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  • AVE 0991 Endurance exercise training results in adipose lipo


    Endurance exercise training results in adipose lipolysis and attenuation of fibrosis (Kawanishi et al., 2013a) and inflammation (Linden et al., 2014; Vieira et al., 2009) in adipose and skeletal muscle, independent of weight loss. Thus, participation in an endurance training program is a well-established recommendation for individuals diagnosed with Type 2 diabetes. Currently, the impact of an endurance training on stromal cell quantity and function in both adipose and skeletal muscle has not been investigated, particularly in the context of obesity. We have previously established that muscle-derived MSC (mMSC) relative quantity is increased in skeletal muscle in response to an acute bout of eccentric exercise, and that mMSC transplantation can facilitate improvements in myofiber growth and strength in response to training (Valero et al., n.d.). Thus, we speculate that resident stromal AVE 0991 may provide the basis for positive changes in the structure and function of a variety of tissues, including both skeletal muscle and adipose, observed as a result of exercise. In the present study, we hypothesized that ADSC quantity would be reduced (Ferrer-Lorente et al., 2014), yet expression of genes related to ECM would be enhanced with HFD-induced obesity to sustain adipocyte growth. We also predicted that a 16week endurance training program would prevent adipocyte growth and concomitant changes in ADSC quantity and gene expression. Using the same rationale, we hypothesized that muscle-derived stromal cell (MDSC) ECM gene expression would be elevated in skeletal muscle following endurance training to facilitate structural remodeling.
    Materials and methods
    Discussion The purpose of this study was to investigate adipose- and skeletal muscle-resident Sca-1+CD45− stromal cell responses to long-term HFD-induced obesity, alone or in combination with a 16week endurance exercise program. Adult mice (3month old at onset and 9month old at the end of the study) were exposed to prolonged 60% HFD (total of 24weeks) to mimic an obesogenic lifestyle. Accordingly, HFD resulted in a doubling of average body weight (60g HFD versus 30g Con), as well as insulin resistance and fasting hyperglycemia (over 200mg/dl). Long-term HFD-induced obesity did not affect stromal cell quantity or function in skeletal muscle, but significantly influenced stromal cell relative quantity and gene expression in adipose tissue. Most importantly, obesity resulted in striking and consistent changes in ADSC gene expression related to ECM remodeling, yet endurance training did not alter this profile. Despite the significant increase in body weight and diabetic state with long-term HFD, average epididymal fat weight was not different between the groups. Subcutaneous fat pads were visibly increased in response to HFD, but we intentionally targeted epididymal fat due to the amount of readily accessible tissue in mice and the established association of visceral fat with metabolic disease. These results are similar to seminal work previously published by Surwit and colleagues almost 30years ago (Surwit et al., 1988) and more recently by Strissel et al. (2007). In the latter study, epididymal fat pad weight decreased while subcutaneous fat pad mass increased with sustained HFD during weeks 12 through 20 (Strissel et al., 2007). Hepatosteatosis was also observed, which together with subcutaneous fat accumulation, may account for the increase in body weight (Strissel et al., 2007). It is interesting to speculate that differences in ADSC quantity or function may underlie the divergent growth responses in depot-specific growth. ADSC relative quantity was reduced in epididymal adipose with HFD in the current study, and several factors may account for the decrease, including 1) SVF enrichment (fibroblasts, endothelial cells, and immune cells) (Church et al., 2014) and 2) cell death due to inflammation. Our preliminary examination of early and late adipogenic marker gene expression (ZFP423, Ebf1, DLK1, and PPARγ) in both whole tissue and ADSCs suggests minimal capacity for adipogenesis, an event that may force existing adipocytes to hypertrophy with long-term HFD. Hyperplasia is, in fact, lower in omental fat compared to subcutaneous fat in women (Drolet et al., 2008). Thus, resistance to adipogenesis and subsequent adipocyte hypertrophy may prompt changes in the microenvironment to accommodate growth.