Exercise-induced attenuation of obesity, hyperinsulinemia, and skeletal muscle lipid peroxidation in the OLETF rat

Abstract

Morris RT, Laye MJ, Lees SJ, Rector RS, Thyfault JP, Booth FW. Exercise-induced attenuation of obesity, hyperinsulinemia, and skeletal muscle lipid peroxidation in the OLETF rat. J Appl Physiol 104: 708-715, 2008. First published December 13, 2007 doi:10.1152/japplphysiol.01034.2007.-The Otsuka Long-Evans Tokushima fatty (OLETF) rat is a model of hyperphagic obesity in which the animals retain the desire to run voluntarily. Running wheels were provided for 4-wk-old OLETF rats for 16 wk before they were killed 5 h (WL5), 53 h (WL53), or 173 h (WL173) after the wheels were locked. Sedentary (SED) OLETF rats that were not given access to running wheels served as age-matched cohorts. Epididymal fat pad mass, adipocyte volume, and adipocyte number were 58%, 39%, and 47% less, respectively, in WL5 than SED rats. Contrary to cessation of daily running in Fischer 344 ϫ Brown Norway rats, epididymal fat did not increase during the first 173 h of running cessation in the OLETF runners. Serum insulin and glucose levels were 77% and 29% less, respectively, in WL5 than SED rats. Oil red O staining for intramyocellular lipid accumulation was not statistically different among groups. However, lipid peroxidation levels, as determined by total trans-4-hydroxy-2-nonenal (4-HNE) and 4-HNE normalized to oil red O, was higher in epitrochlearis muscles of SED than WL5, WL53, and WL173 rats. mRNA levels of glutathione S-transferase-␣ type 4, an enzyme involved in cellular defense against electrophilic compounds such as 4-HNE, were higher in epitrochlearis muscle of WL53 than WL173 and SED rats. In contrast, 4-HNE levels in omental fat were unaltered. Epitrochlearis muscle palmitate oxidation and relative transcript levels for peroxisome proliferator-activated receptor-␦ and peroxisome proliferator-activated receptor-␥ coactivator type 1 were surprisingly not different between runners and SED rats. In summary, voluntary running was associated with lower levels of lipid peroxidation in skeletal muscle without significant changes in intramyocellular lipids or mitochondrial markers in OLETF rats at 20 wk of age. Therefore, even in a genetic animal model of extreme overeating, daily physical activity promotes improved health of skeletal muscle. physical activity; oxidative stress; chronic disease THE INCIDENCE OF OVERWEIGHT in children and adolescents has tripled to 17.1% in 2004 from the late 1960s in the United States (40). Obesity is caused by a positive energy balance, with excess energy intake and insufficient physical activity being major causal factors. An understanding of the biological basis for energy partitioning from fat to skeletal muscle is imperative for prevention of fat gain as young subjects grow to adults.The Otsuka Long-Evans Tokushima fatty (OLETF) rat, which was selectively bred for null expression of the cholecystokinin (CCK)-1 receptor (27), is an animal model characterized by hyperphagia, obesity, decreased glucose infusion rate in a euglycemic clamp at 16 wk of age, and hyperinsulinemia at 24 wk of age in respons...

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

“…2A). Similar to our previous reports (26,35), running animals displayed initial running distances of ϳ4 km/day at 4 wk of age and 12 km/day at 9 -10 wk of age and averaging 5-8 km/day for the remainder of the study (weeks 10 -20). The health benefits of daily physical activity were lower body weight, body fat percentage, and fat pad mass (omental and retroperitoneal) in the OLETF-WL5hr (P Ͻ 0.05; see Fig.…”

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

“…Similar to what we have reported previously (19,21), initial running distance at 4 wk of age averaged ϳ5 km/day (ϳ170 min/day, ϳ33 m/min), with daily distances peaking between 8 and 11 wk of age (ϳ11-12 km/day, ϳ275 min/day, ϳ43 m/min) and declining to ϳ6 -8 km/day (ϳ200 min/day, ϳ32 m/min) at 20 wk of age, and ϳ4 km/day (ϳ150 min/day, ϳ27 m/min) by 40 wk of age in the OLETF-EX rats. It remains unknown why the OLETF animals exhibited decreased voluntary wheel running as they aged, but perhaps the OLETFs appropriately mirror the human condition, in which aging is often associated with reduced physical activity.…”

“…We have previously shown that 16 wk of daily voluntary exercise in the OLETF rat was associated with lower levels of lipid peroxidation without significant changes in intramyocellular lipids (21). In the current report, OLETF-SED rats exhibited increases in SOD and catalase activity from 20 to 40 wk when the health of the animal deteriorated, changes not witnessed in OLETF-EX and LETO-SED rats.…”

Lipid Peroxidation by-Products and the Metabolic Syndrome

“…In obese mice roughly 7% of the AFABP in adipose tissue is covalently modified by HNE resulting in a decreased binding affinity for fatty acids. Lipid peroxidation is however not restricted to adipose tissue since HNE is also elevated in skeletal muscles of Otsuka Long-Evans Tokushima fatty (OLETF) rat, a model for hyperphagic obesity (Morris et al, 2008). Intracellular triglyacylglycerols accumulate in the muscle of obese humans where it is considered as a pathogenic factor in the development of insulin resistance.…”