Effects of exercise training on hepatic steatosis in high fat diet-induced obese mice

Transcription

1 Effets of exerise trining on hepti stetosis in high ft diet-indued oese mie Hyunsik Kng, PhD Sungkyunkwn University

2 Non-Aloholi Ftty Liver Disese (NAFLD) A reversile ondition tht is hrterized y hepti lipid umultion in the sene of signifint lohol onsumption. (Soure: Wikipedi, the free enylopedi)

3 NAFLD Spetrum of Disese Stetosis Stetoheptitis (NASH) NASH with Firosis Cirrhosis

4 By 2020

5 Risk Ftors for NAFLD Oesity Type 2 DM Dyslipidemi Metoli syndrome Insulin Resistne (IR) (modified from J Clin Gstroenterol., 40: S1, 2006) NAFLD is hepti mnifesttion of insulin resistne

6 Current Guidelines for NAFLD Dietry restrition plus inresed physil tivity shows ler hepti enefits when weight loss pproximtely 3%-10% of ody weight is hieved (Sreenivs et l., 2006 J Gstroenterol Heptol; Lrson-Meyer et l., 2006 Dietes Cre). The poor sustinility of weight loss hllenges the urrent therpeuti fous on weight loss nd highlights the need for lterntive strtegies for NAFLD mngement. Epidemiologi dt show n independent reltionship etween ftty liver, physil tivity nd physil fitness (Churh et l., 2006 Gstroenterology; MMilln et l., 2007 Appy Physiol Nutr Met). A growing ody of longitudinl reserh demonstrtes tht inresed physil tivity per se signifintly redues hepti stetosis nd serum minotrnsferse in individuls with NAFLD, independent of weight loss (St George et l., 2009 Heptology; Kntrtzis et l., 2009 Gut).

7 Aims of the Study To study the role(s) of physil tivity per se s therpeuti mens ginst oesity-indued NAFLD. To delinete the mehnisti insights to explin the hepti enefits of inresed physil tivity.

8 Desription of Study Design Stndrd Chow (SC, n=20) SC+SED (n=10) C57BL/6 mie t 5-wk (N=60) HFD + SED (n=10) High-Ft Diet (HFD, n=40) 60% high-ft diet HFD+HIT (n=10) HFD + MIT (n=10) Adption First 8 weeks Seond 8 weeks **SED: sedentry; MIT: moderte-intensity trining; HIT: high-intensity trining

9 Exerise Trining Protool A. High-intensity trining (HIT) Wrm-up 17m/min Tredmill running Cool-down 8m/min 10m/min 5 min 1 min 2 min 1-yle Totl exerise time: 46 min Totl distne: 524 m 12 yles 8m/min 5 min B. Moderte-intensity trining (MIT) 8m/min 10m/min 8m/min 5 min 5 min 44 min Totl exerise time: 54 min Totl distne: 524 m Tredmill running

10 Primry Mesurements of the Study - Body mss - Immunostining (i.e., Oil-Red O, H & E, Trihome stining) - Gluose tolerne test (GTT) nd insulin tolerne test (ITT) - Blood lipoprotein lipids - Asprte minotrnsferse (AST) nd lnine minotrnsferse (ALT) - Adiponetins in serum nd dipose tissue - Rel time-pcr for mrnas nd Western lot for proteins

11 RESULTS

12 After the initil 8 weeks of High-Ft Diet

13 Gluose (mg/dl) Gluose (mg/dl) Weight (g) A. C57BL/6 mie B. Chnges in ody weight SC HFD * * * * * SC HFD Time (wk) C. Gluose tolerne test D. Insulin tolerne test * * * SC HFD SC HFD * Time (min) Time (min)

14 Serum AST(U/l) Serum ALT(U/l) A. H&E stining in hepti tissue mrovesiulr stetosis SC HFD B. Serum sprtte- nd lnine-minotrnsferse 70 p=1 60 p= SC HFD 0 SC HFD

15 Serum TC (mg/dl) Serum diponetin (μg/ml) A. Serum totl holesterol (TC) levels B. Serum totl diponetin levels 250 p = p = SC HFD SC HFD

16 A 60% HFD for 8 weeks results in : 1) n oese nd insulin resistne phenotype, 2) hepti stetosis nd injury, 3) elevted risk for rtheroslerosis, 4) hypodiponetinemi.

17 Effets of exerise trining intervened t the seond hlf of the 16-week highft diet regimen

18 Exerise trining ttenutes weight gins, hepti injury, nd rtherosleorosis seondry to HFD, with no signifint intensity-dependent differenes. Tle 1. Metoli profiles fter the 16-wk HFD nd/or exerise trining SC+SED HFD+SED HFD+HIT HFD+MIT Finl ody mss, g 32.5± ± ± ±1.7 ALT, U/l 31.5± ± ± ±19.9 AST, U/l 54.0± ± ± ±32.8 FFA, meq/l 2.1± ± ±9 2.0±0.18 TG, mg/dl 61.2± ± ± ±9.4 TC, mg/dl 88.2± ± ± ±12.5 d HDLC, mg/dl 43.6± ± ± ±17.5

19 Serum gluose (mg/dl) (Aritrry unit) Serum gluose (mg/dl) (Aritrry unit) Exerise trining ttenutes insulin resistne phenotype seondry to HFD, with no signifint intensity-dependent differenes. A. Gluose tolerne test (GTT) B. Are under the urve for GTT SC+SED HFD+SED HFD+HIT HFD+MIT 4,000 3,000 2,000 1, (min) 0 C. Insulin tolerne test (ITT) D. Are under the urve for the ITT SC+SED HFD+SED HFD+HIT HFD+MIT (min) 0

20 Liver TG (mg/mg) Exerise trining, espeilly t the high-intensity, llevites hepti stetosis seondry to HFD. A. Oil Red O stining C. TG ontents in the liver d 40 SC+SED HFD+SED HFD+HIT HFD+MIT B. H&E stining 0 SC+SED HFD+SED HFD+HIT HFD+MIT SC+SED HFD+SED SC+SED HFD+SED HFD+HIT HFD+MIT

21 Reltive to β-tin Exerise trining suppresses deresed mrna mrkers for ftty id ox./mrc pity s well s inresed mrna mrkers for lipogenesis seondry to HFD in the liver A. mrnas of FA OX/MRC tivity Pprα Cpt1α Cyp410 Cyp2e B. mrnas of de novo lipogenesis Srep Cd Lipin Irs

22 HMW diponetin (μg/ml) Reltive to β-tin Totl diponetin (μg/ml) Exerise trining, espeilly t the high-intensity, suppresses hypodiponetinemi seondry to HFD. A. Totl diponetin in serum IB: C. Adiponetin in dipose tissue 30 kd Adiponetin kd β-tin 0 SC+SED HFD+SED HFD+HIT HFD+MIT B. HMW diponetin in serum SC+SED HFD+SED HFD+HIT HFD+MIT 0 SC+SED HFD+SED HFD+HIT HFD+MIT

23 AdipoR2 mrna/18s rrna Reltive to β-tin AdipoR1 mrna/18s rrna Exerise trining, espeilly t the high-intensity, inreses diponetin reeptor-2 in the liver. A. Adiponetin reeptor 1 (AdipoR1) mrna C. AdipoR1/2 proteins IB 42 kd dipor kd dipor2 0.2 SC+SED HFD+SED HFD+HIT HFD+MIT 42 kd β-tin B. Adiponetin reeptor 2 (AdipoR2) mrna 1.5 AdipoR1 AdipoR SC+SED HFD+SED HFD+HIT HFD+MIT

24 Reltive to β-tin Exerise trining, espeilly t the high-intensity, reverses deresed expression of AMPK /SIRT1 proteins seondry to HFD in the liver. IB: 62 KD 62 KD 110 KD 105 KD 280 KD 280 KD 42KD pampkα (Thr172) AMPKα SIRT1 PGC1α pacc (Ser79) ACC β-tin d 0.5 pampk/ampk SIRT1 PGC1α pacc/acc

25 Exerise trining suppresses HFD-indued hypodiponetinemi while tivting diponetin/adipor2-medited AMPK/SIRT1 pthwy in the liver.

26 Reltive to β-tin Reltive to β-tin Exerise trining suppresses elevted mrna mrkers for inflmmtion nd firosis seondry to HFD in the liver. A. Msson s Trihome stining SC+SED HFD+SED HFD+HIT HFD+MIT B. mrnas of inflmmtory mrkers C. mrnas of firosis mrkers Cd68 Lgls3 Ly6d Timp Col11

27 Nuleuus NF-kB p65 TNF- (pg/ml) Exerise trining, espeilly t high-intensity, suppresses elevted TNF-α s well s tivted NF-kB proteins seondry to HFD in the liver. A. TNF- levels B. Nuleus NF-kB p d B 65 kd 40 kd IB: Nuleus NF-kB p65 IkBα kd LminB SC HFD HFD+INT HFD+MOD 42 kd β-tin SC HFD HFD+INT HFD+MOD

28 Exerise trining suppresses TNF-α-medited tivtion of the NF-kB pthwy seondry to HFD in the liver.

29 CONCLUSIONS - Exerise trining intervened t the seond hlf of 16-HFD regimen llevites hepti stetosis nd metoli omplitions ssoited with oesity. - Compred to moderte intensity, high-intensity trining indues greter enefits ginst oesity-indued NAFLD. - Hepti enefits of exerise trining ginst HFD-indued NAFLD re ssoited with diponetin/adipor2-medited tivtion of the AMPK/SIRT1 pthwy (i.e., ftty id oxidtion, MRC tivity, ipogenesis) s well s suppression of TNF- -medited tivtion of the NF-kB pthwy (i.e., inflmmtion, firosis).

30 Exerise Trining (Modified from Exp Biol Med 234: , 2009)

31 ACKNOWLEDGEMENT This study ws supported y the Koren Government Reserh Foundtion funded y the Koren Government (NRF- 2012R1A1A ) (NRF-2013S1A2A ).