Treating NAFLD in OLETF rats with vigorous-intensity interval exercise training

Abstract

Background: There is increasing use of high-intensity interval-type exercise training in the management of many lifestyle-related diseases.

Purpose: This study aimed to test the hypothesis that vigorous-intensity interval exercise is as effective as traditional moderate-intensity aerobic exercise training for nonalcoholic fatty liver disease (NAFLD) outcomes in obese, Otsuka Long-Evans Tokushima Fatty (OLETF) rats.

Methods: OLETF rats (age, 20 wk; n = 8-10 per group) were assigned to sedentary (O-SED), moderate-intensity exercise training (O-MOD EX; 20 m·min(-1), 15% incline, 60 min·d(-1), 5 d·wk(-1) of treadmill running), or vigorous-intensity interval exercise training (O-VIG EX; 40 m·min(-1), 15% incline, 6 × 2.5 min bouts per day, 5 d·wk(-1) of treadmill running) groups for 12 wk.

Results: Both MOD EX and VIG EX effectively lowered hepatic triglycerides, serum alanine aminotransferase (ALT), perivenular fibrosis, and hepatic collagen 1α1 messenger RNA (mRNA) expression (vs O-SED, P < 0.05). In addition, both interventions increased hepatic mitochondrial markers (citrate synthase activity and fatty acid oxidation) and suppressed markers of de novo lipogenesis (fatty acid synthase, acetyl coenzyme A carboxylase, Elovl fatty acid elongase 6, and steroyl CoA desaturase-1), whereas only MOD EX increased hepatic mitochondrial Beta-hydroxyacyl-CoA dehydrogenase (β-HAD) activity and hepatic triglyceride export marker apoB100 and lowered fatty acid transporter CD36 compared with O-SED. Moreover, whereas total hepatic macrophage population markers (CD68 and F4/80 mRNA) did not differ among groups, MOD EX and VIG EX lowered M1 macrophage polarization markers (CD11c, interleukin-1β, and tumor necrosis factor α mRNA) and MOD EX increased M2 macrophage marker, CD206 mRNA, compared with O-SED.

Conclusions: The accumulation of 15 min·d(-1) of VIG EX for 12 wk had similar effectiveness as 60 min·d(-1) of MOD EX in the management of NAFLD in OLETF rats. These findings may have important health outcome implications as we work to design better exercise training programs for patients with NAFLD.

Figure 1

Moderate and vigorous exercise-induced alterations in glycemic control. Fasting glucose (A), fasting insulin (B), post-glucose challenge glucose curves (C), glucose area under the curve (D), post-glucose challenge insulin curves (E), insulin area under the curve (F), IG index (G), and hemoglobin A1c (HbA1c; H). Values (n=6–10 per group, means ± SE) with different letter superscripts are significantly different (p<0.05).

Figure 2

Effects of MOD EX vs. VIG EX on measures of NAFLD. Representative images of hematoxylin and eosin and trichrome staining. Note the large lipid vacuoles, macro- and micro-vesicular steatosis, hepatocyte ballooning, nuclear displacement, and thickening of collagen in the O-SED animals compared with the other animal groups (A). Hepatic TGs, collagen 1α1 mRNA expression, and serum ALTs are shown in B, C, and D respectively. Values (n=8–10 per group, means ± SE) with different letter superscripts are significantly different (p<0.05).

Figure 3

Mitochondrial and glycolytic adaptations with MOD EX or VIG EX. Citrate synthase activity (A), β-HAD activity (B), complete palmitate oxidation (C), mitochondrial proteins (D), carnitine palmitoyltransferase-1a mRNA expression (CPT-1a; E), representative Western blots (F), glycogen synthase kinase 3β (G), glycogen synthase (H), and liver glycogen (I). Values (n=8–10 per group, means ± SE) with different letter superscripts are significantly different (p<0.05).

Figure 4

Hepatic markers of fatty acid uptake, de novo lipogenesis, and triglyceride secretion. CD36/FAT protein expression (A), Elovl fatty acid elongase 6 mRNA expression (Elovl6; B), acetyl CoA carboxylase protein expression (ACC; C), fatty acid synthase protein expression (FAS; D), steroyl CoA desaturase-1 protein expression (SCD-1; E), AMPK (F), microsomal triglyceride transfer protein protein expression (MTTP; G), apolipoprotein B100 protein expression (ApoB;H), Apo B48 (I), representative Western blot images (J), and representative amido black stain (K).Values (n=8–10 per group, means ± SE) with different letter superscripts are significantly different (p<0.05).

Figure 5

Altered hepatic macrophage markers in MOD and VIG EX. F4/80 mRNA expression (A), CD68 mRNA expression (B), CD68 protein content (C), CD11c mRNA expression(D), tumor necrosis factor α mRNA expression (TNFα; E), interleukin-1β mRNA expression (IL-1β; F), IL-1β protein content (G), CD163 mRNA expression (H), CD206 mRNA expression (I), and CD206 protein content (J). Values (n=8–10 per group, means ± SE) with different letter superscripts are significantly different (p<0.05).