Abstract
Metabolic inflammation in adipose tissue and the liver is frequently observed as a result of diet-induced obesity in human and rodent studies. Although the adipose tissue and the liver are both prone to become chronically inflamed with prolonged obesity, their individual contribution to the development of metabolic inflammation remains speculative. Thus, we aimed to elucidate the sequence of inflammatory events in adipose and hepatic tissues to determine their contribution to the development of metabolic inflammation and insulin resistance (IR) in diet-induced obesity. To confirm our hypothesis that adipose tissue (AT) inflammation is initiated prior to hepatic inflammation, C57BL/6J male mice were fed a low-fat diet (LFD; 10% kcal fat) or high-fat diet (HFD; 45% kcal fat) for either 24, 40 or 52 weeks. Lipid accumulation and inflammation was measured in AT and liver. Glucose tolerance was assessed and plasma levels of glucose, insulin, leptin and adiponectin were measured at various time points throughout the study. With HFD, C57BL/6j mice developed a progressive obese phenotype, accompanied by IR at 24 and 40 weeks of HFD, but IR was attenuated after 52 weeks of HFD. AT inflammation was present after 24 weeks of HFD, as indicated by the increased presence of crown-like structures and up-regulation of pro-inflammatory genes Tnf, Il1β, Mcp1 and F4/80. As hepatic inflammation was not detected until 40 weeks of HFD, we show that AT inflammation is established prior to the development of hepatic inflammation. Thus, AT inflammation is likely to have a greater contribution to the development of IR compared to hepatic inflammation.
Highlights
Obesity and associated metabolic disorders like insulin resistance (IR), type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) are marked by a state of inflammation initiated by nutrient overload [1]
Body weight gradually increased between mice fed a high-fat diet (HFD) for 24 weeks and 40 weeks (Fig. 1B; p
We observed a significant increase in the NAFLD activity score (NAS) (Fig. 4E), the number of inflammatory foci (Fig. 4F) and hepatocellular ballooning (Fig. 4G) for all HFD groups as compared to low‐fat diet (LFD) groups
Summary
Obesity and associated metabolic disorders like insulin resistance (IR), type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) are marked by a state of inflammation initiated by nutrient overload [1]. In addition to regulating fat mass and nutrient homeostasis, adipocytes mediate the inflammatory response through the secretion of adipokines, cytokines, and chemokines that enhance the recruitment of immune cells, especially macrophages, to the AT [3]. These AT macrophages (ATMs) are a major source of pro-inflammatory cytokines and chemokines and once activated can propagate the inflammatory state and interfere with insulin sensitivity in insulin target cells [4]. What tissue provides the main contribution to the development of IR remains unknown
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