Changes in skeletal muscle mitochondria in response to the development of type 2 diabetes or prevention by daily wheel running in hyperphagic OLETF rats

Rector, R. Scott; Uptergrove, Grace M.; Borengasser, Sarah J.; Mikus, Catherine R.; Morris, E. Matthew; Naples, Scott P.; Laye, Matthew J.; Laughlin, M. Harold; Booth, Frank W.; Ibdah, Jamal A.; Thyfault, John P.

doi:10.1152/ajpendo.00703.2009

Cited by 46 publications

(48 citation statements)

References 36 publications

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“…These animals are selectively bred with a mutated and functionally inoperative cholecystokinin-1 receptor (34, 35), which results in hyperphagia and the progressive development of obesity, insulin resistance, type 2 diabetes, and NAFLD (43). We have demonstrated previously that these pathological metabolic events are prevented in physically active OLETF rats given daily access to voluntary running wheels (41,42,45,46). …”

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confidence: 89%

Combining metformin and aerobic exercise training in the treatment of type 2 diabetes and NAFLD in OLETF rats

Linden

Fletcher

Morris

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Thyfault JP, Rector RS. Combining metformin and aerobic exercise training in the treatment of type 2 diabetes and NAFLD in OLETF rats. Am J Physiol Endocrinol Metab 306: E300 -E310, 2014. First published December 10, 2013; doi:10.1152/ajpendo.00427.2013.-Here, we sought to compare the efficacy of combining exercise and metformin for the treatment of type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) in hyperphagic, obese, type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. OLETF rats (age: 20 wk, hyperglycemic and hyperinsulinemic; n ϭ 10/group) were randomly assigned to sedentary (O-SED), SED plus metformin (O-SED ϩ M; 300 mg·kg Ϫ1 ·day Ϫ1 ), moderate-intensity exercise training (O-EndEx; 20 m/min, 60 min/day, 5 days/wk treadmill running), or O-EndEx ϩ M groups for 12 wk. Long-Evans Tokushima Otsuka (L-SED) rats served as nonhyperphagic controls. O-SED ϩ M, O-EndEx, and O-EndEx ϩ M were effective in the management of type 2 diabetes, and all three treatments lowered hepatic steatosis and serum markers of liver injury; however, O-EndEx lowered liver triglyceride content and fasting hyperglycemia more than O-SED ϩ M. In addition, exercise elicited greater improvements compared with metformin alone on postchallenge glycemic control, liver diacylglycerol content, hepatic mitochondrial palmitate oxidation, citrate synthase, and ␤-HAD activities and in the attenuation of markers of hepatic fatty acid uptake and de novo fatty acid synthesis. Surprisingly, combining metformin and aerobic exercise training offered little added benefit to these outcomes, and in fact, metformin actually blunted exerciseinduced increases in complete mitochondrial palmitate oxidation and ␤-HAD activity. In conclusion, aerobic exercise training was more effective than metformin administration in the management of type 2 diabetes and NAFLD outcomes in obese hyperphagic OLETF rats. Combining therapies offered little additional benefit beyond exercise alone, and findings suggest that metformin potentially impairs exercise-induced hepatic mitochondrial adaptations. exercise training; metformin; nonalcoholic fatty liver disease; hepatic mitochondria; de novo lipogenesis; Otsuka Long-Evans Tokushima Fatty rats NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) is a progressive liver disease characterized by hepatic triglyceride (TG) accumulation (Ն5% by weight for diagnosis) that occurs in the absence of excess alcohol consumption (Ͼ20 g/day). It encompasses a histological spectrum ranging from simple hepatic steatosis to nonalcoholic steatohepatitis, advanced fibrosis, and cirrhosis (40). NAFLD is considered the hepatic manifestation of the metabolic syndrome (11), and it affects ϳ30% of the US adult population (3, 7) and ϳ70% of type 2 diabetics (52). However, there are currently no clear guidelines for the treatment of NAFLD.A component of prevention and treatment recommendations addressing NAFLD involves lifestyle modifications that alter net energy status. Indeed, both short-term (6) and longer-term caloric restriction (10, 23), a...

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confidence: 89%

Combining metformin and aerobic exercise training in the treatment of type 2 diabetes and NAFLD in OLETF rats

Linden

Fletcher

Morris

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Running volumes can vary from ϳ1 up to 20 km over a 12-h dark cycle period but are typically consistent within experiments. In addition, the mitochondrial adaptations in skeletal muscle after VWR (29,39) are usually very modest and pale in comparison to what is measured in rats forced to run on treadmills (11). Therefore, it could be argued that VWR in rats is analogous to higher daily ambulatory activity in humans, while treadmill running in rats would mimic programmed endurance exercise in humans.…”

Section: Wheel Lock Studies In Rodentsmentioning

confidence: 99%

“…Both high-fat diets and hyperphagic-dietary overconsumption induce insulin resistance in sedentary rodent models; however, if the rodents in these studies are allowed to obtain physical activity (VWR, treadmill running, or swimming), insulin resistance does not develop. For example, we have shown that providing VWR to Otsuka Long Evans Tokushima Fatty rats (OLETF; hyperphagic-obese model prone to T2D) out to 40 wk of age prevents insulin resistance and the development of T2D unequivocally (39). This protection occurs even though the running OLETF have a large decrease in running distance by 40 wk of age (ϳ4 km/day by 40 wk of age down from ϳ11-12 km/day at 12 wk of age).…”

Section: Response To Inactivity: Preservation or Pathologymentioning

confidence: 99%

Metabolic disruptions induced by reduced ambulatory activity in free-living humans

Thyfault

Krogh-Madsen

2011

Journal of Applied Physiology

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.-Physical inactivity likely plays a role in the development of insulin resistance and obesity; however, direct evidence is minimal and mechanisms of action remain unknown. Studying metabolic outcomes that occur after transitioning from higher to lower levels of physical activity is the best tool to answer these questions. Previous studies have successfully used more extreme models of inactivity, including bed rest, or the cessation of exercise in highly trained endurance athletes, to provide novel findings. However, these models do not accurately reflect the type of inactivity experienced by a large majority of the population. Recent studies have used a more applicable model in which active (ϳ10,000 steps/day), healthy young controls are asked to transition to an inactive lifestyle (ϳ1,500 steps/day) for a 14-day period. The transition to inactivity resulted in reduced insulin sensitivity and increased central adiposity. This review will discuss the outcomes of these studies, their implications for the cause/effect relationship between central adiposity and insulin resistance, and provide rationale for why inactivity induces these factors. In addition, the experimental challenges of directly linking acute responses to inactivity to chronic disease will also be discussed. inactivity; skeletal muscle; insulin sensitivity; obesity TYPE 2 DIABETES AND CENTRAL OBESITYOBESITY and obesity-associated metabolic diseases are increasing at epidemic rates. The World Health Organization's (WHO) latest estimates indicate that ϳ400 million adults were obese (body mass index Ͼ 30 kg/m 2 ) globally in 2006 and predict that these numbers will rise to 700 million by the year 2015. This increase in obesity parallels a dramatic increase in the number of persons diagnosed with Type 2 diabetes (T2D). In 2009, WHO estimated that more than 200 million people worldwide have T2D, and it is estimated that worldwide T2D rates will double between the year 2000 and 2030 (46). Although excess adiposity in all regions can cause metabolic consequences, excess central adiposity (visceral adiposity) is most tightly linked to the development of T2D (1,3,9,12,13). The current dogma implies that central adiposity first develops, leading to inflammation and/or an increased storage of ectopic lipids in skeletal muscle and liver, which induces insulin resistance and ultimately leads to T2D (31), but this order of events has never been proven (33). The causes of both increased central obesity and type 2 diabetes are undoubtedly multifactorial and complex; however, we (5, 43) and others (15, 23) believe that a lack of regular exercise, or physical inactivity, plays a fundamental role. This hypothesis is backed by epidemiological evidence suggesting that physical inactivity plays a causal role in the development of T2D (20, 21) and obesity (10) while regular physical activity significantly lowers risk (2, 23, 24) for both conditions. While these studies strongly associate inactivity to T2D and obesity, historically, there have been a limited number of stu...

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“…In fact, significant hepatic TAG accumulation occurred in as little as 4 -5 wk postweaning in the sedentary, hyperphagic OLETF rats (witnessed at 8 wk of age) (44). In a series of studies, we have demonstrated that these pathological metabolic events are prevented when the OLETFs (4) are given daily access to voluntary running wheels and allowed to be physically active (42,43,45,46). However, it is unclear how long these pathological events can be prevented after becoming inactive.…”

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confidence: 99%

Hepatic steatosis development with four weeks of physical inactivity in previously active, hyperphagic OLETF rats

Linden

Meers

Ruebel

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Changes in skeletal muscle mitochondria in response to the development of type 2 diabetes or prevention by daily wheel running in hyperphagic OLETF rats

Cited by 46 publications

References 36 publications

Combining metformin and aerobic exercise training in the treatment of type 2 diabetes and NAFLD in OLETF rats

Combining metformin and aerobic exercise training in the treatment of type 2 diabetes and NAFLD in OLETF rats

Metabolic disruptions induced by reduced ambulatory activity in free-living humans

Hepatic steatosis development with four weeks of physical inactivity in previously active, hyperphagic OLETF rats

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