-Curi TC, Fernandes LC, Gorjão R, Curi R. Fish oil supplementation for two generations increases insulin sensitivity in rats. J Nutr Biochem 2012; 24:1136-45. [PMID: 23246156 DOI: 10.1016/j.jnutbio.2012.08.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2012] [Revised: 08/13/2012] [Accepted: 08/20/2012] [Indexed: 11/26/2022]
Abstract
We investigated the effect of fish oil supplementation for two consecutive generations on insulin sensitivity in rats. After the nursing period (21 days), female rats from the same prole were divided into two groups: (a) control group and (b) fish oil group. Female rats were supplemented with water (control) or fish oil at 1 g/kg body weight as a single bolus for 3 months. After this period, female rats were mated with male Wistar rats fed on a balanced chow diet (not supplemented). Female rats continued to receive supplementation throughout gestation and lactation periods. The same treatment was performed for the next two generations (G1 and G2). At 75 days of age, male offspring from G1 and G2 generations from both groups were used in the experiments. G1 rats did not present any difference with control rats. However, G2 rats presented reduction in glycemia and lipidemia and improvement in in vivo insulin sensitivity (model assessment of insulin resistance, insulin tolerance test) as well as in vitro insulin sensitivity in soleus muscle (glucose uptake and metabolism). This effect was associated with increased insulin-stimulated p38 MAP kinase phosphorylation and lower n-6/n-3 fatty acid ratio, but not with activation of proteins from insulin signaling (IR, IRS-1 and Akt). Global DNA methylation was decreased in liver but not in soleus muscle. These results suggest that long-term fish oil supplementation improves insulin sensitivity in association with increased insulin-stimulated p38 activation and decreased n-6:n-3 ratio in skeletal muscle and decreased global DNA methylation in liver.
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Affiliation(s)
- Sandro M Hirabara
- Institute of Physical Activity Sciences and Sport, Cruzeiro do Sul University, São Paulo, Brazil.
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Changes in food intake, metabolic parameters and insulin resistance are induced by an isoenergetic, medium-chain fatty acid diet and are associated with modifications in insulin signalling in isolated rat pancreatic islets. Br J Nutr 2012. [PMID: 23182275 DOI: 10.1017/s0007114512004576] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Long-chain fatty acids are capable of inducing alterations in the homoeostasis of glucose-stimulated insulin secretion (GSIS), but the effect of medium-chain fatty acids (MCFA) is poorly elucidated. In the present study, we fed a normoenergetic MCFA diet to male rats from the age of 1 month to the age of 4 months in order to analyse the effect of MCFA on body growth, insulin sensitivity and GSIS. The 45% MCFA substitution of whole fatty acids in the normoenergetic diet impaired whole body growth and resulted in increased body adiposity and hyperinsulinaemia, and reduced insulin-mediated glucose uptake in skeletal muscle. In addition, the isolated pancreatic islets from the MCFA-fed rats showed impaired GSIS and reduced protein kinase Ba (AKT1) protein expression and extracellular signal-related kinase isoforms 1 and 2 (ERK(1/2)) phosphorylation, which were accompanied by increased cellular death. Furthermore, there was a mildly increased cholinergic sensitivity to GSIS. We discuss these findings in further detail, and advocate that they might have a role in the mechanistic pathway leading to the compensatory hyperinsulinaemic status found in this animal model.
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Carvalho-Filho MA, Carvalho BM, Oliveira AG, Guadagnini D, Ueno M, Dias MM, Tsukumo DM, Hirabara SM, Reis LF, Curi R, Carvalheira JBC, Saad MJA. Double-stranded RNA-activated protein kinase is a key modulator of insulin sensitivity in physiological conditions and in obesity in mice. Endocrinology 2012; 153:5261-5274. [PMID: 22948222 DOI: 10.1210/en.2012-1400] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The molecular integration of nutrient- and pathogen-sensing pathways has become of great interest in understanding the mechanisms of insulin resistance in obesity. The double-stranded RNA-dependent protein kinase (PKR) is one candidate molecule that may provide cross talk between inflammatory and metabolic signaling. The present study was performed to determine, first, the role of PKR in modulating insulin action and glucose metabolism in physiological situations, and second, the role of PKR in insulin resistance in obese mice. We used Pkr(-/-) and Pkr(+/+) mice to investigate the role of PKR in modulating insulin sensitivity, glucose metabolism, and insulin signaling in liver, muscle, and adipose tissue in response to a high-fat diet. Our data show that in lean Pkr(-/-) mice, there is an improvement in insulin sensitivity, and in glucose tolerance, and a reduction in fasting blood glucose, probably related to a decrease in protein phosphatase 2A activity and a parallel increase in insulin-induced thymoma viral oncogene-1 (Akt) phosphorylation. PKR is activated in tissues of obese mice and can induce insulin resistance by directly binding to and inducing insulin receptor substrate (IRS)-1 serine307 phosphorylation or indirectly through modulation of c-Jun N-terminal kinase and inhibitor of κB kinase β. Pkr(-/-) mice were protected from high-fat diet-induced insulin resistance and glucose intolerance and showed improved insulin signaling associated with a reduction in c-Jun N-terminal kinase and inhibitor of κB kinase β phosphorylation in insulin-sensitive tissues. PKR may have a role in insulin sensitivity under normal physiological conditions, probably by modulating protein phosphatase 2A activity and serine-threonine kinase phosphorylation, and certainly, this kinase may represent a central mechanism for the integration of pathogen response and innate immunity with insulin action and metabolic pathways that are critical in obesity.
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Affiliation(s)
- M A Carvalho-Filho
- Department of Internal Medicine, State University of Campinas, São Paulo, Brazil
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Sunflower oil supplementation has proinflammatory effects and does not reverse insulin resistance in obesity induced by high-fat diet in C57BL/6 mice. J Biomed Biotechnol 2012; 2012:945131. [PMID: 22988427 PMCID: PMC3441046 DOI: 10.1155/2012/945131] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2012] [Accepted: 08/05/2012] [Indexed: 12/21/2022] Open
Abstract
High consumption of polyunsaturated fatty acids, such as sunflower oil has been associated to beneficial effects in plasma lipid profile, but its role on inflammation and insulin resistance is not fully elucidated yet. We evaluated the effect of sunflower oil supplementation on inflammatory state and insulin resistance condition in HFD-induced obese mice. C57BL/6 male mice (8 weeks) were divided in four groups: (a) control diet (CD), (b) HFD, (c) CD supplemented with n-6 (CD + n-6), and (d) HFD supplemented with n-6 (HFD + n-6). CD + n-6 and HFD + n-6 were supplemented with sunflower oil by oral gavage at 2 g/Kg of body weight, three times per week. CD and HFD were supplemented with water instead at the same dose. HFD induced whole and muscle-specific insulin resistance associated with increased inflammatory markers in insulin-sensitive tissues and macrophage cells. Sunflower oil supplementation was not efficient in preventing or reducing these parameters. In addition, the supplementation increased pro-inflammatory cytokine production by macrophages and tissues. Lipid profile, on the other hand, was improved with the sunflower oil supplementation in animals fed HFD. In conclusion, sunflower oil supplementation improves lipid profile, but it does not prevent or attenuate insulin resistance and inflammation induced by HFD in C57BL/6 mice.
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Pop-Busui R. What do we know and we do not know about cardiovascular autonomic neuropathy in diabetes. J Cardiovasc Transl Res 2012; 5:463-78. [PMID: 22644723 DOI: 10.1007/s12265-012-9367-6] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2012] [Accepted: 04/12/2012] [Indexed: 12/16/2022]
Abstract
Cardiovascular autonomic neuropathy (CAN) in diabetes is generally overlooked in practice, although awareness of its serious consequences is emerging. Challenges in understanding the complex, dynamic changes in the modulation of the sympathetic/parasympathetic systems' tone and their interactions with physiologic mechanisms regulating the control of heart rate, blood pressure, and other cardiovascular functions in the presence of acute hyper-or-hypoglycemic stress, other stressors or medication, and challenges with sensitive evaluations have contributed to lower CAN visibility compared with other diabetes complications. Yet, CAN is a significant cause of morbidity and mortality, due to a high-risk of cardiac arrhythmias, silent myocardial ischemia and sudden death. While striving for aggressive risk factor control in diabetes practice seemed intuitive, recent reports of major clinical trials undermine established thinking concerning glycemic control and cardiovascular risk. This review covers current understanding and gaps in that understanding of the clinical implications of CAN and prevention and treatment of CAN.
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Affiliation(s)
- Rodica Pop-Busui
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
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Lambertucci RH, Silveira LDR, Hirabara SM, Curi R, Sweeney G, Pithon-Curi TC. Effects of moderate electrical stimulation on reactive species production by primary rat skeletal muscle cells: cross talk between superoxide and nitric oxide production. J Cell Physiol 2012; 227:2511-8. [PMID: 21898396 DOI: 10.1002/jcp.22989] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The effects of a moderate electrical stimulation on superoxide and nitric oxide production by primary cultured skeletal muscle cells were evaluated. The involvement of the main sites of these reactive species production and the relationship between superoxide and nitric oxide production were also examined. Production of superoxide was evaluated by cytochrome c reduction and dihydroethidium oxidation assays. Electrical stimulation increased superoxide production after 1 h incubation. A xanthine oxidase inhibitor caused a partial decrease of superoxide generation and a significant amount of mitochondria-derived superoxide was also observed. Nitric oxide production was assessed by nitrite measurement and by using 4,5-diaminofluorescein diacetate (DAF-2-DA) assay. Using both methods an increased production of nitric oxide was obtained after electrical stimulation, which was also able to induce an increase of iNOS content and NF-κB activation. The participation of superoxide in nitric oxide production was investigated by incubating cells with DAF-2-DA in the presence or absence of electrical stimulation, a superoxide generator system (xanthine-xanthine oxidase), a mixture of NOS inhibitors and SOD-PEG. Our data show that the induction of muscle contraction by a moderate electrical stimulation protocol led to an increased nitric oxide production that can be controlled by superoxide generation. The cross talk between these reactive species likely plays a role in exercise-induced maintenance and adaptation by regulating muscular glucose metabolism, force of contraction, fatigue, and antioxidant systems activities.
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Affiliation(s)
- Rafael Herling Lambertucci
- Post-Graduate Program in Human Movement Sciences, Biological Sciences and Health Center, Cruzeiro do Sul University, Sao Paulo, Brazil.
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Abstract
Diabetic autonomic neuropathies are a heterogeneous and progressive disease entity and commonly complicate both type 1 and type 2 diabetes mellitus. Although the aetiology is not entirely understood, hyperglycaemia, insulin deficiency, metabolic derangements and potentially autoimmune mechanisms are thought to play an important role. A subgroup of diabetic autonomic neuropathy, cardiovascular autonomic neuropathy (CAN), is one of the most common diabetes-associated complications and is ultimately clinically important because of its correlation with increased mortality. The natural history of CAN is unclear, but is thought to progress from a subclinical stage characterized by impaired baroreflex sensitivity and abnormalities of spectral analysis of heart rate variability to a clinically apparent stage with diverse and disabling symptoms. Early diagnosis of CAN, using spectral analysis of heart rate variability or scintigraphic imaging techniques, might enable identification of patients at highest risk for the development of clinical CAN and, thereby, enable the targeting of intensive therapeutic approaches. This Review discusses methods for diagnosis, epidemiology, natural history and potential causes and consequences of CAN.
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Affiliation(s)
- Michael Kuehl
- Cardiovascular Research Department, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
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Martins AR, Nachbar RT, Gorjao R, Vinolo MA, Festuccia WT, Lambertucci RH, Cury-Boaventura MF, Silveira LR, Curi R, Hirabara SM. Mechanisms underlying skeletal muscle insulin resistance induced by fatty acids: importance of the mitochondrial function. Lipids Health Dis 2012; 11:30. [PMID: 22360800 PMCID: PMC3312873 DOI: 10.1186/1476-511x-11-30] [Citation(s) in RCA: 198] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2012] [Accepted: 02/23/2012] [Indexed: 01/06/2023] Open
Abstract
Insulin resistance condition is associated to the development of several syndromes, such as obesity, type 2 diabetes mellitus and metabolic syndrome. Although the factors linking insulin resistance to these syndromes are not precisely defined yet, evidence suggests that the elevated plasma free fatty acid (FFA) level plays an important role in the development of skeletal muscle insulin resistance. Accordantly, in vivo and in vitro exposure of skeletal muscle and myocytes to physiological concentrations of saturated fatty acids is associated with insulin resistance condition. Several mechanisms have been postulated to account for fatty acids-induced muscle insulin resistance, including Randle cycle, oxidative stress, inflammation and mitochondrial dysfunction. Here we reviewed experimental evidence supporting the involvement of each of these propositions in the development of skeletal muscle insulin resistance induced by saturated fatty acids and propose an integrative model placing mitochondrial dysfunction as an important and common factor to the other mechanisms.
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Affiliation(s)
- Amanda R Martins
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Avenida Professor Lineu Prestes 1524, Butantã, São Paulo, SP, Brazil
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Caricilli AM, Picardi PK, de Abreu LL, Ueno M, Prada PO, Ropelle ER, Hirabara SM, Castoldi Â, Vieira P, Camara NOS, Curi R, Carvalheira JB, Saad MJA. Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice. PLoS Biol 2011; 9:e1001212. [PMID: 22162948 PMCID: PMC3232200 DOI: 10.1371/journal.pbio.1001212] [Citation(s) in RCA: 197] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2011] [Accepted: 10/27/2011] [Indexed: 02/07/2023] Open
Abstract
Environmental factors and host genetics interact to control the gut microbiota, which may have a role in the development of obesity and insulin resistance. TLR2-deficient mice, under germ-free conditions, are protected from diet-induced insulin resistance. It is possible that the presence of gut microbiota could reverse the phenotype of an animal, inducing insulin resistance in an animal genetically determined to have increased insulin sensitivity, such as the TLR2 KO mice. In the present study, we investigated the influence of gut microbiota on metabolic parameters, glucose tolerance, insulin sensitivity, and signaling of TLR2-deficient mice. We investigated the gut microbiota (by metagenomics), the metabolic characteristics, and insulin signaling in TLR2 knockout (KO) mice in a non-germ free facility. Results showed that the loss of TLR2 in conventionalized mice results in a phenotype reminiscent of metabolic syndrome, characterized by differences in the gut microbiota, with a 3-fold increase in Firmicutes and a slight increase in Bacteroidetes compared with controls. These changes in gut microbiota were accompanied by an increase in LPS absorption, subclinical inflammation, insulin resistance, glucose intolerance, and later, obesity. In addition, this sequence of events was reproduced in WT mice by microbiota transplantation and was also reversed by antibiotics. At the molecular level the mechanism was unique, with activation of TLR4 associated with ER stress and JNK activation, but no activation of the IKKβ-IκB-NFκB pathway. Our data also showed that in TLR2 KO mice there was a reduction in regulatory T cell in visceral fat, suggesting that this modulation may also contribute to the insulin resistance of these animals. Our results emphasize the role of microbiota in the complex network of molecular and cellular interactions that link genotype to phenotype and have potential implications for common human disorders involving obesity, diabetes, and even other immunological disorders.
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Affiliation(s)
- Andréa M. Caricilli
- Department of Internal Medicine, State University of Campinas, Campinas, Brazil
| | - Paty K. Picardi
- Department of Internal Medicine, State University of Campinas, Campinas, Brazil
| | - Lélia L. de Abreu
- Department of Nursing, State University of Campinas, Campinas, Brazil
| | - Mirian Ueno
- Department of Internal Medicine, State University of Campinas, Campinas, Brazil
| | - Patrícia O. Prada
- Department of Internal Medicine, State University of Campinas, Campinas, Brazil
| | - Eduardo R. Ropelle
- Department of Internal Medicine, State University of Campinas, Campinas, Brazil
| | - Sandro Massao Hirabara
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Ângela Castoldi
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Pedro Vieira
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Niels O. S. Camara
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Rui Curi
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - José B. Carvalheira
- Department of Internal Medicine, State University of Campinas, Campinas, Brazil
| | - Mário J. A. Saad
- Department of Internal Medicine, State University of Campinas, Campinas, Brazil
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Silveira LR, Pinheiro CHDJ, Zoppi CC, Hirabara SM, Vitzel KF, Bassit RA, Barbosa MR, Sampaio IH, Melo IHP, Fiamoncini J, Carneiro EM, Curi R. [Regulation of glucose and fatty acid metabolism in skeletal muscle during contraction]. ACTA ACUST UNITED AC 2011; 55:303-13. [PMID: 21881812 DOI: 10.1590/s0004-27302011000500002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2011] [Accepted: 05/12/2011] [Indexed: 03/10/2023]
Abstract
The glucose-fatty acid cycle explains the preference for fatty acid during moderate and long duration physical exercise. In contrast, there is a high glucose availability and oxidation rate in response to intense physical exercise. The reactive oxygen species (ROS) production during physical exercise suggests that the redox balance is important to regulate of lipids/carbohydrate metabolism. ROS reduces the activity of the Krebs cycle, and increases the activity of mitochondrial uncoupling proteins. The opposite effects happen during moderate physical activity. Thus, some issues is highlighted in the present review: Why does skeletal muscle prefer lipids in the basal and during moderate physical activity? Why does glucose-fatty acid fail to carry out their effects during intense physical exercise? How skeletal muscles regulate the lipids and carbohydrate metabolism during the contraction-relaxation cycle?
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Affiliation(s)
- Leonardo R Silveira
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, SP, Brasil.
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Hormetics: dietary triggers of an adaptive stress response. Pharm Res 2011; 28:2680-94. [PMID: 21818712 DOI: 10.1007/s11095-011-0551-1] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2011] [Accepted: 07/27/2011] [Indexed: 12/31/2022]
Abstract
A series of dietary ingredients and metabolites are able to induce an adaptive stress response either by generation of reactive oxygen species (ROS) and/or via activation of the Nrf2/Keap1 stress response network. Most of the molecules belong to activated Michael acceptors, electrophiles capable to S-alkylate redox sensitive cysteine thiols. This review summarizes recent advances in the (re)search of these compounds and classifies them into distinct groups. More than 60 molecules are described that induce the Nrf2 network, most of them found in our daily diet. Although known as typical antioxidants, a closer look reveals that these molecules induce an initial mitochondrial or cytosolic ROS formation and thereby trigger an adaptive stress response and hormesis, respectively. This, however, leads to higher levels of intracellular glutathione and increased expression levels of antioxidant enzymes such as glutathione peroxidase, thioredoxin reductase, and superoxide dismutase. According to this principle, the author suggests the term hormetics to describe these indirect antioxidants.
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Edwards LM, Murray AJ, Holloway CJ, Carter EE, Kemp GJ, Codreanu I, Brooker H, Tyler DJ, Robbins PA, Clarke K. Short-term consumption of a high-fat diet impairs whole-body efficiency and cognitive function in sedentary men. FASEB J 2011; 25:1088-96. [PMID: 21106937 DOI: 10.1096/fj.10-171983] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2025]
Abstract
We recently showed that a short-term high-fat diet blunted exercise performance in rats, accompanied by increased uncoupling protein levels and greater respiratory uncoupling. In this study, we investigated the effects of a similar diet on physical and cognitive performance in humans. Twenty sedentary men were assessed when consuming a standardized, nutritionally balanced diet (control) and after 7 d of consuming a diet comprising 74% kcal from fat. Efficiency was measured during a standardized exercise task, and cognition was assessed using a computerized assessment battery. Skeletal muscle mitochondrial function was measured using (31)P magnetic resonance spectroscopy. The diet increased mean ± se plasma free fatty acids by 44% (0.32±0.03 vs. 0.46±0.05 mM; P<0.05) and decreased whole-body efficiency by 3% (21±1 vs. 18±1%; P<0.05), although muscle uncoupling protein (UCP3) content and maximal mitochondrial function were unchanged. High-fat diet consumption also increased subjects' simple reaction times (P<0.01) and decreased power of attention (P<0.01). Thus, we have shown that a high-fat diet blunts whole-body efficiency and cognition in sedentary men. We suggest that this effect may be due to increased respiratory uncoupling.
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Affiliation(s)
- Lindsay M Edwards
- Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
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de Melo JF, Aloulou N, Duval JL, Vigneron P, Bourgoin L, Leandro CG, de Castro CMMB, Nagel MD. Effect of a neonatal low-protein diet on the morphology of myotubes in culture and the expression of key proteins that regulate myogenesis in young and adult rats. Eur J Nutr 2010; 50:243-50. [DOI: 10.1007/s00394-010-0132-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2010] [Accepted: 08/30/2010] [Indexed: 12/11/2022]
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41
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Galindo MF, Ikuta I, Zhu X, Casadesus G, Jordán J. Mitochondrial biology in Alzheimer's disease pathogenesis. J Neurochem 2010; 114:933-45. [PMID: 20492350 DOI: 10.1111/j.1471-4159.2010.06814.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Despite the increasing knowledge of Alzheimer's disease (AD) management with novel pharmacologic agents, most of them are only transiently fixing symptomatic pathology. Currently there is rapid growth in the field of neuroprotective pharmacology and increasing focus on the involvement of mitochondria in this devastating disease. This review is directed at understanding the role of mitochondria-mediated pathways in AD and integrating basic biology of the mitochondria with knowledge of possible pharmacologic targets for AD treatment in an attempt to elucidate novel mitochondria-driven therapeutic interventions useful to both clinical and basic research.
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Affiliation(s)
- María F Galindo
- Unidad de Neuropsicofarmacología Translacional, Complejo Hospitalario Universitario de Albacete, Albacete, Spain
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42
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Membrane biophysics and mechanics in Alzheimer's disease. Mol Neurobiol 2010; 41:138-48. [PMID: 20437210 DOI: 10.1007/s12035-010-8121-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2009] [Accepted: 03/17/2010] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease is a chronic neurodegenerative disorder characterized by neuronal loss, cerebrovascular inflammation, and accumulation of senile plaques in the brain parenchyma and cerebral blood vessels. Amyloid-beta peptide (Abeta), a major component of senile plaques, has been shown to exert multiple toxic effects to neurons, astrocytes, glial cells, and brain endothelium. Oligomeric Abeta can disturb the structure and function of cell membranes and alter membrane mechanical properties, such as membrane fluidity and molecular order. Much of these effects are attributed to their capability to trigger oxidative stress and inflammation. In this review, we discuss the effects of Abeta on neuronal cells, astrocytes, and cerebral endothelial cells with special emphasis on cell membrane properties and cell functions.
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43
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Dikov D, Aulbach A, Muster B, Dröse S, Jendrach M, Bereiter-Hahn J. Do UCP2 and mild uncoupling improve longevity? Exp Gerontol 2010; 45:586-95. [PMID: 20332018 DOI: 10.1016/j.exger.2010.03.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2009] [Revised: 03/04/2010] [Accepted: 03/16/2010] [Indexed: 11/18/2022]
Abstract
Mild uncoupling of mitochondrial respiration is considered to prolong life span of organisms by reducing the production of reactive oxygen species (ROS). Experimental evidence against this hypothesis has been brought forward by premature senescence in cell cultures treated with uncouplers. Exposing HUVEC to a mixture of nutritionally important fatty acids (oil extract of chicken yolk) mild uncoupling with "naturally acting substances" was performed. This treatment also resulted in premature senescence although ROS production did not increase. Fatty acids activate uncoupling proteins (UCP) in the inner mitochondrial membrane. UCP2 expression proved to be sensitive to the presence of fatty acids but remains unchanged during the ageing process. UCP3 expression in senescent HUVEC and avUCP expression in senescent CEF were considerably less than in young cultures. No indication for protonophoric reduction of mitochondrial membrane potential was found in UCP2 overexpressing HeLa cells and only little in HUVEC. ROS levels increased instead of being reduced in these cells. Stable transfection with UCP2-GFP was possible only in chick embryo fibroblasts and HeLa cells and resulted in decreased proliferation. Stable transfection of HUVEC with UCP2-GFP resulted in death of cultures within one or two weeks. The reason for this behaviour most probably is apoptosis preceded by mitochondrial fragmentation and loss of membrane potential.
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Affiliation(s)
- Daniel Dikov
- Institute for Cell Biology and Neurosciences, Biocenter. Goethe University, Max von Lauestrasse 9, Frankfurt am Main, Germany
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44
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Samudio I, Harmancey R, Fiegl M, Kantarjian H, Konopleva M, Korchin B, Kaluarachchi K, Bornmann W, Duvvuri S, Taegtmeyer H, Andreeff M. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Invest 2009; 120:142-56. [PMID: 20038799 DOI: 10.1172/jci38942] [Citation(s) in RCA: 561] [Impact Index Per Article: 35.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2009] [Accepted: 10/21/2009] [Indexed: 12/16/2022] Open
Abstract
The traditional view is that cancer cells predominately produce ATP by glycolysis, rather than by oxidation of energy-providing substrates. Mitochondrial uncoupling--the continuing reduction of oxygen without ATP synthesis--has recently been shown in leukemia cells to circumvent the ability of oxygen to inhibit glycolysis, and may promote the metabolic preference for glycolysis by shifting from pyruvate oxidation to fatty acid oxidation (FAO). Here we have demonstrated that pharmacologic inhibition of FAO with etomoxir or ranolazine inhibited proliferation and sensitized human leukemia cells--cultured alone or on bone marrow stromal cells--to apoptosis induction by ABT-737, a molecule that releases proapoptotic Bcl-2 proteins such as Bak from antiapoptotic family members. Likewise, treatment with the fatty acid synthase/lipolysis inhibitor orlistat also sensitized leukemia cells to ABT-737, which supports the notion that fatty acids promote cell survival. Mechanistically, we generated evidence suggesting that FAO regulates the activity of Bak-dependent mitochondrial permeability transition. Importantly, etomoxir decreased the number of quiescent leukemia progenitor cells in approximately 50% of primary human acute myeloid leukemia samples and, when combined with either ABT-737 or cytosine arabinoside, provided substantial therapeutic benefit in a murine model of leukemia. The results support the concept of FAO inhibitors as a therapeutic strategy in hematological malignancies.
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Affiliation(s)
- Ismael Samudio
- Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
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45
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Kokubun E, Hirabara SM, Fiamoncini J, Curi R, Haebisch H. Changes of glycogen content in liver, skeletal muscle, and heart from fasted rats. Cell Biochem Funct 2009; 27:488-95. [PMID: 19711486 DOI: 10.1002/cbf.1602] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Glycogen content of white and red skeletal muscles, cardiac muscle, and liver was investigated in conditions where changes in plasma levels of non-esterified fatty acids (NEFA) occur. The experiments were performed in fed and 12 and 48 h-fasted rats. The animals were also submitted to swimming for 10 and 30 min. Glycogen content was also investigated in both pharmacologically induced low plasma NEFA levels fasted rats and pharmacologically induced high plasma NEFA levels fed rats. The participation of Akt and glycogen synthase kinase-3 (GSK-3) in the changes observed was investigated. Plasma levels of NEFA, glucose, and insulin were determined in all conditions. Fasting increased plasma NEFA levels and reduced glycogen content in the liver and skeletal muscles. However, an increase of glycogen content was observed in the heart under this condition. Akt and GSK-3 phosphorylation was reduced during fasting in the liver and skeletal muscles but it remained unchanged in the heart. Our results suggest that in conditions of increased plasma NEFA levels, changes in insulin-stimulated phosphorylation of Akt and GSK-3 and glycogen content vary differently in liver, skeletal muscles, and heart. Akt and GSK-3 phosphorylation and glycogen content are decreased in liver and skeletal muscles, but in the heart it remain unchanged (Akt and GSK-3 phosphorylation) or increased (glycogen content) due to consistent increase of plasma NEFA levels.
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Affiliation(s)
- Eduardo Kokubun
- Department of Physical Education, São Paulo State University, Rio Claro, Brazil
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46
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Hirabara SM, Curi R, Maechler P. Saturated fatty acid-induced insulin resistance is associated with mitochondrial dysfunction in skeletal muscle cells. J Cell Physiol 2009; 222:187-94. [PMID: 19780047 DOI: 10.1002/jcp.21936] [Citation(s) in RCA: 143] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Increased plasma levels of free fatty acids (FFA) occur in states of insulin resistance such as obesity and type 2 diabetes mellitus. These high levels of plasma FFA are proposed to play an important role for the development of insulin resistance but the mechanisms involved are still unclear. This study investigated the effects of saturated and unsaturated FFA on insulin sensitivity in parallel with mitochondrial function. C2C12 myotubes were treated for 24 h with 0.1 mM of saturated (palmitic and stearic) and unsaturated (oleic, linoleic, eicosapentaenoic, and docosahexaenoic) FFA. After this period, basal and insulin-stimulated glucose metabolism and mitochondrial function were evaluated. Saturated palmitic and stearic acids decreased insulin-induced glycogen synthesis, glucose oxidation, and lactate production. Basal glucose oxidation was also reduced. Palmitic and stearic acids impaired mitochondrial function as demonstrated by decrease of both mitochondrial hyperpolarization and ATP generation. These FFA also decreased Akt activation by insulin. As opposed to saturated FFA, unsaturated FFA did not impair glucose metabolism and mitochondrial function. Primary cultures of rat skeletal muscle cells exhibited similar responses to saturated FFA as compared to C2C12 cells. These results show that in muscle cells saturated FFA-induced mitochondrial dysfunction associated with impaired insulin-induced glucose metabolism.
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Affiliation(s)
- Sandro M Hirabara
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Butantã, São Paulo, Brazil.
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47
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Romanatto T, Roman EA, Arruda AP, Denis RG, Solon C, Milanski M, Moraes JC, Bonfleur ML, Degasperi GR, Picardi PK, Hirabara S, Boschero AC, Curi R, Velloso LA. Deletion of tumor necrosis factor-alpha receptor 1 (TNFR1) protects against diet-induced obesity by means of increased thermogenesis. J Biol Chem 2009; 284:36213-36222. [PMID: 19858212 DOI: 10.1074/jbc.m109.030874] [Citation(s) in RCA: 119] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
In diet-induced obesity, hypothalamic and systemic inflammatory factors trigger intracellular mechanisms that lead to resistance to the main adipostatic hormones, leptin and insulin. Tumor necrosis factor-alpha (TNF-alpha) is one of the main inflammatory factors produced during this process and its mechanistic role as an inducer of leptin and insulin resistance has been widely investigated. Most of TNF-alpha inflammatory signals are delivered by TNF receptor 1 (R1); however, the role played by this receptor in the context of obesity-associated inflammation is not completely known. Here, we show that TNFR1 knock-out (TNFR1 KO) mice are protected from diet-induced obesity due to increased thermogenesis. Under standard rodent chow or a high-fat diet, TNFR1 KO gain significantly less body mass despite increased caloric intake. Visceral adiposity and mean adipocyte diameter are reduced and blood concentrations of insulin and leptin are lower. Protection from hypothalamic leptin resistance is evidenced by increased leptin-induced suppression of food intake and preserved activation of leptin signal transduction through JAK2, STAT3, and FOXO1. Under the high-fat diet, TNFR1 KO mice present a significantly increased expression of the thermogenesis-related neurotransmitter, TRH. Further evidence of increased thermogenesis includes increased O(2) consumption in respirometry measurements, increased expressions of UCP1 and UCP3 in brown adipose tissue and skeletal muscle, respectively, and increased O(2) consumption by isolated skeletal muscle fiber mitochondria. This demonstrates that TNF-alpha signaling through TNFR1 is an important mechanism involved in obesity-associated defective thermogenesis.
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Affiliation(s)
- Talita Romanatto
- Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil
| | - Erika A Roman
- Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil
| | - Ana P Arruda
- Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil
| | - Raphael G Denis
- Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil
| | - Carina Solon
- Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil
| | - Marciane Milanski
- Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil
| | - Juliana C Moraes
- Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil
| | - Maria L Bonfleur
- Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil
| | - Giovanna R Degasperi
- Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil
| | - Paty K Picardi
- Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil
| | - Sandro Hirabara
- Department of Physiology and Biophysics, University of São Paulo, 05508-900 São Paulo, Brazil
| | - Antonio C Boschero
- Department of Physiology and Biophysics, University of Campinas, 13084-761 São Paulo, Brazil
| | - Rui Curi
- Department of Physiology and Biophysics, University of São Paulo, 05508-900 São Paulo, Brazil
| | - Licio A Velloso
- Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil.
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48
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Morgan D, Rebelato E, Abdulkader F, Graciano MFR, Oliveira-Emilio HR, Hirata AE, Rocha MS, Bordin S, Curi R, Carpinelli AR. Association of NAD(P)H oxidase with glucose-induced insulin secretion by pancreatic beta-cells. Endocrinology 2009; 150:2197-201. [PMID: 19147679 DOI: 10.1210/en.2008-1149] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
We previously described the presence of nicotinamide adenine dinucleotide phosphate reduced form [NAD(P)H]oxidase components in pancreatic beta-cells and its activation by glucose, palmitic acid, and proinflammatory cytokines. In the present study, the importance of the NAD(P)H oxidase complex for pancreatic beta-cell function was examined. Rat pancreatic islets were incubated in the presence of glucose plus diphenyleneiodonium, a NAD(P)H oxidase inhibitor, for 1 h or with the antisense oligonucleotide for p47(PHOX) during 24 h. Reactive oxygen species (ROS) production was determined by a fluorescence assay using 2,7-dichlorodihydrofluorescein diacetate. Insulin secretion, intracellular calcium responses, [U-(14)C]glucose oxidation, and expression of glucose transporter-2, glucokinase and insulin genes were examined. Antisense oligonucleotide reduced p47(PHOX) expression [an important NAD(P)H oxidase cytosolic subunit] and similarly to diphenyleneiodonium also blunted the enzyme activity as indicated by reduction of ROS production. Suppression of NAD(P)H oxidase activity had an inhibitory effect on intracellular calcium responses to glucose and glucose-stimulated insulin secretion by isolated islets. NAD(P)H oxidase inhibition also reduced glucose oxidation and gene expression of glucose transporter-2 and glucokinase. These findings indicate that NAD(P)H oxidase activation plays an important role for ROS production by pancreatic beta-cells during glucose-stimulated insulin secretion. The importance of this enzyme complex for the beta-cell metabolism and the machinery involved in insulin secretion were also shown.
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Affiliation(s)
- D Morgan
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Avenue Prof. Lineu Prestes 1524, 05508-900 São Paulo, Brazil
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49
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Luchessi AD, Cambiaghi TD, Hirabara SM, Lambertucci RH, Silveira LR, Baptista IL, Moriscot AS, Costa-Neto CM, Curi R. Involvement of eukaryotic translation initiation factor 5A (eIF5A) in skeletal muscle stem cell differentiation. J Cell Physiol 2009; 218:480-9. [PMID: 19006180 DOI: 10.1002/jcp.21619] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The eukaryotic translation initiation factor 5A (eIF5A) contains a special amino acid residue named hypusine that is required for its activity, being produced by a post-translational modification using spermidine as substrate. Stem cells from rat skeletal muscles (satellite cells) were submitted to differentiation and an increase of eIF5A gene expression was observed. Higher content of eIF5A protein was found in satellite cells on differentiation in comparison to non-differentiated satellite cells and skeletal muscle. The treatment with N1-guanyl-1,7-diaminoheptane (GC7), a hypusination inhibitor, reversibly abolished the differentiation process. In association with the differentiation blockage, an increase of glucose consumption and lactate production and a decrease of glucose and palmitic acid oxidation were observed. A reduction in cell proliferation and protein synthesis was also observed. L-Arginine, a spermidine precursor and partial suppressor of muscle dystrophic phenotype, partially abolished the GC7 inhibitory effect on satellite cell differentiation. These results reveal a new physiological role for eIF5A and contribute to elucidate the molecular mechanisms involved in muscle regeneration.
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Affiliation(s)
- Augusto D Luchessi
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
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50
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Soriguer F, García-Serrano S, García-Almeida JM, Garrido-Sánchez L, García-Arnés J, Tinahones FJ, Cardona I, Rivas-Marín J, Gallego-Perales JL, García-Fuentes E. Changes in the serum composition of free-fatty acids during an intravenous glucose tolerance test. Obesity (Silver Spring) 2009; 17:10-5. [PMID: 18948964 DOI: 10.1038/oby.2008.475] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Recent studies suggest that measuring the free-fatty acids (FFA) during an intravenous glucose tolerance test (IVGTT) may provide information about the metabolic associations between serum FFA and carbohydrate and insulin metabolism. We evaluated the FFA profile during an IVGTT and determined whether this test changes the composition and concentration of FFA. An IVGTT was given to 38 severely obese persons before and 7 months after undergoing bariatric surgery and also to 12 healthy, nonobese persons. The concentration and composition of the FFA were studied at different times during the test. The concentration of FFA fell significantly faster during the IVGTT in the controls and in the severely obese persons with normal-fasting glucose (NFG) than in the severely obese persons with impaired-fasting glucose (IFG) or type 2 diabetes mellitus (T2DM) (P < 0.05). Significant differences were found in the time to minimum serum concentrations of FFA (control = NFG < IFG < T2DM) (P < 0.001). These variables improved after bariatric surgery in the three groups. The percentage of monounsaturated and n-6 polyunsaturated FFA in the control subjects and in the obese persons, both before and after surgery, decreased significantly during the IVGTT. In conclusion, during an IVGTT, severely obese persons with IFG or T2DM experienced a lower fall in the FFA than the severely obese persons with NFG and the controls, becoming normal after bariatric surgery.
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Affiliation(s)
- Federico Soriguer
- Servicio de Endocrinología y Nutrición, Hospital Regional Universitario Carlos Haya, Málaga, Spain
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