Surgical removal of inflamed epididymal white adipose tissue attenuates the development of non-alcoholic steatohepatitis in obesity.
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.
Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.|Leiden University Medical Center, Department of Cardiovascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.
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http://orcid.org/0000-0002-0982-4466
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Mulder
Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.
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Morrison
Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.
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Wielinga
Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.
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van Duyvenvoorde
Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.
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T
Kooistra
Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.|Leiden University Medical Center, Department of Cardiovascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.
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Kleemann
D052436:Adipose Tissue, White / Q000473:pathology* / Q000601:surgery*; D000818:Animals; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D007249:Inflammation / Q000473:pathology / Q000601:surgery; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000473:pathology* / Q000517:prevention & control*; D009765:Obesity / Q000150:complications / Q000473:pathology*