Can physical exercise and exercise mimetics improve metabolic health in humans?

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1 Can physical exercise and exercise mimetics improve metabolic health in humans? Patrick Schrauwen, PhD NUTRIM school for Nutrition and Translational Research in Metabolism Department of Human Biology, Maastricht University

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3 Domino effect: diabetes increases risk on many complications

4 Obesity is the major risk factor for type 2 diabetes > 90% of type 2 diabetes patients is obese!

5 Ectopic fat accumulation connects obesity with metabolic disorders

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7 Muscle fat accumulation (IMCL) is negatively associated with insulin sensitivity Krssak et al., Diabetologia 2002 Sinha et al., Diabetes 2002 Fourouhi et al., Diabetologia 1999 Jacob et al., Diabetes 1999

8 Lipotoxicity; a delicate balance between oxidation and storage? Dietary fat Storage Fat Oxidation

9 Q: Is mitochondrial dysfunction the basis for lipotoxicity?

10 signal intensity (arbitrary units) Relative PCr content Knee extension Against weight 31 P-coil Exercise is performed in MRI scanner during 31P-MRS measurement PCr 100% 80% ATP p i 60% relative resonance frequency 40% time (s) rest exercise recovery

11 Decreased in vivo mitochondrial function in T2DM and first-degree relatives p<0.05 # p=0.08 Phielix et al., Diabetes 2008

12 Intrinsic mitochondrial function using highresolution respirometry O2 Concentration (A) [nmol/ml] State 3 O2 Flux per V (A) [pmol/(sml)] State u :00:00 00:07:30 00:15:00 00:22:30 00:30:00 00:37:30 Range [hh:mm:ss]: 00:45:00 vezels mal glut A DP succ FCCP +1+1 R1 00:19:06 00:21:30 00:26:07 00:33:39 00:36: :45:00

13 intrinsic mitochondrial function is decreased in T2DM and FDR cont fdr t2dm cont fdr t2dm No differences in mtdna copy number Phielix et al., Diabetes 2008

14 Conclusion: Diabetes is associated with lower mitochondrial function in skeletal muscle Q: does an improved mitochondrial function improve insulin resistance?

15 12 week endurance and strength training programme Meex et al., Diabetes 2010

16 Study design Screening Baseline measurements Training 12 weeks Post intervention measurements ` Resistance training: 1x/week, 8 exercises 1 set, 8 repetitions, 50% of MVC 2 sets, 8 repetitions, 75% of MVC Endurance training: 2x/week. 30 minutes on 55% of max power output With permission Progressive training program 5 minutes of warming up and cooling down before and after every training session on 45% of max power output on the ergometer Supervised training and heart rate monitored

17 ml/min/kg body mass watt Exercise training improves physical performance VO2max/kg body mass Maximal power output C T2D 0 C T2D Data are means ± SE Before training After training Meex et al., Diabetes 2010

18 % kg Exercise training barely affects body mass or composition Body mass Fat percentage C T2D 0 C T2D Data are means ± SE No changes in fat free mass Before training After training Meex et al., Diabetes in press Meex et al., Diabetes 2010

19 Exercise training improves metabolic flexibility Metabolic flexibility (Δ RER) Δ CHO oxidation (g/h) Δ Fat oxidation (g/h) C T2D C T2D C T2D Data are means ± SE Before training After training Meex et al., Diabetes 2010

20 PCr recovery rate constant (s -1 ) OXPHOS protein content Exercise training improves mitochondrial function Mitochondrial function (MRS) Mitochondrial density ,06 0,05 0,04 0,03 0,02 0,01 0,00 C T2D 2,0 1,8 1,6 1,4 1,2 1,0 0,8 0,6 0,4 0,2 0,0 C T2D Data are means ± SE Before training After training Meex et al., Diabetes 2010

21 Delta Rd (umol/kg/min) Exercise training improves insulin sensitivity Enodgenous glucose production umol/kg/min Muscle insulin sensitivity Before training After training C T2D hepatic insulin sensitivity basal 4 insulin 2 Meex et al., Diabetes C C pre training post training T2D pre training T2D post training

22 Q: What about effects beyond muscle metabolism?

23 Quantification of cardiac lipid content by 1 H-MRS 128 averages CH 2 CH resonance frequency (ppm) cardiac triggering and breath holds, breathing commands or respiratory gating (resp. sensor or navigator)

24 Exercise training decreases cardiac lipid content in obese subjects Schrauwen-hinderling et al., JCEM 2010

25 Exercise training and metabolic risk Not all subjects respond similarly to exercise training subjects with a high baseline ALAT activity (marker of fatty liver) improve more in TG, HDL, VLDL Optimizing the exercise regime for diabetes also needs focus on the liver!

26 Mitochondrial function?fatty liver glucose uptake insulin sensitivity fatty acid handling metabolic flexibility VLDL-TG output FA clearance inflammatory lipids Glucose output reduced metabolic risk

27 Conclusion: Exercise training improves metabolic health Q: can mitochondrial function be improved without exercise?

28 Calorie restriction mimetics that target sirtuin 1 Sirtuin 1 (SIRT1) = NAD + -dependent histone deacetylase SIRT1 acts as a metabolic sensor, capable of modulating gene expression according to the metabolic state of the cell In 2003, Howitz and colleagues performed an in vitro screen to identify small molecule activators of SIRT1 and identified resveratrol as the most potent activator (Howitz et al., 2003, Nature)

29 Resveratrol Polyphenolic compound Main dietary sources: grapes, wine, peanuts Richest source: Japanese knotweed

30 Q: Can mitochondrial function be improved by functional foods? Hoeks and Schrauwen, TEM 2012

31 Resveratrol in rodents Prevented weight gain in mice on a high-fat diet Improved various biomarkers in the plasma: triglycerides, FFA levels, glucose and insulin values Improved insulin sensitivity Activated AMPK and SIRT1 Increased mitochondrial number and decreases acetylation of PGC-1α Resveratrol shifts the metabolic phenotype of mice on a high-calorie diet towards those on a standard chow diet Baur et al., 2006, Nature Lagouge et al., 2006, Cell

32 Clinical study design placebo d0 d7 d14 d21 d29 d30 placebo d0 d7 d14 d21 d29 d30 resveratrol resveratrol d0 d7 d14 d21 d29 d30 d0 d7 d14 d21 d29 d30 placebo / resveratrol d0 d7 d14 d21 d28 d30 Body weight Blood sample DEXA scan VO 2 max test Body weight Blood sample Body weight Blood sample Body weight Blood sample Intrahepatic lipid content Mitochondrial function Respiration chamber Body weight Blood sample Muscle biopsy Microdialysis test Timmers et al., Cell Metabolism 2011

33 Subjects baseline characteristics (day 0) Timmers et al., Cell Metabolism 2011

34 FIGURE 2 A Molecular mechanism of resveratrol C Mouse vehicle RSV placebo B placebo RSV placebo NDUFB11 NDUFA3 NDUFS6 ETFB NDUFS8 COX7B COX7C UQCRB NDUFB9 SDHC KEGG pathway: oxidative phosphorylation FYN HLA C CBL IFNAR2 JAK1 IRF1 STAT5A ISG20 PRKCD IRAK4 RSV RSV Timmers et al., Cell Metabolism 2011

35 Molecular mechanism of resveratrol pampk / AMPK placebo resveratrol SIRT1 / tubulin placebo resveratrol Timmers et al., Cell Metabolism 2011

36 Mitochondrial metabolism Timmers et al., Cell Metabolism 2011

37 Energy metabolism (day 30) SMR (MJ/d) placebo resveratrol h EE (MJ/d) body weight (kg) placebo resveratrol 0 placebo resveratrol Timmers et al., Cell Metabolism 2011

38 Adipose tissue Konings et al., IJO 2014

39 FIGURE 4 A FIGURE 4 A 4 B B Relative signal intensity Relative signal intensity Relative signal intensity Relative signal intensity (scaled to water resonance) Ectopic lipid accumulation placebo resveratrol 4 placebo resveratrol placebo 3 resveratrol (scaled to water resonance) (scaled to water resonance) (scaled to water resonance) placebo RSV 0 Relative resonance 0frequency (ppm) placebo RSV Relative 3 resonance frequency 3 (ppm) placebo Relative 1 0 resonance frequency (ppm) placebo RSV Relative resonance type frequency 1 stain (ppm) oil-red-o type 1 stain oil-red-o type 1 stain oil-red-o type 1 stain oil-red-o placebo placebo placebo placebo 20 20resveratrol placebo resveratrol resveratrol resveratrol 1 placebo resveratrol Liver fat (%) 3 2 Muscle fat (area fraction) Liver fat (%) Muscle fat (area fraction) Liver fat (%) Liver fat (%) 1 Muscle fat (area fraction) Muscle fat (area fraction) total 0 type 1 0 type 2 total total type 1 type type 1 2 type RSV placebo placebo resveratrol resveratrol placebo resveratrol total type 1 type 2 Timmers et al., Cell Metabolism 2011

40 Blood pressure

41 Plasma biochemistry (day 30) Timmers et al., Cell Metabolism 2011

42 There is more than resveratrol: central role for nutritional sensors in regulating mitochondrial function

43 Acipimox a lipolysis inhibitor - increased rather than decreased FFA: rebound effect Type 2 diabetic patients treated with acipimox or placebo for 2 weeks

44 Acipimox a NAD+ analogue increases muscle mitochondrial function in humans Type 2 diabetic patients treated with acipimox or placebo for 2 weeks C2C12 Van de Weijer et al., Diabetes 2014

45 Conclusion: Mitochondrial function can be improved by NAD+ boosters, also in humans Clinical intervention studies are needed to test if NAD+ is a target to prevent/treat type 2 diabetes

46 Stimulating energy turnover as a target to improve metabolic health Dietary fat Storage Fat Oxidation