Abstract
Obesity is associated with muscle lipid accumulation. Experimental models suggest that inflammatory cytokines, low mitochondrial oxidative capacity and paradoxically high insulin signaling activation favor this alteration. The gastric orexigenic hormone acylated ghrelin (A-Ghr) has antiinflammatory effects in vitro and it lowers muscle triglycerides while modulating mitochondrial oxidative capacity in lean rodents. We tested the hypothesis that A-Ghr treatment in high-fat feeding results in a model of weight gain characterized by low muscle inflammation and triglycerides with high muscle mitochondrial oxidative capacity. A-Ghr at a non-orexigenic dose (HFG: twice-daily 200-µg s.c.) or saline (HF) were administered for 4 days to rats fed a high-fat diet for one month. Compared to lean control (C) HF had higher body weight and plasma free fatty acids (FFA), and HFG partially prevented FFA elevation (P<0.05). HFG also had the lowest muscle inflammation (nuclear NFkB, tissue TNF-alpha) with mitochondrial enzyme activities higher than C (P<0.05 vs C, P = NS vs HF). Under these conditions HFG prevented the HF-associated muscle triglyceride accumulation (P<0.05). The above effects were independent of changes in redox state (total-oxidized glutathione, glutathione peroxidase activity) and were not associated with changes in phosphorylation of AKT and selected AKT targets. Ghrelin administration following high-fat feeding results in a novel model of weight gain with low inflammation, high mitochondrial enzyme activities and normalized triglycerides in skeletal muscle. These effects are independent of changes in tissue redox state and insulin signaling, and they suggest a potential positive metabolic impact of ghrelin in fat-induced obesity.
Highlights
Obesity may be characterized by lipid accumulation in skeletal muscle, and this alteration likely contributes to long-term metabolic complications [1]
The study demonstrated that acylated ghrelin administration following high-fat diet-induced weight gain induces anti-inflammatory changes and prevents triglyceride accumulation in rat skeletal muscle
These effects were associated with higher mitochondrial enzyme activities compared to control animals, and they were independent of changes in muscle redox state and of insulin signaling activation
Summary
Obesity may be characterized by lipid accumulation in skeletal muscle, and this alteration likely contributes to long-term metabolic complications [1]. Experimental models suggest that inflammatory cytokines, changes in muscle mitochondrial function and paradoxical enhancement of insulin signaling at the AKT level contribute to increase tissue lipid deposition in the presence of weight gain and high lipid availability [1,2,3]. Pro-oxidant changes in redox state may further contribute to inflammation and altered mitochondrial function, and they are commonly associated with muscle lipid accumulation [4,5]. Acylated ghrelin (A-Ghr) has been reported to lower muscle triglyceride content in healthy and uremic lean rodents, associated with enhanced skeletal muscle mitochondrial oxidative capacity [8,9]. The impact of A-Ghr administration on muscle redox state, inflammatory mediators, mitochondrial oxidative capacity and triglyceride content following diet-induced weight gain remains undetermined
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