Surgical removal of inflamed epididymal white adipose tissue attenuates the development of non-alcoholic steatohepatitis in obesity

Abstract

Background:Non-alcoholic fatty liver disease (NAFLD) is strongly associated with abdominal obesity. Growing evidence suggests that inflammation in specific depots of white adipose tissue (WAT) has a key role in NAFLD progression, but experimental evidence for a causal role of WAT is lacking.Methods:A time-course study in C57BL/6J mice was performed to establish which WAT depot is most susceptible to develop inflammation during high-fat diet (HFD)-induced obesity. Crown-like structures (CLS) were quantified in epididymal (eWAT), mesenteric (mWAT) and inguinal/subcutaneous (iWAT) WAT. The contribution of inflamed WAT to NAFLD progression was investigated by surgical removal of a selected WAT depot and compared with sham surgery. Plasma markers were analyzed by enzyme-linked immunosorbent assay (cytokines/adipokines) and lipidomics (lipids).Results:In eWAT, CLS were formed already after 12 weeks of HFD, which coincided with maximal adipocyte size and fat depot mass, and preceded establishment of non-alcoholic steatohepatitis (NASH). By contrast, the number of CLS were low in mWAT and iWAT. Removal of inflamed eWAT after 12 weeks (eWATx group), followed by another 12 weeks of HFD feeding, resulted in significantly reduced NASH in eWATx. Inflammatory cell aggregates (−40% P<0.05) and inflammatory genes (e.g., TNFα, −37% P<0.05) were attenuated in livers of eWATx mice, whereas steatosis was not affected. Concomitantly, plasma concentrations of circulating proinflammatory mediators, viz. leptin and specific saturated and monounsaturated fatty acids, were also reduced in the eWATx group.Conclusions:Intervention in NAFLD progression by removal of inflamed eWAT attenuates the development of NASH and reduces plasma levels of specific inflammatory mediators (cytokines and lipids). These data support the hypothesis that eWAT is causally involved in the pathogenesis of NASH.

Increased intake of energy-dense diet and negative energy balance in a mouse model of chronic psychosocial defeat

“…In comparison with other strains, C57BL/6J are obesityprone mice and their eWAT is a higher HFD-susceptible fat depot, whose mass increases more than mesenteric or inguinal WAT depots [34]. However, besides epididymal, other fat depots such as mesenteric, inguinal/subcutaneous and perirenal fat depots can also account for the increase of body weight in UN/HFD mice.…”

Reduction of obesity-associated white adipose tissue inflammation by rosiglitazone is associated with reduced non-alcoholic fatty liver disease in LDLr-deficient mice

“…Notably, these fatty acids are also increased in patients with diagnosed NASH41. Furthermore, surgical excision of inflamed WAT in mice lowered palmitic acid in plasma and reduced progression towards NASH5. In vitro experiments have shown that conditioned medium from palmitic acid-treated hepatocytes induces the expression of pro-fibrotic genes in hepatic stellate cells42, providing mechanistic support for a crucial role of inflammatory lipid mediators in NASH.…”

Adipose type I interferon signalling protects against metabolic dysfunction

“…Liver and epididymal white adipose tissue (eWAT) was weighed at the closure of the high-fat diet experiments and stored for further analyses at –80°C. We analysed eWAT as it can be reliably identified and weighed and because inflamed eWAT consequent to a high-fat diet has been implicated in the pathogenesis of non-alcoholic fatty liver disease 23 24…”