Gut microbiota dysbiosis has been repeatedly observed in obesity and type 2 diabetes mellitus, two metabolic diseases strongly intertwined with non-alcoholic fatty liver disease (NAFLD). Animal ...studies have demonstrated a potential causal role of gut microbiota in NAFLD. Human studies have started to describe microbiota alterations in NAFLD and have found a few consistent microbiome signatures discriminating healthy individuals from those with NAFLD, non-alcoholic steatohepatitis or cirrhosis. However, patients with NAFLD often present with obesity and/or insulin resistance and type 2 diabetes mellitus, and these metabolic confounding factors for dysbiosis have not always been considered. Patients with different NAFLD severity stages often present with heterogeneous lesions and variable demographic characteristics (including age, sex and ethnicity), which are known to affect the gut microbiome and have been overlooked in most studies. Finally, multiple gut microbiome sequencing tools and NAFLD diagnostic methods have been used across studies that could account for discrepant microbiome signatures. This Review provides a broad insight into microbiome signatures for human NAFLD and explores issues with disentangling these signatures from underlying metabolic disorders. More advanced metagenomics and multi-omics studies using system biology approaches are needed to improve microbiome biomarkers.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Obesity originates from an imbalance between caloric intake and energy expenditure that promotes adipose tissue expansion, which is necessary to buffer nutrient excess. Patients with higher visceral ...fat mass are at a higher risk of developing severe complications such as type 2 diabetes and cardiovascular and liver diseases. However, increased fat mass does not fully explain obesity's propensity to promote metabolic diseases. With chronic obesity, adipose tissue undergoes major remodeling, which can ultimately result in unresolved chronic inflammation leading to fibrosis accumulation. These features drive local tissue damage and initiate and/or maintain multiorgan dysfunction. Here, we review the current understanding of adipose tissue remodeling with a focus on obesity-induced adipose tissue fibrosis and its relevance to clinical manifestations.
Absence of proopiomelanocortin results in early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism. Two affected patients received setmelanotide, a new melanocortin-4 receptor agonist, ...which led to sustainable reduction of hunger and substantial weight loss.
Melanocyte-stimulating hormone, which is produced from proopiomelanocortin, plays a pivotal role in the regulation of satiety and energy expenditure. In the hypothalamic leptin–melanocortin signaling pathway, melanocyte-stimulating hormone transmits the anorexic effect of leptin through the melanocortin-4 receptor.
1
Patients with a mutation in the gene encoding proopiomelanocortin (
POMC
), a very rare condition, have early-onset obesity due to severe hyperphagia as a result of the lack of hypothalamic melanocyte-stimulating hormone. Furthermore, the lack of melanocyte-stimulating hormone at the melanocortin-1 receptor in melanocytes and hair follicles may lead to pale skin and red hair. In addition, affected persons have secondary hypocortisolism . . .
OBJECTIVES—To examine the role of adipose-produced chemokine, chemokine ligand (CCL) 5, on the recruitment and survival of macrophages in human white adipose tissue (WAT).
METHODS AND RESULTS—CCL5 ...levels measured by enzyme immunoassay in serum and by real-time polymerase chain reaction in WAT were higher in obese compared to lean subjects. CCL5, but not CCL2, secretion was higher in visceral compared to subcutaneous WAT. CCL5 mRNA expression was positively correlated with the inflammatory macrophage markers as CD11b, tumor necrosis factor-α, and IL-6 in visceral WAT (n=24 obese subjects), and was higher in macrophages than other WAT cells. We found that CCL5 triggered adhesion and transmigration of blood monocytes to/through endothelial cells of human WAT. Whereas in obese WAT apoptotic macrophages were located around necrotic adipocytes, we demonstrated that CCL5, but not CCL2, protected macrophages from free cholesterol-induced apoptosis via activation of the Akt/Erk pathways.
CONCLUSIONS—CCL5 could participate in the inflammation of obese WAT by recruiting blood monocytes and exerting antiapoptotic properties on WAT macrophages. This specific role of CCL5 on macrophage survival with maintenance of their lipid scavenging function should be taken into account for future therapeutic strategies in obesity-related diseases.
Decreased gut microbial gene richness (MGR) and compositional changes are associated with adverse metabolism in overweight or moderate obesity, but lack characterisation in severe obesity. Bariatric ...surgery (BS) improves metabolism and inflammation in severe obesity and is associated with gut microbiota modifications. Here, we characterised severe obesity-associated dysbiosis (ie, MGR, microbiota composition and functional characteristics) and assessed whether BS would rescue these changes.
Sixty-one severely obese subjects, candidates for adjustable gastric banding (AGB, n=20) or Roux-en-Y-gastric bypass (RYGB, n=41), were enrolled. Twenty-four subjects were followed at 1, 3 and 12 months post-BS. Gut microbiota and serum metabolome were analysed using shotgun metagenomics and liquid chromatography mass spectrometry (LC-MS). Confirmation groups were included.
Low gene richness (LGC) was present in 75% of patients and correlated with increased trunk-fat mass and comorbidities (type 2 diabetes, hypertension and severity). Seventy-eight metagenomic species were altered with LGC, among which 50% were associated with adverse body composition and metabolic phenotypes. Nine serum metabolites (including
,
and
) and functional modules containing protein families involved in their metabolism were strongly associated with low MGR. BS increased MGR 1 year postsurgery, but most RYGB patients remained with low MGR 1 year post-BS, despite greater metabolic improvement than AGB patients.
We identified major gut microbiota alterations in severe obesity, which include decreased MGR and related functional pathways linked with metabolic deteriorations. The lack of full rescue post-BS calls for additional strategies to improve the gut microbiota ecosystem and microbiome-host interactions in severe obesity.
NCT01454232.
Nonalcoholic fatty liver disease (i.e., increased intrahepatic triglyceride IHTG content), predisposes to type 2 diabetes and cardiovascular disease. Adipose tissue lipolysis and hepatic de novo ...lipogenesis (DNL) are the main pathways contributing to IHTG. We hypothesized that dietary macronutrient composition influences the pathways, mediators, and magnitude of weight gain-induced changes in IHTG.
We overfed 38 overweight subjects (age 48 ± 2 years, BMI 31 ± 1 kg/m
, liver fat 4.7 ± 0.9%) 1,000 extra kcal/day of saturated (SAT) or unsaturated (UNSAT) fat or simple sugars (CARB) for 3 weeks. We measured IHTG (
H-MRS), pathways contributing to IHTG (lipolysis (
H
glycerol) and DNL (
H
O) basally and during euglycemic hyperinsulinemia), insulin resistance, endotoxemia, plasma ceramides, and adipose tissue gene expression at 0 and 3 weeks.
Overfeeding SAT increased IHTG more (+55%) than UNSAT (+15%,
< 0.05). CARB increased IHTG (+33%) by stimulating DNL (+98%). SAT significantly increased while UNSAT decreased lipolysis. SAT induced insulin resistance and endotoxemia and significantly increased multiple plasma ceramides. The diets had distinct effects on adipose tissue gene expression.
Macronutrient composition of excess energy influences pathways of IHTG: CARB increases DNL, while SAT increases and UNSAT decreases lipolysis. SAT induced the greatest increase in IHTG, insulin resistance, and harmful ceramides. Decreased intakes of SAT could be beneficial in reducing IHTG and the associated risk of diabetes.
Context: Macrophages accumulate in adipose tissue and possibly participate in metabolic complications in obesity. Macrophage number varies with adipose tissue site and weight loss, but whether this ...is accompanied by phenotypic changes is unknown.
Objective: The objective of the study was to characterize the activation state of adipose tissue macrophages in human obesity.
Design/Setting: We performed a single-center prospective study.
Participants/Interventions: Paired biopsies of sc and omental adipose tissue were obtained during gastric surgery in 16 premenopausal obese women (aged 41.1 ± 8.6 yr; body mass index 43.8 ± 3.4 kg/m2). Subcutaneous adipose tissue biopsies were obtained 3 months later in obese subjects and in 10 nonobese women (aged 43.3 ± 3.5 yr; body mass index 22.5 ± 0.75 kg/m2). The number of macrophages stained with CD40, CD206, and CD163 surface markers was determined by immunochemistry.
Main Outcomes: The number of CD40+ macrophages significantly increased with obesity and in omental vs. sc adipose tissue in obese women. No significant changes in CD163+ and CD206+ macrophage counts was found with obesity and fat pad anatomical location. Three months after gastric surgery, the ratio of CD40+ to CD206+ macrophages was 2-fold lower than before surgery in the sc adipose tissue of obese subjects (P < 0.001) due to a concomitant decrease of CD40+ and increase of CD206+ macrophages counts.
Conclusion: We suggest that the activation state of adipose tissue macrophages is weighted toward M1 over M2 status in obese subjects and switch to a less proinflammatory profile 3 months after gastric bypass.
Immunohistochemistry analyses suggest that gastric surgery switches the activation state of adipose tissue macrophages towards a M2-oriented, less pro-inflammatory phenotype in morbidly obese subjects.
The mechanisms that drive nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This large multicenter study characterized the transcriptional changes that occur in liver tissue ...across the NAFLD spectrum as disease progresses to cirrhosis to identify potential circulating markers. We performed high-throughput RNA sequencing on a discovery cohort comprising histologically characterized NAFLD samples from 206 patients. Unsupervised clustering stratified NAFLD on the basis of disease activity and fibrosis stage with differences in age, aspartate aminotransferase (AST), type 2 diabetes mellitus, and carriage of
, a genetic variant associated with NAFLD. Relative to early disease, we consistently identified 25 differentially expressed genes as fibrosing steatohepatitis progressed through stages F2 to F4. This 25-gene signature was independently validated by logistic modeling in a separate replication cohort (
= 175), and an integrative analysis with publicly available single-cell RNA sequencing data elucidated the likely relative contribution of specific intrahepatic cell populations. Translating these findings to the protein level, SomaScan analysis in more than 300 NAFLD serum samples confirmed that circulating concentrations of proteins AKR1B10 and GDF15 were strongly associated with disease activity and fibrosis stage. Supporting the biological plausibility of these data, in vitro functional studies determined that endoplasmic reticulum stress up-regulated expression of
,
, and
, whereas GDF15 supplementation tempered the inflammatory response in macrophages upon lipid loading and lipopolysaccharide stimulation. This study provides insights into the pathophysiology of progressive fibrosing steatohepatitis, and proof of principle that transcriptomic changes represent potentially tractable and clinically relevant markers of disease progression.
Reduction of Macrophage Infiltration and Chemoattractant Gene Expression Changes in White Adipose Tissue of Morbidly Obese
Subjects After Surgery-Induced Weight Loss
Raffaella Cancello 1 ,
Corneliu ...Henegar 1 2 ,
Nathalie Viguerie 3 ,
Soraya Taleb 1 ,
Christine Poitou 1 ,
Christine Rouault 1 ,
Muriel Coupaye 1 ,
Veronique Pelloux 1 ,
Danielle Hugol 4 ,
Jean-Luc Bouillot 5 ,
Anne Bouloumié 3 6 ,
Giorgio Barbatelli 7 ,
Saverio Cinti 7 ,
Per-Arne Svensson 8 ,
Gregory S. Barsh 9 ,
Jean-Daniel Zucker 1 10 ,
Arnaud Basdevant 1 ,
Dominique Langin 3 and
Karine Clément 1
1 Inserm “Avenir”, Paris 6 University EA3502 and Human Research Center on Nutrition (CRNH), Hôtel Dieu Hospital, AP/HP, Paris,
France
2 SPIM “Santé publique et informatique médicale” laboratory, INSERM ERM202, Paris, France
3 INSERM UPS U586, Obesity Research Unit, Louis Bugnard Institute, Paul Sabatier University, Toulouse, France
4 Department of Anatomo-Pathology, Hôtel Dieu Hospital, Paris, France
5 Department of Surgery, Hôtel Dieu Hospital, Paris, France
6 Cardiovascular Physiology Department, J.-W. Goethe University, Frankfurt, Germany
7 Institute of Normal Human Morphology-Anatomy, School of Medicine, Polytechnic University of Marche, Ancona, Italy
8 Department of Internal Medicine, Research Centre for Endocrinology and Metabolism, Sahlgrenska Academy, Goteborg University,
Goteborg, Sweden
9 Department of Pediatrics and Genetics, Howard Hugues Medical Institute, Beckman Center, Stanford University School of Medicine,
Stanford, California
10 LIM & BIO, Paris-Nord University, Paris, France
Address correspondence and reprint requests to Karine Clément, MD, PhD, Department of Nutrition, Hôtel-Dieu Hospital, 1, Place
du Parvis Notre-Dame, 75004 Paris, France. E-mail: karine.clement{at}htd.ap-hop-paris.fr
Abstract
In human obesity, the stroma vascular fraction (SVF) of white adipose tissue (WAT) is enriched in macrophages. These cells
may contribute to low-grade inflammation and to its metabolic complications. Little is known about the effect of weight loss
on macrophages and genes involved in macrophage attraction. We examined subcutaneous WAT (scWAT) of 7 lean and 17 morbidly
obese subjects before and 3 months after bypass surgery. Immunomorphological changes of the number of scWAT-infiltrating macrophages
were evaluated, along with concomitant changes in expression of SVF-overexpressed genes. The number of scWAT-infiltrating
macrophages before surgery was higher in obese than in lean subjects (HAM56+/CD68+; 22.6 ± 4.3 vs. 1.4 ± 0.6%, P < 0.001). Typical “crowns” of macrophages were observed around adipocytes. Drastic weight loss resulted in a significant
decrease in macrophage number (−11.63 ± 2.3%, P < 0.001), and remaining macrophages stained positive for the anti-inflammatory protein interleukin 10. Genes involved in
macrophage attraction (monocyte chemotactic protein MCP-1, plasminogen activator urokinase receptor PLAUR, and colony-stimulating
factor CSF-3) and hypoxia (hypoxia-inducible factor-1α HIF-1α), expression of which increases in obesity and decreases
after surgery, were predominantly expressed in the SVF. We show that improvement of the inflammatory profile after weight
loss is related to a reduced number of macrophages in scWAT. MCP-1, PLAUR, CSF-3, and HIF-1α may play roles in the attraction
of macrophages in scWAT.
CRP, C-reactive protein
CSF, colony-stimulating factor
GO, Gene Ontology Consortium
FDR, false discovery rate
HIF-1α, hypoxia-inducible factor-1α
IL, interleukin
MCP, monocyte chemotactic protein
ORO, orosomucoid
PLAUR, plasminogen activator urokinase receptor
RTqPCR, real-time quantitative PCR
SAA, serum amyloid A
SAM, significance analysis of microarrays
scWAT, subcutaneous WAT
SVF, stroma vascular fraction
WAT, white adipose tissue
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted May 16, 2005.
Received January 17, 2005.
DIABETES
Complex gene-environment interactions are considered important in the development of obesity. The composition of the gut microbiota can determine the efficacy of energy harvest from food and changes ...in dietary composition have been associated with changes in the composition of gut microbial populations. The capacity to explore microbiota composition was markedly improved by the development of metagenomic approaches, which have already allowed production of the first human gut microbial gene catalogue and stratifying individuals by their gut genomic profile into different enterotypes, but the analyses were carried out mainly in non-intervention settings. To investigate the temporal relationships between food intake, gut microbiota and metabolic and inflammatory phenotypes, we conducted diet-induced weight-loss and weight-stabilization interventions in a study sample of 38 obese and 11 overweight individuals. Here we report that individuals with reduced microbial gene richness (40%) present more pronounced dys-metabolism and low-grade inflammation, as observed concomitantly in the accompanying paper. Dietary intervention improves low gene richness and clinical phenotypes, but seems to be less efficient for inflammation variables in individuals with lower gene richness. Low gene richness may therefore have predictive potential for the efficacy of intervention.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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