Effets of exerise trining on hepti stetosis in high ft diet-indued oese mie Hyunsik Kng, PhD Sungkyunkwn University
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)
NAFLD Spetrum of Disese Stetosis Stetoheptitis (NASH) NASH with Firosis Cirrhosis
By 2020
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
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).
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.
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
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
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
RESULTS
After the initil 8 weeks of High-Ft Diet
Gluose (mg/dl) Gluose (mg/dl) Weight (g) A. C57BL/6 mie B. Chnges in ody weight 45 40 35 30 25 SC HFD * * * * * 20 15 SC HFD 10 0 1 2 3 4 5 6 7 8 9 Time (wk) C. Gluose tolerne test D. Insulin tolerne test 600 500 * * * SC HFD 250 200 SC HFD 400 300 200 * 150 100 100 50 0 0 50 100 150 Time (min) 0 0 20 40 60 Time (min)
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=3 60 50 40 30 20 10 50 40 30 20 10 0 SC HFD 0 SC HFD
Serum TC (mg/dl) Serum diponetin (μg/ml) A. Serum totl holesterol (TC) levels B. Serum totl diponetin levels 250 p =01 5.0 p =4 200 4.0 150 3.0 100 2.0 50 SC HFD SC HFD
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.
Effets of exerise trining intervened t the seond hlf of the 16-week highft diet regimen
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±1.8 48.0±1.6 45.2±2.0 46.0±1.7 ALT, U/l 31.5±7.2 236.0±49.3 145.8±50.5 182.8±19.9 AST, U/l 54.0±17.2 167.4±27.9 155.8±40.1 147.4±32.8 FFA, meq/l 2.1±0.35 2.4±0.33 2.0±9 2.0±0.18 TG, mg/dl 61.2±11.6 64.2±16.8 60.8±7.2 61.8±9.4 TC, mg/dl 88.2±9.0 208.2±34.1 16±22.2 180.2±12.5 d HDLC, mg/dl 43.6±11.2 134.0±15.0 165.0±17.3 160.4±17.5
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 600 500 400 300 200 100 SC+SED HFD+SED HFD+HIT HFD+MIT 4,000 3,000 2,000 1,000 0 0 30 60 90 120 (min) 0 C. Insulin tolerne test (ITT) D. Are under the urve for the ITT 300 250 200 SC+SED 600 500 400 150 HFD+SED 300 100 HFD+HIT 200 50 HFD+MIT 100 0 0 30 60 (min) 0
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 60 50 d 40 SC+SED HFD+SED HFD+HIT HFD+MIT 30 20 10 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
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 Cyp2e1 1.2 0.8 0.6 1.2 0.8 0.6 2.0 1.5 1.2 0.8 0.6 0.4 0.2 0.4 0.2 0.5 0.4 0.2 B. mrnas of de novo lipogenesis Srep-1 1.8 1.6 1.4 1.2 Cd36 3.0 2.5 2.0 Lipin1 3.0 2.5 2.0 Irs2 1.8 1.6 1.4 1.2 0.8 0.6 1.5 1.5 0.8 0.6 0.4 0.2 0.5 0.5 0.4 0.2
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 40 30 20 IB: C. Adiponetin in dipose tissue 30 kd Adiponetin 10 42 kd β-tin 0 SC+SED HFD+SED HFD+HIT HFD+MIT B. HMW diponetin in serum 12 10 8 6 4 2 1.5 0.5 SC+SED HFD+SED HFD+HIT HFD+MIT 0 SC+SED HFD+SED HFD+HIT HFD+MIT
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 1.6 1.4 1.2 IB 42 kd dipor1 0.8 0.6 0.4 43 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 AdipoR2 2.5 2.0 1.5 0.5 0.5 SC+SED HFD+SED HFD+HIT HFD+MIT
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 2.5 2.0 1.5 d 0.5 pampk/ampk SIRT1 PGC1α pacc/acc
Exerise trining suppresses HFD-indued hypodiponetinemi while tivting diponetin/adipor2-medited AMPK/SIRT1 pthwy in the liver.
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 3.0 2.5 2.0 1.5 0.5 Cd68 Lgls3 Ly6d 4.5 4.0 3.5 3.0 2.5 2.0 1.5 0.5 1 1 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 3.5 3.0 2.5 2.0 1.5 0.5 Timp1 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 0.5 Col11
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 p65 8.0 6.0 4.0 d B 65 kd 40 kd IB: Nuleus NF-kB p65 IkBα 2.0 67 kd LminB SC HFD HFD+INT HFD+MOD 42 kd β-tin 2.5 2.0 1.5 0.5 SC HFD HFD+INT HFD+MOD
Exerise trining suppresses TNF-α-medited tivtion of the NF-kB pthwy seondry to HFD in the liver.
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).
Exerise Trining (Modified from Exp Biol Med 234:850 859, 2009)
ACKNOWLEDGEMENT This study ws supported y the Koren Government Reserh Foundtion funded y the Koren Government (NRF- 2012R1A1A2006180) (NRF-2013S1A2A2034953).