Abstract
BackgroundDiet-induced obesity is a rising health concern which can lead to the development of glucose intolerance and muscle insulin resistance and, ultimately, type II diabetes mellitus. This research investigates the associations between glucose intolerance or muscle insulin resistance and tissue specific changes during the progression of diet-induced obesity.MethodologyC57BL/6J mice were fed a normal or high-fat diet (HFD; 60% kcal fat) for 3 or 8 weeks. Disease progression was monitored by measurements of body/tissue mass changes, glucose and insulin tolerance tests, and ex vivo glucose uptake in intact muscles. Lipid metabolism was analyzed using metabolic chambers and ex vivo palmitate assays in intact muscles. Skeletal muscle, liver and adipose tissues were analyzed for changes in inflammatory gene expression. Plasma was analyzed for insulin levels and inflammatory proteins. Histological techniques were used on muscle and liver cryosections to assess metabolic and morphological changes.Principal Findings/ConclusionsA rapid shift in whole body metabolism towards lipids was observed with HFD. Following 3 weeks of HFD, elevated total lipid oxidation and an oxidative fiber type shift had occurred in the skeletal muscle, which we propose was responsible for delaying intramyocellular lipid accumulation and maintaining muscle’s insulin sensitivity. Glucose intolerance was present after three weeks of HFD and was associated with an enlarged adipose tissue depot, adipose tissue inflammation and excess hepatic lipids, but not hepatic inflammation. Furthermore, HFD did not significantly increase systemic or muscle inflammation after 3 or 8 weeks of HFD suggesting that early diet-induced obesity does not cause inflammation throughout the whole body. Overall these findings indicate skeletal muscle did not contribute to the development of HFD-induced impairments in whole-body glucose tolerance following 3 weeks of HFD.
Highlights
An unhealthy lifestyle including a high fat diet (HFD) has become common in Western societies and contributes to obese, insulin resistant states such as pre-diabetes, which if left untreated, can progress to Type 2 Diabetes Mellitus (T2DM) [1,2,3]
To determine if total calories consumed would differ when corrected for weight gain on high-fat diet (HFD), statistics were performed on values from the last day of normal diet (ND) and HFD relative to body mass at these times
Our results indicate that the early, whole body response to HFD, that of skeletal muscle, is a protective adaptation which provides a buffering period of time before the onset of insulin resistance in muscle after 8 weeks of HFD as previously demonstrated in this model [18]
Summary
An unhealthy lifestyle including a high fat diet (HFD) has become common in Western societies and contributes to obese, insulin resistant states such as pre-diabetes, which if left untreated, can progress to Type 2 Diabetes Mellitus (T2DM) [1,2,3]. Our lab previously reported that mice fed a HFD (60% kcal from fat) for 8 weeks exhibited obesity and muscle insulin resistance accompanied by impaired muscle lipid oxidation and excessive IMCL deposition [18]. Despite significant reductions in glucose and palmitate oxidation rates, histological/immunofluorescent analysis of skeletal muscle from HFD fed mice revealed a significant shift towards an oxidative phenotype. This paradoxical observation led us to hypothesize that the shift towards a more oxidative phenotype was an early, adaptive response to the HFD in order to enhance lipid utilization. This research investigates the associations between glucose intolerance or muscle insulin resistance and tissue specific changes during the progression of diet-induced obesity
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