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

Published on Apr 1, 2016in International Journal of Obesity4.51
· DOI :10.1038/ijo.2015.226
Petra Mulder8
Estimated H-index: 8
Martine C. Morrison11
Estimated H-index: 11
+ 3 AuthorsRobert Kleemann11
Estimated H-index: 11
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.
  • References (39)
  • Citations (30)
Published on Dec 23, 2014in PLOS ONE2.78
Wen Liang7
Estimated H-index: 7
(LUMC: Leiden University Medical Center),
Aswin L. Menke3
Estimated H-index: 3
+ 6 AuthorsAnita M. van den Hoek15
Estimated H-index: 15
Results: The criteria macrovesicular steatosis, microvesicular steatosis, hepatocellular hypertrophy, inflammation and fibrosis were generally applicable to rodent NAFLD. The inter-observer reproducibility (evaluated using the Intraclass Correlation Coefficient) between the ten observers was high for the analysis of macrovesicular steatosis and microvesicular steatosis (ICC50.784 and 0.776, all p,0.001, respectively) and moderate for the analysis of hypertrophy and inflammation (ICC50.685 and 0....
Published on Sep 1, 2014in Gastroenterology19.23
Fabio Marra64
Estimated H-index: 64
(UniFI: University of Florence),
Frank Tacke61
Estimated H-index: 61
(RWTH Aachen University)
Sustained hepatic inflammation is an important factor in progression of chronic liver diseases, including hepatitis C or non-alcoholic steatohepatitis. Liver inflammation is regulated by chemokines, which regulate the migration and activities of hepatocytes, Kupffer cells, hepatic stellate cells, endothelial cells, and circulating immune cells. However, the effects of the different chemokines and their receptors vary during pathogenesis of different liver diseases. During development of chronic ...
Published on Nov 1, 2013in Nature Reviews Gastroenterology & Hepatology23.57
Rohit Loomba53
Estimated H-index: 53
Arun J. Sanyal97
Estimated H-index: 97
Global differences in the prevalence and presentation of NAFLD are presented in this Perspectives article. The authors also convey how scientific advances in our understanding and management of NAFLD now need to be translated to improve awareness at the level of society, influence global health policy and research priorities and ensure a better future for our coming generations.
Published on Sep 25, 2013in PLOS ONE2.78
Wen Liang7
Estimated H-index: 7
Giulia Tonini6
Estimated H-index: 6
+ 9 AuthorsTeake Kooistra41
Estimated H-index: 41
Background:Chronic metabolic overload results in lipid accumulation and subsequent inflammation in white adipose tissue (WAT), often accompanied by non-alcoholic fatty liver disease (NAFLD). In response to metabolic overload, the expression of genes involved in lipid metabolism and inflammatory processes is adapted. However, it still remains unknown how these adaptations in gene expression in expanding WAT and liver are orchestrated and whether they are interrelated.Methodology/Principal Finding...
Published on Dec 1, 2012in Journal of Nutritional Biochemistry4.49
Jérôme Salles14
Estimated H-index: 14
(INRA: Institut national de la recherche agronomique),
Nicolas Tardif5
Estimated H-index: 5
(INRA: Institut national de la recherche agronomique)
+ 11 AuthorsJustine Bertrand-Michel25
Estimated H-index: 25
Abstract Aims/hypothesis Inflammation and ectopic lipid deposition contribute to obesity-related insulin resistance (IR). Studies have shown that deficiency of the proinflammatory cytokine tumor necrosis factor-α (TNFα) protects against the IR induced by a high-fat diet (HFD). We aimed to evaluate the relationship between HFD-related inflammation and lipid deposition in skeletal muscle and liver. Experimental design Wild-type (WT) and TNFα-deficient (TNFα-KO) mice were subjected to an HFD for 12...
Published on Jun 29, 2012in PLOS ONE2.78
Xin Guo11
Estimated H-index: 11
(A&M: Texas A&M University),
Honggui Li13
Estimated H-index: 13
(A&M: Texas A&M University)
+ 12 AuthorsDouglas G. Mashek30
Estimated H-index: 30
(UMN: University of Minnesota)
The interaction between fat deposition and inflammation during obesity contributes to the development of non-alcoholic fatty liver disease (NAFLD). The present study examined the effects of palmitoleate, a monounsaturated fatty acid (16:1n7), on liver metabolic and inflammatory responses, and investigated the mechanisms by which palmitoleate increases hepatocyte fatty acid synthase (FAS) expression. Male wild-type C57BL/6J mice were supplemented with palmitoleate and subjected to the assays to a...
Published on May 1, 2012in Journal of Hepatology18.95
Joan Tordjman34
Estimated H-index: 34
(UPMC: Pierre-and-Marie-Curie University),
Adeline Divoux3
Estimated H-index: 3
(UPMC: Pierre-and-Marie-Curie University)
+ 9 AuthorsPierre Bedossa83
Estimated H-index: 83
(Beaujon Hospital)
Background & Aims In addition to total body fat, the regional distribution and inflammatory status of enlarged adipose tissue are strongly associated with metabolic co-morbidities of obesity. We recently showed that the severity of histological liver lesions related to obesity increases with the amount of macrophage accumulation in visceral adipose tissue (VAT), while no association was found with the subcutaneous adipose tissue (SAT). In the abdominal region, SAT is anatomically divided into tw...
Published on Mar 1, 2012in Nutrition & Diabetes3.10
Sherman J. Bigornia14
Estimated H-index: 14
Melissa G. Farb2
Estimated H-index: 2
+ 6 AuthorsNoyan Gokce45
Estimated H-index: 45
BACKGROUND: A low-grade state of adipose tissue inflammation associated with obesity has been linked to mechanisms of systemic metabolic dysfunction. However, the relation of clinical phenotypes to depot-specific inflammation has not been well examined in human obesity. OBJECTIVE: To characterize the inflammatory status of subcutaneous and visceral fat depots, as assessed by tissue presence of macrophage crown-like structures (CLS) as a hallmark of chronic inflammation, and determine the relatio...
Published on Jan 1, 2012in Endocrine Journal1.94
Takayoshi Suganami23
Estimated H-index: 23
(Tokyo Medical and Dental University),
Miyako Tanaka17
Estimated H-index: 17
(Tokyo Medical and Dental University),
Yoshihiro Ogawa93
Estimated H-index: 93
(Tokyo Medical and Dental University)
Obesity may be viewed as a chronic low-grade inflammatory disease as well as a metabolic disease. Indeed, unbalanced production of pro- and anti-inflammatory adipocytokines critically contributes to the obesity-induced insulin resistance. In addition to lipid-laden mature adipocytes, adipose tissue is composed of various stromal cells such as preadipocytes, endothelial cells, fibroblasts, and immune cells that may be involved in adipose tissue functions. Accumulating evidence has suggested that ...
Published on Dec 1, 2012in Obesity Reviews8.19
Flurin Item8
Estimated H-index: 8
(Boston Children's Hospital),
Daniel Konrad27
Estimated H-index: 27
(UZH: University of Zurich)
Summary Abdominal (central) obesity strongly correlates with (hepatic) insulin resistance and type 2 diabetes. Among several hypotheses that have been formulated, the ‘portal theory’ proposes that the liver is directly exposed to increasing amounts of free fatty acids and pro-inflammatory factors released from visceral fat into the portal vein of obese patients, promoting the development of hepatic insulin resistance and liver steatosis. Thus, visceral obesity may be particularly hazardous in th...
Cited By30
Published on Jan 3, 2019in BMC Complementary and Alternative Medicine2.48
Yea-Jin Park (Sangji University), Gui-Sun Lee + 2 AuthorsHyo-Jin An18
Estimated H-index: 18
(Sangji University)
Background Recently, it has been noted that natural herbal medications may be effective in treating obesity. Tongbi-san (TBS) is a traditional medicine usually used for dysuria (i.e., painful urination), containing three herbs, Cyperus rotundus L., Citrus unshiu Markovich, and Poria cocos. In this study, we aimed to examine whether TBS can inhibit high-fat diet (HFD)-induced adipogenesis in the liver and epididymal adipose tissue of obese mice.
Published in Nutrients4.17
Sophie A.H. Jacobs , Eveline Gart1
Estimated H-index: 1
+ -3 AuthorsMartine C. Morrison11
Estimated H-index: 11
Background: Sex-specific differences play a role in metabolism, fat storage in adipose tissue, and brain structure. At juvenile age, brain function is susceptible to the effects of obesity; little is known about sex-specific differences in juvenile obesity. Therefore, this study examined sex-specific differences in adipose tissue and liver of high-fat diet (HFD)-induced obese mice, and putative alterations between male and female mice in brain structure in relation to behavioral changes during t...
Published in Obesity3.97
Anarina L. Murillo3
Estimated H-index: 3
(UAB: University of Alabama at Birmingham),
Kathryn A. Kaiser16
Estimated H-index: 16
(UAB: University of Alabama at Birmingham)
+ -3 AuthorsDavid B. Allison111
Estimated H-index: 111
(IU: Indiana University Bloomington)
Published on Apr 30, 2019in Seminars in Liver Disease3.46
Hannelie Korf20
Estimated H-index: 20
(Katholieke Universiteit Leuven),
Markus Boesch (Katholieke Universiteit Leuven)+ 1 AuthorsSchalk Van der Merwe24
Estimated H-index: 24
(Katholieke Universiteit Leuven)
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries that could lead to serious health problems including liver failure, cancer, or death. The term NAFLD includes a spectrum of disease states with histological features ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). A key aspect within this research field is the identification of pathogenic factors that trigger inflammation, thus fueling the transition from nonalcoh...
Published on Jun 25, 2019in Oxidative Medicine and Cellular Longevity4.87
Christian Neves2
Estimated H-index: 2
(UC: University of Coimbra),
Tiago Rodrigues19
Estimated H-index: 19
(UC: University of Coimbra)
+ 9 AuthorsM. R. M. Domingues23
Estimated H-index: 23
(University of Aveiro)
Nonalcoholic fatty liver disease (NAFLD) is caused by excessive liver lipid accumulation, but insulin resistance is specifically associated with impaired lipid saturation, oxidation, and storage (esterification), besides increased de novo lipogenesis. We hypothesized that dietary glycotoxins could impair hepatic lipid metabolism in obesity contributing to lipotoxicity-driven insulin resistance and thus to the onset of nonalcoholic steatohepatitis (NASH). In diet-induced obese rats with methylgly...
Published on Jun 24, 2019in PLOS ONE2.78
Kanita Salic4
Estimated H-index: 4
Robert Kleemann41
Estimated H-index: 41
+ 3 AuthorsMelissa J Palmer7
Estimated H-index: 7
Interruption of bile acid recirculation through inhibition of the apical sodium-dependent bile acid transporter (ASBT) is a promising strategy to alleviate hepatic cholesterol accumulation in non-alcoholic steatohepatitis (NASH), and improve the metabolic aspects of the disease. Potential disease-attenuating effects of the ASBT inhibitor volixibat (5, 15, and 30 mg/kg) were investigated in high-fat diet (HFD)-fed Ldlr-/-.Leiden mice over 24 weeks. Plasma and fecal bile acid levels, plasma insuli...
Published on Dec 20, 2018in International Journal of Molecular Sciences4.18
Eveline Gart1
Estimated H-index: 1
Everton Souto Lima1
Estimated H-index: 1
+ 7 AuthorsRobert Kleemann41
Estimated H-index: 41
Development of non-alcoholic fatty liver disease (NAFLD) is linked to obesity, adipose tissue inflammation, and gut dysfunction, all of which depend on diet. So far, studies have mainly focused on diet-related fecal microbiota changes, but other compartments may be more informative on host health. We present a first systematic analysis of microbiota changes in the ileum and colon using multiple diets and investigating both fecal and mucosal samples. Ldlr−/−.Leiden mice received one of three diff...
Published on Dec 1, 2018
Martine C. Morrison11
Estimated H-index: 11
Lars Verschuren18
Estimated H-index: 18
(TNO: Netherlands Organisation for Applied Scientific Research)
+ 17 AuthorsScott M. Turner25
Estimated H-index: 25
Concerns have been raised about whether preclinical models sufficiently mimic molecular disease processes observed in nonalcoholic steatohepatitis (NASH) patients, bringing into question their translational value in studies of therapeutic interventions in the process of NASH/fibrosis. We investigated the representation of molecular disease patterns characteristic for human NASH in high-fat diet (HFD)-fed Ldlr-/-.Leiden mice and studied the effects of obeticholic acid (OCA) on these disease profi...
Zhe Wu2
Estimated H-index: 2
(PKU: Peking University),
Jiang Tan (PKU: Peking University)+ 6 AuthorsYulan Liu7
Estimated H-index: 7
(PKU: Peking University)
The mesenteric adipose tissue (MAT) lies between the gut and liver and plays a critical role in hepatic metabolic diseases. In the present study, we found that the MAT was prone to inflammation in ...