Effects of Aerobic Exercise Training on C1q Tumor Necrosis Factor ...

J C E M

O N L I N E

B r i e f

R e p o r t — E n d o c r i n e

R e s e a r c h

Effects of Aerobic Exercise Training on C1q Tumor Necrosis Factor ␣-Related Protein Isoform 5 (Myonectin): Association with Insulin Resistance and Mitochondrial DNA Density in Women Soo Lim, Sung Hee Choi, Bo Kyung Koo, Seon Mee Kang, Ji Won Yoon, Hak Chul Jang, Soon Mi Choi, Man Gyoon Lee, Wan Lee, Hayley Shin, Young-Bum Kim, Hong Kyu Lee, and Kyong Soo Park Department of Internal Medicine (S.L., S.H.C., S.M.K., J.W.Y., H.C.J.), Seoul National University Bundang Hospital, Seongnam, Korea 463-707; Department of Internal Medicine (B.K.K.), Boramae Medical Center, Seoul, Korea 156-707; Department of Internal Medicine (S.L., S.H.C., S.M.K., J.W.Y., H.C.J., H.K.L., K.S.P.), Seoul National University College of Medicine, Seoul, Korea 110-744; Graduate School of Physical Education (S.M.C., M.G.L.), Kyung Hee University, Yongin, Korea 446-701; Department of Biochemistry (W.L.), Dongguk University College of Medicine, Kyungju, Korea 780-714; Johns Hopkins Bloomberg School of Public Health (H.S.), Baltimore, Maryland 21205; Division of Endocrinology (Y.B.K.), Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

Context: The C1q TNF␣-related protein (C1QTNF) families exhibit a C-terminal complement factor C1q globular domain similar to that of TNF. However, their clinical implications are largely unknown. We recently found that the C1q TNF␣-related protein isoform 5 (C1QTNF5 or myonectin) level was increased in insulin-resistant rodents and mitochondrial DNA (mtDNA)-depleted myocytes. Objective: We aimed to determine the effects of aerobic exercise training on C1QTNF5 level and its association with insulin resistance and mtDNA density in young and old healthy women. Design and Setting: Fourteen healthy young women aged 22.5 ⫾ 2.7 yr and 14 healthy older women aged 60.3 ⫾ 5.2 yr performed aerobic exercise at 60 – 80% of maximal oxygen consumption (VO2max) over three 1-h sessions per week for 10 wk. Insulin resistance was assessed by homeostasis model assessment of insulin resistance and adiponectin concentration. Serum C1QTNF5 level was estimated by immunoblotting. The mtDNA/28S rRNA ratio was used to determine mtDNA density. Results: VO2max increased significantly after the exercise training from 33.1 ⫾ 6.2 to 35.3 ⫾ 5.3 ml/kg 䡠 min in younger women and from 23.2 ⫾ 3.1 to 27.2 ⫾ 4.8 ml/kg 䡠 min in older women (P ⬍ 0.05). The C1QTNF5 level and homeostasis model assessment of insulin resistance decreased significantly after exercise training and were correlated positively (r ⫽ 0.462; P ⬍ 0.01). There were negative correlations between the changes in C1QTNF5 level and the changes in VO2max, mtDNA density, and adiponectin level (r ⫽ ⫺0.495, ⫺0.672, and ⫺0.569, respectively; all P ⬍ 0.01). Conclusion: These findings suggest a physiological function for C1QTNF5 (myonectin) in linking insulin resistance with quantitative changes in mtDNA. Further research exploring the role of C1QTNF5 in the development of insulin resistance is warranted. (J Clin Endocrinol Metab 97: E88 –E93, 2012)

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2012 by The Endocrine Society doi: 10.1210/jc.2011-1743 Received June 11, 2011. Accepted October 3, 2011. First Published Online October 26, 2011

E88

jcem.endojournals.org

Abbreviations: AMPK, AMP-activated protein kinase; AUC, area under the curve; BMI, body mass index; C1QTNF5, C1q TNF-␣-related protein isoform 5; HNF, hepatocyte nuclear factor; HOMA, homeostasis model assessment; LDL, low-density lipoprotein; mtDNA, mitochondrial DNA; OGTT, oral glucose tolerance test; VO2max, maximal oxygen consumption.

J Clin Endocrinol Metab, January 2012, 97(1):E88 –E93


itochondrial DNA (mtDNA) plays a key role in mitochondrial function, and quantitative as well as qualitative changes in mtDNA are associated with impaired glucose regulation (1–3). It was demonstrated that mitochondrial density was reduced in muscle of insulinresistant offspring of type 2 diabetic parents, and mitochondrial function was dependent on mtDNA density (4, 5). Thus, a low level of mtDNA density is explicitly implicated in the etiology of insulin resistance (6, 7). C1q TNF-␣-related protein isoform 5 (C1QTNF5 or myonectin) belongs to a family of proteins characterized by an N-terminal signal peptide, a collagen repeat domain, and a C-terminal C1q-like globular domain (8). C1QTNF5 (myonectin) is homologous to adiponectin with respect to domain structure and its expression and secretion from myocytes. However, unlike adiponectin, which is expressed exclusively by differentiated adipocytes, C1QTNF are expressed in a wide variety of tissues and appear to have more structural or extracellular matrix-related functions (9). Until recently, the roles of C1QTNF have been largely unknown. In one study, C1QTNF5 was expressed in the retinal pigment epithelium, and mutations in this gene caused late-onset retinal macular degeneration in humans (10). Wong et al. (8) reported that injecting mice with C1QTNF5 had no effect on their glucose levels. However, our group demonstrated the increased level of C1QTNF5 (myonectin) in mtDNA-depleted myocytes and its association with elevated AMP-activated protein kinase (AMPK) activity. Moreover, the serum level of myonectin increased significantly in obese/diabetic animals (11). These findings suggest that myonectin may have a functional role in insulin resistance. Regular exercise is known to increase insulin sensitivity (12), and the beneficial effects of exercise training on glucose metabolism can be explained by multiple mechanisms including increase in mtDNA density (13, 14). Thus, we investigated the effects of aerobic exercise training on myonectin levels and its association with mtDNA density and surrogate indices of insulin resistance in both young and old healthy women.

M

Subjects and Methods Study participants A total of 56 women (mean age, 45.6 yr) from a local fitness center were recruited and underwent a 2-h, 75-g oral glucose tolerance test (OGTT) as a screening test. Among them, five subjects were diabetics, three subjects had impaired fasting glucose, and 10 subjects had impaired glucose tolerance as determined by fasting or postload glucose criteria and were all excluded. One current smoker and seven other participants with hypertension (n ⫽ 5) or cardiovascular diseases (n ⫽ 2) were also excluded. Two subjects were excluded because their age was not


E89

appropriate for the current study. Finally, 14 healthy young women aged 18 –28 yr (younger group) and 14 healthy elderly women aged 55–77 yr (older group) were selected to assess agerelated differences in myonectin levels. None of the participants were taking ␤-blockers, diuretics, corticosteroids, or any other medications known to significantly affect metabolic parameters. Elderly women were all postmenopausal without hormone replacement therapy, and young women were not taking oral contraceptives. All subjects volunteered to participate in the study and provided written informed consent. The study protocol was approved by Seoul National University Hospital Ethics Committee (B-1011/115-004).

Anthropometric and biochemical parameters Height, weight, waist circumference, and blood pressure were measured by standard methods. All participants underwent a 2-h, 75-g OGTT at baseline and after 10 wk of exercise training. The total integrated glucose response during the OGTT was quantified by calculating the area under the curve (AUC) of changes in theplasmaglucoseconcentrationwithtime(AUCglucose).The homeostasis model assessment (HOMA) was used for assessing pancreatic ␤-cell function (HOMA-␤) and insulin resistance (HOMA-IR). Adiponectin level was measured using an ELISA kit (Adipogen Inc., Seoul, Korea).

Exercise program The exercise training program consisted of three sessions of aerobics per week for 1 h per session performed at 60 – 80% maximal oxygen consumption (VO2max). The percentage of attendance for all subjects was 95%. VO2max was determined by a maximal graded exercise test, performed on a bicycle ergometer (Combi, Tokyo, Japan). The test protocol comprised three increments of loading every 4 min, after which the load was increased by 15–20 W/min until volitional exhaustion. Expired gas was collected in a Douglas bag, and oxygen consumption and carbon dioxide production were analyzed with an expired-gas monitor (model 1H2A; San-Ei, Tokyo, Japan).

Quantification of C1QTNF5 and quantitative realtime PCR measurement of mtDNA density Serum C1QTNF5 was analyzed semiquantitatively by immunoblotting (Supplemental Fig. 1, published on The Endocrine Society’s JournalsOnlinewebsiteathttp://jcem.endojournals.org).Apolyclonal antibody against human C1QTNF5 was raised in rabbits using the synthetic peptide SAKRSESRVPPPSDAPLC (amino acids 107–123 located on the globular domain of human C1QTNF5). The relative mtDNA density was measured by quantitative PCR through simultaneous measurement of a nuclear gene (28S rRNA) with an ABI Prism 7900HT (Applied Biosystems, Foster City, CA). The mtDNA/28S rRNA ratio was used to determine the mtDNA density. Detailed protocol is described in the online supplement.

Statistical analysis All data are presented as the mean ⫾ SD. Student’s t test was used to compare variables between the groups, and paired t tests were used to analyze changes in mean parameters before and after exercise training. Pearson’s correlation coefficient was estimated to analyze any correlation between parameters. To test for an independent association between C1QTNF5 level and

E90

Lim et al.

Aerobic Exercise Training and C1QTNF5 Levels


insulin resistance, multivariate regression models including age, baseline body mass index (BMI), ⌬triglycerides, ⌬low-density lipoprotein (LDL)-cholesterol, and ⌬VO2max as covariates and ⌬HOMA-IR or ⌬adiponectin as a dependent variable were conducted. SPSS for Windows version 15.0 (SPSS Inc., Chicago, IL) was used for analyses, and P ⬍ 0.05 was considered statistically significant.

Results

(Table 1). After 10 wk of exercise training, the mtDNA density increased, whereas the C1QTNF5 level decreased significantly in both groups (Fig. 1, A and B). Correlations of preexercise C1QTNF5 level with mtDNA density, HOMA-IR, adiponectin, and VO2max At baseline, there was no significant correlation between C1QTNF5 levels and mtDNA density, HOMA-IR, adiponectin, and VO2max levels, except between C1QTNF5 levels and HOMA-IR in the older group (r ⫽ 0.346; P ⬍ 0.05) (Supplemental Fig. 2).

Changes of physiological and biochemical parameters before and after exercise Body weight, BMI, waist circumference, and blood pressure decreased significantly in the older but not in the younger group. In both groups, fasting plasma glucose and insulin levels, total and LDL-cholesterol concentrations, and HOMA-IR and AUCglucose values decreased significantly, whereas high-density lipoprotein-cholesterol and adiponectin concentrations and VO2max increased significantly after the exercise training (Table 1).

Correlations between the change in C1QTNF5 level and changes of various parameters Changes in serum C1QTNF5 levels were correlated significantly with changes in VO2max, mtDNA density, HOMA-IR, and adiponectin levels in both age groups (Fig. 1, C–F).

Changes in C1QTNF5 level and mtDNA density after exercise training The baseline C1QTNF5 level was significantly higher in the older group than the younger group (P ⬍ 0.05)

Multivariate regression analysis for independent associations with insulin resistance In the multivariate regression model with age, baseline BMI, ⌬triglycerides, ⌬LDL-cholesterol, and

TABLE 1. Changes in anthropometric and biochemical parameters after 10 wk of exercise training in the younger and older groups of healthy women Younger age group Age 关yr (range)兴 Height (cm) Body weight (kg) BMI (kg/m2) Waist circumference (cm) SBP (mm Hg) DBP (mm Hg) FPG (mg/dl) FPI (␮IU/ml) TC (mg/dl) TG (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) HOMA-IR HOMA-␤ AUCglucose Adiponectin (␮g/ml) VO2max (ml/kg/min) mtDNA density C1QTNF5

Before exercise 22.5 ⫾ 2.7 (18 –28) 160.9 ⫾ 4.1 57.5 ⫾ 4.3 22.2 ⫾ 1.8 67.8 ⫾ 4.9 115.9 ⫾ 10.9 74.2 ⫾ 8.8 84.9 ⫾ 11.8 10.2 ⫾ 2.7 179.2 ⫾ 15.9 94.2 ⫾ 26.9 56.9 ⫾ 10.3 89.7 ⫾ 17.7 1.9 ⫾ 0.4 235.8 ⫾ 235.4 256.7 ⫾ 23.7 7.9 ⫾ 2.3 33.1 ⫾ 6.2 555.2 ⫾ 300.0 58.37 ⫾ 10.93

After exercise

55.1 ⫾ 5.1 21.3 ⫾ 2.5 66.2 ⫾ 5.0 116.2 ⫾ 7.6 73.6 ⫾ 6.0 81.7 ⫾ 6.9c 8.8 ⫾ 3.4c 173.1 ⫾ 20.7b 82.3 ⫾ 18.3 60.0 ⫾ 7.3c 87.9 ⫾ 20.3b 1.8 ⫾ 0.7b 215.2 ⫾ 185.6 249.5 ⫾ 33.6b 9.8 ⫾ 4.2b 35.3 ⫾ 5.3b 652.2 ⫾ 288.4b 46.59 ⫾ 13.99c

Older age group Before exercise 60.3 ⫾ 5.2 (55–71)a 156.1 ⫾ 4.3a 61.9 ⫾ 6.3a 25.4 ⫾ 2.9a 74.6 ⫾ 8.1a 134.7 ⫾ 9.5a 85.2 ⫾ 9.1a 87.9 ⫾ 8.2 13.0 ⫾ 3.0a 211.0 ⫾ 24.2a 125.4 ⫾ 46.0a 49.9 ⫾ 12.2a 125.4 ⫾ 22.9a 2.8 ⫾ 0.9a 212.8 ⫾ 88.4 276.3 ⫾ 35.9a 12.7 ⫾ 5.9a 23.2 ⫾ 3.1a 377.7 ⫾ 221.3 62.75 ⫾ 14.55a

After exercise

58.3 ⫾ 6.0c 23.9 ⫾ 2.7c 72.1 ⫾ 6.3c 126.4 ⫾ 8.9c 79.3 ⫾ 5.0c 83.0 ⫾ 6.7c 9.9 ⫾ 3.1c 190.1 ⫾ 27.9c 113.9 ⫾ 38.9c 56.2 ⫾ 8.4c 102.7 ⫾ 25.3c 2.0 ⫾ 0.6c 211.0 ⫾ 132.7 255.8 ⫾ 34.0c 15.7 ⫾ 5.5c 27.2 ⫾ 4.8b 514.1 ⫾ 242.1b 46.66 ⫾ 16.99c

All data are expressed as the mean ⫾ SD. DBP, Diastolic blood pressure; FPG, fasting plasma glucose; FPI, fasting plasma insulin; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides. Student’s t test was used to compare means of parameters between the younger and older age groups. Paired t tests were used to analyze changes in parameters before and after exercise. a

P ⬍ 0.05 by Student’s t test.

b

P ⬍ 0.05 by paired t test.

c

P ⬍ 0.01 by paired t test.



E91

Discussion In this study, a 10-wk exercise training program increased VO2max, mtDNA density, and plasma adiponectin level significantly and decreased HOMA-IR and C1QTNF5 (myonectin) levels significantly in both groups of women. Changes in the myonectin level were correlated positively with changes in HOMA-IR and negatively with changes in VO2max, mtDNA density, and adiponectin level. The C1QTNF proteins have a C-terminal complement factor C1q globular domain with a molecular structure similar to that of TNF. Seven members of these widely expressed adiponectin paralogs (C1QTNF1–7) share a similar modular organization to adiponectin (15). Among the C1QTNF families, C1QTNF5 is expressed in a wide variety of tissues and appears to have more structural or extracellular matrixrelated functions (9). We have recently demonstrated that treatment with myonectin phosphorylated AMPK in myocytes, increased glucose uptake via activating the AMPK signaling pathway, and subsequently stimulated glucose FIG. 1. A and B, Changing patterns in C1QTNF5 level (A) and mtDNA (B) density after 10 wk transporter-4 translocation in skeletal of aerobic exercise training in younger and older groups of healthy women. The C1QTNF5 muscle cells (11). Furthermore, mylevels decreased significantly, and mtDNA density increased significantly in both groups. The onectin levels were increased signifidecreases in C1QTNF5 level and increases in mtDNA density were significantly greater in the older group than younger group. *, P ⬍ 0.05 between groups; †, P ⬍ 0.05 for changes cantly in obese/diabetic animals such as measured before and after the training program. C–F, Correlation between changes in ob/ob and db/db mice (11). It was also C1QTNF5 levels and changes in VO2max (C), mtDNA density (D), HOMA-IR value (E), and demonstrated that myonectin was actiadiponectin levels (F) in the younger and older groups. vated by hepatocyte nuclear factor (HNF)-4␣ via the region ⫺206 to ⫺167 ⌬mtDNA density as covariates and ⌬HOMA-IR as a of the human C1QTNF5 promoter. Thus, HNF-4␣-independent variable, ⌬C1QTNF5 and ⌬VO2max were duced C1QTNF5 promoter activity was decreased signifsignificantly associated with ⌬HOMA-IR after adjusticantly by the deletion of this region (16). In addition, the ing for other variables (P ⫽ 0.032 and 0.023, respecregulation of HNF-4␣ activities is an important mechatively) (Supplemental Table 1). When ⌬adiponectin was nism involved in exercise-induced improvement of glucose used as a dependent variable instead of ⌬HOMA-IR, homeostasis in insulin-resistant states (17). In a prelimiindependent associations with ⌬C1QTNF5 and ⌬VO2max were maintained (P ⫽ 0.041 and 0.028, re- nary assessment, we found that semiquantitatively measpectively). To account for the BMI difference and its sured C1QTNF5 levels were higher in people with type 2 potential confounding effects between two groups, fur- diabetes than those with normal insulin sensitivity ther analysis was done after excluding four overweight (58.6 ⫾ 16.1 vs. 43.2 ⫾ 18.1, P ⬍ 0.05; n ⫽ 8 in each). These subjects whose BMI was over 25.0 kg/m2 in the older findings along with the current study results suggest that age group. As a result, significant associations between C1QTNF5 might be closely associated with insulin resistance. Moderate-intensity exercise training similar to our pro⌬C1QTNF5 and ⌬HOMA-IR or ⌬adiponectin were maintained. gram improved mitochondrial oxidative enzyme activities

E92

Lim et al.

Aerobic Exercise Training and C1QTNF5 Levels

in skeletal muscle (18, 19). In this study, a 10-wk aerobic exercise training regimen increased mtDNA density by 6.6% in the younger group and by 17.2% in the older group. In addition, there were inverse changes in mtDNA density and C1QTNF5 expression level. Decreased mtDNA density and mitochondrial dysfunction are both implicated in the pathogenesis of diabetes and metabolic syndrome (3, 5). Indeed, mtDNA density was decreased to 50% of normal in the muscle tissue of patients with diabetes (20). Of note, the exercise-induced changes in C1QTNF5 expression showed an inverse association with changes in the adiponectin level in this study. Taken together, these investigations along with the negative correlation between expression/secretion of C1QTNF5 and mtDNA density in our previous study (11) may postulate a link between C1QTNF5 and insulin resistance. The baseline C1QTNF5 level and the reduction in C1QTNF5 expression in response to exercise training were greater in the elderly women than the younger women. In addition, there was a significant correlation between the baseline C1QTNF5 level and the HOMA-IR in the older but not in the younger group. Although the reason for the poor correlation in the younger group is not entirely clear, it may be explained by the differences in the degree of insulin resistance and mtDNA density between older and younger groups. In these young women, the baseline insulin resistance was not elevated and might not be a good metabolic indicator for exercise intervention. The younger subjects might have been more physiologically fit at the beginning of the study. Therefore, the beneficial effects of exercise in this age group might have been less pronounced than older women. Other possible explanations for the poor correlation are 1) only healthy volunteers were selected, 2) a relatively small number of participants were selected, and 3) establishment of a more exquisite method for C1QTNF5 measurement may be useful in detecting more subtle difference. In summary, a 10-wk supervised exercise training program performed at moderate intensity resulted in significant decreases in C1QTNF5 (myonectin) level and insulin resistance parameters in both younger and older groups of women. Exercise-induced changes in the C1QTNF5 level were associated with changes in VO2max, mtDNA density, adiponectin levels, and the HOMA-IR. These findings suggest a physiological function for C1QTNF5 because one mechanism linking insulin resistance with quantitative changes in mtDNA. Further research exploring the role and molecular mechanism of C1QTNF5 in the development of insulin resistance is warranted.


Acknowledgments Address all correspondence and requests for reprints to: Kyong Soo Park, M.D., Ph.D., Seoul National University College of Medicine, Department of Internal Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul, Korea 110-744. E-mail: [email protected]. This work was supported by the Ministry of Science and Technology (2006-2005410), the Korea Healthcare R&D Project, Ministry of Health and Welfare (A100370), the 21C Frontier Functional Proteomics Project (FPR08A1-070) to K.S.P., National Research Foundation of Korea Grant (NRF-2010-371E00005), and Korean Diabetes Association Grant (2009) to B.K.K. Disclosure Summary: The authors declare no conflict of interest.

References 1. Lowell BB, Shulman GI 2005 Mitochondrial dysfunction and type 2 diabetes. Science 307:384 –387 2. Park KS, Nam KJ, Kim JW, Lee YB, Han CY, Jeong JK, Lee HK, Pak YK 2001 Depletion of mitochondrial DNA alters glucose metabolism in SK-Hep1 cells. Am J Physiol Endocrinol Metab 280:E1007– E1014 3. Wallace DC 2005 A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359 – 407 4. Morino K, Petersen KF, Dufour S, Befroy D, Frattini J, Shatzkes N, Neschen S, White MF, Bilz S, Sono S, Pypaert M, Shulman GI 2005 Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest 115:3587–3593 5. Phielix E, Meex R, Moonen-Kornips E, Hesselink MK, Schrauwen P 2010 Exercise training increases mitochondrial content and ex vivo mitochondrial function similarly in patients with type 2 diabetes and in control individuals. Diabetologia 53:1714 –1721 6. Bonnard C, Durand A, Peyrol S, Chanseaume E, Chauvin MA, Morio B, Vidal H, Rieusset J 2008 Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulinresistant mice. J Clin Invest 118:789 – 800 7. Wang CH, Wang CC, Wei YH 2010 Mitochondrial dysfunction in insulin insensitivity: implication of mitochondrial role in type 2 diabetes. Ann NY Acad Sci 1201:157–165 8. Wong GW, Krawczyk SA, Kitidis-Mitrokostas C, Revett T, Gimeno R, Lodish HF 2008 Molecular, biochemical and functional characterizations of C1q/TNF family members: adipose-tissue-selective expression patterns, regulation by PPAR-␥ agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions. Biochem J 416:161–177 9. Tom Tang Y, Hu T, Arterburn M, Boyle B, Bright JM, Palencia S, Emtage PC, Funk WD 2005 The complete complement of C1qdomain-containing proteins in Homo sapiens. Genomics 86:100 – 111 10. Hayward C, Shu X, Cideciyan AV, Lennon A, Barran P, Zareparsi S, Sawyer L, Hendry G, Dhillon B, Milam AH, Luthert PJ, Swaroop A, Hastie ND, Jacobson SG, Wright AF 2003 Mutation in a shortchain collagen gene, CTRP5, results in extracellular deposit formation in late-onset retinal degeneration: a genetic model for age-related macular degeneration. Hum Mol Genet 12:2657–2667 11. Park SY, Choi JH, Ryu HS, Pak YK, Park KS, Lee HK, Lee W 2009 C1q tumor necrosis factor ␣-related protein isoform 5 is increased in mitochondrial DNA-depleted myocytes and activates AMP-activated protein kinase. J Biol Chem 284:27780 –27789


12. Lim S, Kim SK, Park KS, Kim SY, Cho BY, Yim MJ, Lee HK 2000 Effect of exercise on the mitochondrial DNA content of peripheral blood in healthy women. Eur J Appl Physiol 82:407– 412 13. Goodyear LJ, Kahn BB 1998 Exercise, glucose transport, and insulin sensitivity. Annu Rev Med 49:235–261 14. Wang H, Hiatt WR, Barstow TJ, Brass EP 1999 Relationships between muscle mitochondrial DNA content, mitochondrial enzyme activity and oxidative capacity in man: alterations with disease. Eur J Appl Physiol Occup Physiol 80:22–27 15. Wong GW, Wang J, Hug C, Tsao TS, Lodish HF 2004 A family of Acrp30/adiponectin structural and functional paralogs. Proc Natl Acad Sci USA 101:10302–10307 16. Kim MJ, Lee W, Park EJ, Park SY 2010 Role of hepatocyte nuclear


17.

18. 19.

20.

E93

factor-4␣ in transcriptional regulation of C1qTNF-related protein 5 in the liver. FEBS Lett 584:3080 –3084 De Souza CT, Frederico MJ, da Luz G, Cintra DE, Ropelle ER, Pauli JR, Velloso LA 2010 Acute exercise reduces hepatic glucose production through inhibition of the Foxo1/HNF-4␣ pathway in insulin resistant mice. J Physiol 588:2239 –2253 Henriksson J 1992 Effects of physical training on the metabolism of skeletal muscle. Diabetes Care 15:1701–1711 Robinson DM, Ogilvie RW, Tullson PC, Terjung RL 1994 Increased peak oxygen consumption of trained muscle requires increased electron flux capacity. J Appl Physiol 77:1941–1952 Antonetti DA, Reynet C, Kahn CR 1995 Increased expression of mitochondrial-encoded genes in skeletal muscle of humans with diabetes mellitus. J Clin Invest 95:1383–1388

Learn more about The Endocrine Society’s timely resources on Translational Research and Medicine. http://www.endo-society.org/translational