• 2018-07
  • 2018-10
  • 2018-11
  • cyclobenzaprine hcl br Author Contributions br Funding


    Author Contributions
    Funding Sources This research was funded by National Natural Science Foundation of China grants 81330010 and 81390354, and American Diabetes Association grant #1-13-BS-225. Our funding sources had no role in data collection, analysis or interpretation, and were not involved in the writing of this manuscript.
    Conflict of Interest Statement
    Introduction Long-term weight-loss (WL) interventions, such as prolonged hypocaloric diets and bariatric surgeries, lead to reduced insulin levels, improvement in insulin sensitivity and glycemic homeostasis in formerly obese people and improve glycemic control in individuals with diabetes mellitus type 2 (T2DM) (Klein et al., 2004; Dixon et al., 2012). Although the underlying mechanisms are not precisely understood, one common key effect of these interventions is a long-term caloric restriction (CR) (Klein et al., 2004; Sjöström et al., 2004; Bradley et al., 2012; Knop and Taylor, 2013). Long-term CR, also referred to as dietary restriction (DR), defined as lessening caloric intake (typically by about 30% in rodents and monkeys) without malnutrition cyclobenzaprine hcl is the most robust intervention to extend health and maximum lifespan in most, but not all, laboratory animal models (Speakman and Mitchell, 2011; de Cabo et al., 2014). It is widely accepted that CR protects cyclobenzaprine hcl against oxidative damage (López-Lluch et al., 2008) and induces DNA-repair (López-Otín et al., 2013) and recycling processes such as autophagy (de Cabo et al., 2014). The underlying mechanisms are however not precisely understood. Increasing evidence suggests that reduced growth factor- and nutrient-responsive protein kinase signaling mediate beneficial effects of CR. Conserved CR-responses are reduced growth hormone (GH)/insulin-like growth factor-1 (IGF-1) and insulin signaling (Bartke et al., 2013; Kenyon, 2010). In mammals, GH produced by the pituitary gland induces production and secretion of IGF-1 in the liver, which acts as endocrine regulator. IGF-1 is also produced in peripheral organs by GH-dependent and -independent pathways, which acts locally in paracrine or autocrine fashion (Sonntag et al., 2012; Bartke et al., 2013). The impact of CR on IGF-1 signaling in the periphery is little understood. Another conserved CR-response is reduced activity of the nutrient-responsive protein kinase, mechanistic target of rapamycin (mTOR), associated with lifespan extension in invertebrates and mice (Kapahi et al., 2004; Selman et al., 2009). mTOR forms a network with insulin/IGF-1 signaling, regulating a wide range of cellular processes, such as autophagy, growth, differentiation and metabolism, which are thought to mediate effects of CR (Laplante and Sabatini, 2012). The mechanisms on how CR employs the insulin/IGF-1–mTOR signaling network to influence cellular downstream pathways are the current focus of obesity and aging research. Adipose tissue is a main organ implicated in regulation of healthspan induced by reduced insulin/IGF-1–mTOR signaling (Broughton and Partridge, 2009). Decreased insulin sensitivity in subcutaneous white adipose tissue (sWAT) due to an age-related deterioration of sWAT is a hallmark of aging (Borkan et al., 1983). Long-term CR leads to reduced adipocyte size and remodeling of body fat composition away from visceral (v) WAT to sWAT (Huffman and Barzilai, 2010; Speakman and Mitchell, 2011). Since sWAT has rather beneficial and vWAT detrimental effects in aging and obesity this contributes to extension of healthspan. While sWAT adipocytes seem to be particularly beneficial for insulin action due to their crucial role in maintaining whole body glucose homeostasis and lipid metabolism, increasing evidence suggests that health benefits of CR exceed those directly associated with weight-loss. Adipocytes arise from adipose-derived stromal/progenitor cells (ASCs), which constitute a large pool of precursors, crucial for adipose tissue renewal, homeostasis, expansion and hence function (Berry et al., 2013; Zwierzina et al., 2015). Upon stimulation by insulin, glucocorticoids, cAMP inducers, and additional serum components ASCs enter a differentiation program, referred to as adipogenesis, to acquire their specific functions as adipocytes (Rosen and MacDougald, 2006). According to the current model adipogenesis involves growth arrest, early and terminal differentiation, including morphological changes, lipid accumulation and the expression of fat cell specific genes, such as fatty acid binding protein-4 (FABP4), perilipin and adipokines. The stages of adipogenesis are orchestrated by a transcriptional cascade involving the adipogenic key factor nuclear receptor peroxisome proliferator-activated receptor-γ2 (PPARγ2) and members of the CCAAT/enhancer-binding protein (C/EBP) family.