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    • Conversely ECM accumulation in the liver is a

    2018-10-23

    Conversely, ECM accumulation in the liver is a hallmark of hepatic fibrosis and is associated with hepatic stellate cell activation due to inflammatory signaling (Bataller and Brenner, 2005). ECM reprogramming is necessary for adipose growth and expansion on energy dense diets, and fibrosis in fat tissue is associated with obesity in humans. In children, the presence of collagen in fat is associated with adipocyte size, body mass index and M2 phenotype macrophages, providing further evidence of the association between ECM remodeling and innate immunity (Tam et al., 2012). Interestingly, loss of collagen 18 (significantly down-regulated by ~2–3-fold in Tg-FABP4-RORα4 SAT) results in reduced adiposity, ectopic deposition of fat in the liver and hypertriglyceridemia (Aikio et al., 2014). The phenotype was attributed to reduce fat storage capacity as a result of perturbations in adipocyte development. Interestingly, subcutaneous lipodystrophy, liver steatosis and glucose intolerance are observed in humans with PPAR γ mutations Clearly both are NR dependent, and the metabolic phenotypes have clear parallels (Savage et al., 2003). Another interesting feature revealed by the RNA-seq analysis suggests increased T-cell involvement/recruitment in the SAT of Tg-FABP4-RORα4 mice. While RORα is known to regulate inflammation and influence the development of specific lymphocyte populations, for example T helper 17 BMI1 inhibitor and group 2 innate-like lymphocytes (Halim et al., 2012; Mjosberg et al., 2012), the biological significance of the increased lymphocyte infiltrate in this mouse model and its relation to the phenotypes remains to be elucidated. In humans, there is a positive correlation between greater amounts of lower-body (gluteo-femoral in particular) SAT depots and protection against glucose intolerance and insulin resistance, dyslipidemia and atherosclerosis (reviewed in Manolopoulos et al., 2010). In this context, our data is in line with the view that subcutaneous fat serves as a protective metabolic sink for excess energy and loss of this depot/protection leads to ectopic fat accumulation and impaired glucose clearance. This severely hinders normal tissue function and perpetuates considerable amounts of stress in these organs. Moreover, recent studies report metabolic benefits acquired after SAT transplantation into the intra-abdominal cavity in mice, effectively conferring protection against HFD-induced glucose intolerance and hepatic lipid loading (Hocking et al., 2015; Konrad et al., 2007; Tran et al., 2008). For example, mice implanted intra-abdominally with SAT, but not epididymal visceral tissues, were protected against HFD-induced glucose intolerance. These mice were also protected against hepatic triacylglycerol accumulation and inflammation after HFD. However, the underlying mechanism remains obscure as there were no differences in weight gain, glucose uptake by other tissues (including the skeletal muscle), or plasma adipokine concentrations (Hocking et al., 2015). In light of the metabolic benefits conferred by expansion of SAT and transplantation of SAT into intra-abdominal cavity, it is clear that maintenance (or even supplementation) of SAT integrity offers protection against glucose intolerance and lipid imbalance during metabolic disease. Failure to sustain or expand adequate subcutaneous fat storage adversely impacts glucose tolerance and contributes to ectopic fat accumulation in non-adipose organs such as the liver, increasing susceptibility to inflammatory stress and cancer (Gentile et al., 2015; Hocking et al., 2015; Wree et al., 2011). The pathology presented thus far in the Tg-FABP4-RORα4 transgenic mouse model is reminiscent of metabolic dysfunction, such as those of childhood and adolescent obesity. Obese youths typically present with (i) decreased subcutaneous adiposity, (ii) adipose tissue dysfunction accompanied with macrophage, dendritic cells and T-cells recruitment and pro-inflammatory signaling, (iii) increased hepatic lipid deposition/steatosis and muscle lipid deposition, and (iv) impaired glucose tolerance and insulin sensitivity (Corgosinho et al., 2012; Aguilar et al., 2013; Rigamonti et al., 2013; Burgert et al., 2006; Santoro et al., 2013).