Metabolic Inflexibility with Obesity and the Effects of Fenofibrate on Skeletal Muscle Fatty Acid Oxidation

Kristen E. Boyle; Jacob E. Friedman; Rachel C. Janssen; Chantal Underkofler; Joseph A. Houmard; Neda Rasouli

doi:10.1055/s-0042-111517

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2017; 49(01): 50-57
DOI: 10.1055/s-0042-111517

Endocrine Research

Metabolic Inflexibility with Obesity and the Effects of Fenofibrate on Skeletal Muscle Fatty Acid Oxidation

Kristen E. Boyle

¹Division of Nutrition, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA

,

Jacob E. Friedman

²Division of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA

,

Rachel C. Janssen

²Division of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA

,

Chantal Underkofler

³Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA

,

Joseph A. Houmard

⁴Department of Kinesiology, East Carolina University, Greenville, NC, USA

,

Neda Rasouli

³Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA

⁵Veterans Administration Eastern Colorado Health Care System, Denver, CO, USA

› Author Affiliations

Abstract

This study was designed to investigate mechanisms of lipid metabolic inflexibility in human obesity and the ability of fenofibrate (FENO) to increase skeletal muscle fatty acid oxidation (FAO) in primary human skeletal muscle cell cultures (HSkMC) exhibiting metabolic inflexibility. HSkMC from 10 lean and 10 obese, insulin resistant subjects were treated with excess fatty acid for 24 h (24hFA) to gauge lipid-related metabolic flexibility. Metabolically inflexible HSkMC from obese individuals were then treated with 24hFA in combination with FENO to determine effectiveness for increasing FAO. Mitochondrial enzyme activity and FAO were measured in skeletal muscle from subjects with prediabetes (n=11) before and after 10 weeks of fenofibrate in vivo. 24hFA increased FAO to a greater extent in HSkMC from lean versus obese subjects (+49% vs. +9%, for lean vs. obese, respectively; p<0.05) indicating metabolic inflexibility with obesity. Metabolic inflexibility was not observed for measures of cellular respiration in permeabilized cells using carbohydrate substrate. Fenofibrate co-incubation with 24hFA, increased FAO in a subset of HSkMC from metabolically inflexible, obese subjects (p<0.05), which was eliminated by PPARα antagonist. In vivo, fenofibrate treatment increased skeletal muscle FAO in a subset of subjects with prediabetes but did not affect gene transcription or mitochondrial enzyme activity. Lipid metabolic inflexibility observed in HSkMC from obese subjects is not due to differences in electron transport flux, but rather upstream decrements in lipid metabolism. Fenofibrate increases the capacity for FAO in human skeletal muscle cells, though its role in skeletal muscle metabolism in vivo remains unclear.

Key words

mitochondria - fat oxidation - insulin resistance

Full Text

References

References
1 Muoio DM. Metabolic inflexibility: when mitochondrial indecision leads to metabolic gridlock. Cell 2014; 159: 1253-1262
2 Corpeleijn E, Saris WHM, Blaak EE. Metabolic flexibility in the development of insulin resistance and type 2 diabetes: effects of lifestyle. Obes Rev 2009; 10: 178-193
3 Kelley DE. Skeletal muscle fat oxidation: timing and flexibility are everything. J Clin Invest 2005; 115: 1699-1702
4 Kelley DE, Goodpaster B, Wing RR, Simoneau JA. Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Am J Physiol 1999; 277: E1130-E1141
5 Anderson EJ, Lustig ME, Boyle KE, Woodlief TL, Kane DA, Lin C-T, Price JW, Kang L, Rabinovitch PS, Szeto HH, Houmard JA, Cortright RN, Wasserman DH, Neufer PD. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest 2009; 119: 573-581
6 Battaglia GM, Zheng D, Hickner RC, Houmard JA. Effect of exercise training on metabolic flexibility in response to a high-fat diet in obese individuals. Am J Physiol Endocrinol Metab 2012; 303: E1440-E1445
7 Mogensen M, Sahlin K, Fernström M, Glintborg D, Vind BF, Beck-Nielsen H, Højlund K. Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes. Diabetes 2007; 56: 1592-1599
8 Hulver MW, Berggren JR, Cortright RN, Dudek RW, Thompson RP, Pories WJ, MacDonald KG, Cline GW, Shulman GI, Dohm GL, Houmard JA. Skeletal muscle lipid metabolism with obesity. AJP. Endocrinology and Metabolism 2003; 284: E741-E747
9 Boyle KE, Zheng D, Anderson EJ, Neufer PD, Houmard JA. Mitochondrial lipid oxidation is impaired in cultured myotubes from obese humans. Int J Obes (Lond) 2012; 36: 1025-1031
10 Boyle KE, Canham JP, Consitt LA, Zheng D, Koves TR, Gavin TP, Holbert D, Neufer PD, Ilkayeva O, Muoio DM, Houmard JA. A high-fat diet elicits differential responses in genes coordinating oxidative metabolism in skeletal muscle of lean and obese individuals. J Clin Endocrinol Metab 2011; 96: 775-781
11 Contreras AV, Torres N, Tovar AR. PPAR-α as a key nutritional and environmental sensor for metabolic adaptation. Adv Nutr 2013; 4: 439-452
12 Auwerx J, Schoonjans K, Fruchart JC, Staels B. Transcriptional control of triglyceride metabolism: fibrates and fatty acids change the expression of the LPL and apo C-III genes by activating the nuclear receptor PPAR. Atherosclerosis 1996; 124 Suppl S29-S37
13 Sugden MC, Zariwala MG, Holness MJ. PPARs and the orchestration of metabolic fuel selection. Pharmacol Res 2009; 60: 141-150
14 Perreault L, Bergman BC, Hunerdosse DM, Howard DJ, Eckel RH. Fenofibrate administration does not affect muscle triglyceride concentration or insulin sensitivity in humans. Metabolism 2011; 60: 1107-1114
15 Bergman BC, Hunerdosse DM, Kerege A, Playdon MC, Perreault L. Localisation and composition of skeletal muscle diacylglycerol predicts insulin resistance in humans. Diabetologia 2012; 55: 1140-1150
16 Koh KK, Han SH, Quon MJ, Yeal Ahn J, Shin EK. Beneficial effects of fenofibrate to improve endothelial dysfunction and raise adiponectin levels in patients with primary hypertriglyceridemia. Diabetes Care 2005; 28: 1419-1424
17 Idzior-Walus B, Sieradzki J, Rostworowski W, Zdzienicka A, Kawalec E, Wójcik J, Zarnecki A, Blane G. Effects of comicronised fenofibrate on lipid and insulin sensitivity in patients with polymetabolic syndrome X. Eur J Clin Invest 2000; 30: 871-878
18 Fabbrini E, Mohammed BS, Korenblat KM, Magkos F, McCrea J, Patterson BW, Klein S. Effect of fenofibrate and niacin on intrahepatic triglyceride content, very low-density lipoprotein kinetics, and insulin action in obese subjects with nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2010; 95: 2727-2735
19 Belfort R, Berria R, Cornell J, Cusi K. Fenofibrate reduces systemic inflammation markers independent of its effects on lipid and glucose metabolism in patients with the metabolic syndrome. J Clin Endocrinol Metab 2010; 95: 829-836
20 Anderlová K, Dolezalová R, Housová J, Bosanská L, Haluzíková D, Kremen J, Skrha J, Haluzík M. Influence of PPAR-alpha agonist fenofibrate on insulin sensitivity and selected adipose tissue-derived hormones in obese women with type 2 diabetes. Physiol Res 2007; 56: 579-586
21 Rasouli N, Kern PA, Elbein SC, Sharma NK, Das SK. Improved insulin sensitivity after treatment with PPARγ and PPARα ligands is mediated by genetically modulated transcripts. Pharmacogenetics and Genomics 2012; 22: 484-497
22 Peroxisome Proliferator–Activated Receptor-γ Coactivator-1α Overexpression Increases Lipid Oxidation in Myocytes From Extremely Obese Individuals. 2010; 59: 1407-1415 Available from http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=20200320&retmode=ref&cmd=prlinks
23 Boston RC, Stefanovski D, Moate PJ, Sumner AE, Watanabe RM, Bergman RN. MINMOD Millennium: a computer program to calculate glucose effectiveness and insulin sensitivity from the frequently sampled intravenous glucose tolerance test. Diabetes Technol Ther 2003; 5: 1003-1015
24 Berggren JR, Boyle KE, Chapman WH, Houmard JA. Skeletal muscle lipid oxidation and obesity: influence of weight loss and exercise. AJP. Endocrinology and Metabolism 2008; 294: E726-E732
25 Boyle KE, Newsom SA, Janssen RC, Lappas M, Friedman JE. Skeletal muscle MnSOD, mitochondrial complex II, and SIRT3 enzyme activities are decreased in maternal obesity during human pregnancy and gestational diabetes mellitus. J Clin Endocrinol Metab 2013; 98: E1601-E1609
26 Menshikova EV, Ritov VB, Toledo FGS, Ferrell RE, Goodpaster BH, Kelley DE. Effects of weight loss and physical activity on skeletal muscle mitochondrial function in obesity. AJP. Endocrinology and Metabolism 2005; 288: E818-E825
27 Consitt LA, Boyle KE, Houmard JA. Exercise as an Effective Treatment for Type 2 Diabetes. In: Type 2 Diabetes Mellitus. Totowa, NJ: Humana Press; 2008: 135-150
28 Boushel R, Gnaiger E, Schjerling P, Skovbro M, Kraunsøe R, Dela F. Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle. Diabetologia 2007; 50: 790-796
29 Fisher-Wellman KH, Weber TM, Cathey BL, Brophy PM, Gilliam LAA, Kane CL, Maples JM, Gavin TP, Houmard JA, Neufer PD. Mitochondrial respiratory capacity and content are normal in young insulin-resistant obese humans. Diabetes 2014; 63: 132-141
30 Boyle KE, Zheng D, Anderson EJ, Neufer PD, Houmard JA. Mitochondrial lipid oxidation is impaired in cultured myotubes from obese humans. Int J Obes (Lond) 2012; 36: 1025-1031
31 Noland RC, Koves TR, Seiler SE, Lum H, Lust RM, Ilkayeva O, Stevens RD, Hegardt FG, Muoio DM. Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control. J Biol Chem 2009; 284: 22840-22852
32 Seiler SE, Martin OJ, Noland RC, Slentz DH, DeBalsi KL, Ilkayeva OR, An J, Newgard CB, Koves TR, Muoio DM. Obesity and lipid stress inhibit carnitine acetyltransferase activity. J Lipid Res 2014; 55: 635-644
33 Cree MG, Newcomer BR, Read LK, Sheffield-Moore M, Paddon-Jones D, Chinkes D, Aarsland A, Wolfe RR. Plasma triglycerides are not related to tissue lipids and insulin sensitivity in elderly following PPAR-alpha agonist treatment. Mech Ageing Dev 2007; 128: 558-565
34 Yoon M, Jeong S, Lee H, Han M, Kang JH, Kim EY, Kim M, Oh GT. Fenofibrate improves lipid metabolism and obesity in ovariectomized LDL receptor-null mice. Biochem Biophys Res Commun 2003; 302: 29-34
35 Jeong S, Han M, Lee H, Kim M, Kim J, Nicol CJ, Kim BH, Choi JH, Nam K-H, Oh GT, Yoon M. Effects of fenofibrate on high-fat diet-induced body weight gain and adiposity in female C57BL/6J mice. Metabolism 2004; 53: 1284-1289
36 Furuhashi M, Ura N, Murakami H, Hyakukoku M, Yamaguchi K, Higashiura K, Shimamoto K. Fenofibrate improves insulin sensitivity in connection with intramuscular lipid content, muscle fatty acid-binding protein, and beta-oxidation in skeletal muscle. J Endocrinol 2002; 174: 321-329
37 Mancini FP, Lanni A, Sabatino L, Moreno M, Giannino A, Contaldo F, Colantuoni V, Goglia F. Fenofibrate prevents and reduces body weight gain and adiposity in diet-induced obese rats. FEBS Lett 2001; 491: 154-158
38 Murakami H, Murakami R, Kambe F, Cao X, Takahashi R, Asai T, Hirai T, Numaguchi Y, Okumura K, Seo H, Murohara T. Fenofibrate activates AMPK and increases eNOS phosphorylation in HUVEC. Biochem Biophys Res Commun 2006; 341: 973-978
39 Hong YA, Lim JH, Kim MY, Kim TW, Kim Y, Yang KS, Park HS, Choi SR, Chung S, Kim HW, Kim HW, Choi BS, Chang YS, Park CW. Fenofibrate Improves Renal Lipotoxicity through Activation of AMPK-PGC-1α in db/db Mice. PLoS ONE 2014; 9: e96147
40 Ju H, Shin H, Son C, Park K, Choi I. 3-Iodothyronamine-mediated metabolic suppression increases the phosphorylation of AMPK and induces fuel choice toward lipid mobilization. Horm Metab Res 2015; 47: 605-610
41 Lee WJ, Kim M, Park H-S, Kim HS, Jeon MJ, Oh KS, Koh EH, Won JC, Kim M-S, Oh GT, Yoon M, Lee K-U, Park J-Y. AMPK activation increases fatty acid oxidation in skeletal muscle by activating PPARalpha and PGC-1. Biochem Biophys Res Commun 2006; 340: 291-295
42 Lee SK, Lee JO, Kim JH, Kim N, You GY, Moon JW, Sha J, Kim SJ, Lee YW, Kang HJ, Park SH, Kim HS. Coenzyme Q10 increases the fatty acid oxidation through AMPK-mediated PPARα induction in 3T3-L1 preadipocytes. Cell Signal 2012; 24: 2329-2336
43 Sozio MS, Lu C, Zeng Y, Liangpunsakul S, Crabb DW. Activated AMPK inhibits PPAR-{alpha} and PPAR-{gamma} transcriptional activity in hepatoma cells. Am J Physiol Gastrointest Liver Physiol 2011; 301: G739-G747