Treating NAFLD in OLETF Rats with Vigorous-Intensity Interval Exercise Training

Linden, Melissa A.; Fletcher, Justin A.; Morris, E. Matthew; Meers, Grace M.; Laughlin, M. Harold; Booth, Frank W.; Sowers, James R.; Ibdah, Jamal A.; Thyfault, John P.; Rector, R. Scott

doi:10.1249/mss.0000000000000430

Cited by 74 publications

(79 citation statements)

References 50 publications

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“…Observations in the current investigation support this previous work and further demonstrate that treatment of NAFLD with caloric restriction improves hepatic mitochondrial function, as indicated by increased complete palmitate oxidation and β-HAD activity. As previously reported, metformin treatment did not elicit improvements in any of these indicators of hepatic mitochondrial function (Linden et al 2015). In addition, we have previously reported that met-formin treatment actually attenuated exercise training-induced adaptations in mitochondrial content and function (Linden et al 2014).…”

Section: Discussionsupporting

confidence: 79%

Combining metformin therapy with caloric restriction for the management of type 2 diabetes and nonalcoholic fatty liver disease in obese rats

Linden

Lopez

Fletcher

et al. 2015

Appl. Physiol. Nutr. Metab.

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Weight loss is recommended for patients with nonalcoholic fatty liver disease (NAFLD), while metformin may lower liver enzymes in type 2 diabetics. Yet, the efficacy of the combination of weight loss and metformin in the treatment of NAFLD is unclear. We assessed the effects of metformin, caloric restriction, and their combination on NAFLD in diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Male OLETF rats (age 20 weeks; n = 6–8 per group) were fed ad libitum (AL), given metformin (300 mg·kg−1·day−1; Met), calorically restricted (70% of AL; CR), or calorically restricted and given metformin (CR+Met) for 12 weeks. Met lowered adiposity compared with AL but not to the same magnitude as CR or CR+Met (p < 0.05). Although only CR improved fasting insulin and glucose, the combination of CR+Met was needed to improve post-challenge glucose tolerance. All treatments lowered hepatic triglycerides, but further improvements were observed in the CR groups (p < 0.05, Met vs. CR or CR+Met) and a further reduction in serum alanine aminotransferases was observed in CR+Met rats. CR lowered markers of hepatic de novo lipogenesis (fatty acid synthase, acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase-1 (SCD-1)) and increased hepatic mitochondrial activity (palmitate oxidation and β-hydroxyacyl CoA dehydrogenase (β-HAD) activity). Changes were enhanced in the CR+Met group for ACC, SCD-1, β-HAD, and the mitophagy marker BNIP3. Met decreased total hepatic mTOR content and inhibited mTOR complex 1, which may have contributed to Met-induced reductions in de novo lipogenesis. These findings in the OLETF rat suggest that the combination of caloric restriction and metformin may provide a more optimal approach than either treatment alone in the management of type 2 diabetes and NAFLD.

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Section: Discussionsupporting

confidence: 79%

Combining metformin therapy with caloric restriction for the management of type 2 diabetes and nonalcoholic fatty liver disease in obese rats

Linden

Lopez

Fletcher

et al. 2015

Appl. Physiol. Nutr. Metab.

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“…84 Whether the intrinsic aerobic capacity is afferent or efferent to hepatic lipid oxidative phenotypes is currently unknown. Other markers such as Cpt-1 activity, β-Had activity, citrate synthase activity, Tr4 protein, and cytochrome c oxidase component levels are increased suggesting an increase in mitochondrial function and/or content, 79,80,85–87 which may be dependent on presence of Pgc-1α . 86 Alterations in mitochondrial FA oxidation have typically been accompanied by a decrease in extramitochondrial palmitate oxidation in the OLETF rat model.…”

Section: Hepatic Adaptations To Regular Physical Activitymentioning

confidence: 99%

“…86 Alterations in mitochondrial FA oxidation have typically been accompanied by a decrease in extramitochondrial palmitate oxidation in the OLETF rat model. 79,81,87 This decrease in extramitochondrial palmitate oxidation is hypothesized to represent a decrease in peroxisomal contributions to oxidation. This concomitant increase in mitochondrial oxidation and decreased peroxisomal oxidation may be representative of a more “metabolically healthy” lipid oxidation phenotype resulting in decreased oxidative stress, 88 a hypothesized contributor to liver injury in NAFLD, 89 being a potential result.…”

Section: Hepatic Adaptations To Regular Physical Activitymentioning

confidence: 99%

Exercise and the Regulation of Hepatic Metabolism

Trefts

Williams

Wasserman

2015

Progress in Molecular Biology and Translational Science

132

117

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The accelerated metabolic demands of the working muscle cannot be met without a robust response from the liver. If not for the hepatic response, sustained exercise would be impossible. The liver stores, releases, and recycles potential energy. Exercise would result in hypoglycemia if it were not for the accelerated release of energy as glucose. The energetic demands on the liver are largely met by increased oxidation of fatty acids mobilized from adipose tissue. Adaptations immediately following exercise facilitate the replenishment of glycogen stores. Pancreatic glucagon and insulin responses orchestrate the hepatic response during and immediately following exercise. Like skeletal muscle and other physiological systems, liver adapts to repeated demands of exercise by increasing its capacity to produce energy by oxidizing fat. The ability of regular physical activity to increase fat oxidation is protective and can reverse fatty liver disease. Engaging in regular physical exercise has broad ranging positive health implications including those that improve the metabolic health of the liver.

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“…Blood was collected from mice after euthanasia and tissue removal, centrifuged at 4,000 g for 15 min at 4°C, and then serum was collected and stored at Ϫ80°C. Serum AST and ALT were measured as previously described (19,28). Measurement of TNF-␣, IL-6, IL-1␤, Ccl2, Nos2, IL-10, SOCS3 (MCYTOMAG-70K-06), and FST (MAGPMAG-24K-01) were completed using the Milliplex MAP system (Billerica, MA).…”

Section: Ethicsmentioning

confidence: 99%

Voluntary wheel running attenuates lipopolysaccharide-induced liver inflammation in mice

Peppler

Anderson

Sutton

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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Peppler WT, Anderson ZG, Sutton CD, Rector RS, Wright DC. Voluntary wheel running attenuates lipopolysaccharide-induced liver inflammation in mice. Am J Physiol Regul Integr Comp Physiol 310: R934 -R942, 2016. First published February 17, 2016 doi:10.1152/ajpregu.00497.2015.-Sepsis induces an acute inflammatory response in the liver, which can lead to organ failure and death. Given the anti-inflammatory effects of exercise, we hypothesized that habitual physical activity could protect against acute sepsis-induced liver inflammation via mechanisms, including heat shock protein (HSP) 70/72. Male C57BL/6J mice (n ϭ 80, ϳ8 wk of age) engaged in physical activity via voluntary wheel running (VWR) or cage control (SED) for 10 wk. To induce sepsis, we injected (2 mg/kg ip) LPS or sterile saline (SAL), and liver was harvested 6 or 12 h later. VWR attenuated increases in body and epididymal adipose tissue mass, improved glucose tolerance, and increased liver protein content of PEPCK (P Ͻ 0.05). VWR attenuated increases in LPS-induced IL-6 signaling and mRNA expression of other inflammatory markers (TNF-␣, chemokine C-C motif ligand 2, inducible nitric oxide synthase, IL-10, IL-1␤) in the liver; however, this was not reflected at the whole body level, as systemic markers of inflammation were similar between SED and VWR. Insulin tolerance was greater in VWR compared with SED at 6 but not 12 h after LPS. The protective effect of VWR occurred in parallel with increases in the liver protein content of HSP70/72, a molecular chaperone that can protect against inflammatory challenges. This study provides novel evidence that physical activity protects against the inflammatory cascade induced by LPS in the liver and that these effects may be mediated via HSP70/72. lipopolysaccharide; inflammation; liver; physical activity; exercise SEPSIS IS A CONTINUUM OF CLINICAL events defined by the presence of infection and systemic inflammation (18). The worldwide incidence of sepsis was recently estimated at 437 cases per 100,000 person years between 2003 and 2015, with an associated fatality rate of 17% (11). This puts a significant burden on the health care system, and in the United States alone, the direct hospital costs associated with sepsis are over $24 billion (17).The infiltration of a host with both gram-negative and gram-positive bacterial species is often considered to be the cause of acute sepsis (34). LPS from Escherichia coli, a component of gram-negative bacteria, is often used to produce these effects in rodent models. Upon exposure to LPS, an inflammatory cascade is activated both systemically and at a tissue-specific level (1). Initial signaling involves a Toll-like receptor 4 (TLR4)-myeloid differentiation primary response gene 88 (MyD88) interaction that then propagates the inflammatory response (24). Increases in circulating inflammatory factors, such as TNF-␣, IL-6, and IL-1␤, occur rapidly and are regulated by the dose and duration of exposure (21,29,40). Clearance of inflammatory markers begins as early as 8 h post...

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Treating NAFLD in OLETF Rats with Vigorous-Intensity Interval Exercise Training

Cited by 74 publications

References 50 publications

Combining metformin therapy with caloric restriction for the management of type 2 diabetes and nonalcoholic fatty liver disease in obese rats

Combining metformin therapy with caloric restriction for the management of type 2 diabetes and nonalcoholic fatty liver disease in obese rats

Exercise and the Regulation of Hepatic Metabolism

Voluntary wheel running attenuates lipopolysaccharide-induced liver inflammation in mice

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