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    Inter-breed diversity and temporal dynamics of the faecal microbiota in healthy horses. Massacci Francesca Romana,Clark Allison,Ruet Alice,Lansade Léa,Costa Marcio,Mach Núria Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie Understanding gut microbiota similarities and differences across breeds in horses has the potential to advance approaches aimed at personalized microbial modifications, particularly those involved in improving sport athletic performance. Here, we explore whether faecal microbiota composition based on faecal 16S ribosomal RNA gene sequencing varies across six different sport breeds at two time points 8 months apart within a cohort of 189 healthy horses cared for under similar conditions. Lusitano horses presented the smallest and Hanoverians the greatest bacterial diversity. We found subtle but significant differences in β-diversity between Lusitano, Anglo Arabian and the central European breeds, and we reproduced these results across the two time points. Repeat sampling of subjects showed community to be temporally more stable in Lusitano and Anglo Arabian breeds. Additionally, we found that 27 genera significantly varied in abundance across breeds. Overall, 33% of these taxa overlapped with previously identified taxa that were associated with genetic variation in humans or other species. However, a non-significant correlation was observed between microbial composition and the host pedigree-based kinship. Despite a notable variation in the diversity and composition of the faecal microbiota, breed exerted limited effects on the equine faecal microbiota. 10.1111/jbg.12441
    The equine gastrointestinal microbiome: impacts of weight-loss. Morrison Philippa K,Newbold Charles J,Jones Eleanor,Worgan Hilary J,Grove-White Dai H,Dugdale Alexandra H,Barfoot Clare,Harris Patricia A,Argo Caroline McGregor BMC veterinary research BACKGROUND:Obesity is an important equine welfare issue. Whilst dietary restriction is the most effective weight-loss tool, individual animals range in their weight-loss propensity. Gastrointestinal-derived bacteria play a fundamental role in host-health and have been associated with obesity and weight-loss in other species. This study evaluated the faecal microbiome (next-generation sequencing of 16S rRNA genes) of 15 obese Welsh Mountain pony mares, in the same 11-week period across 2 years (n = 8 Year 1; n = 7 Year 2). Following a 4-week acclimation period (pre-diet phase) during which time individuals were fed the same hay to maintenance (2% body mass (BM) as daily dry matter (DM) intake), animals underwent a 7-week period of dietary restriction (1% BM hay as daily DM intake). Faeces were sampled on the final 3 days of the pre-diet phase and the final 3 days of the dietary restriction phase. Bacterial communities were determined using Next Generation Sequencing of amplified V1-V2 hypervariable regions of bacterial 16S rRNA. RESULTS:Losses in body mass ranged from 7.11 to 11.59%. Changes in the faecal microbiome composition following weight-loss included a reduction in the relative abundance of Firmicutes and Tenericutes and a reduction in indices of bacterial diversity. Pre-diet diversity was negatively associated with weight-loss. Pre-diet faecal acetate concentration was a strong predictor of subsequent weight-loss and negatively associated with Sphaerochaeta (Spirochaetes phylum) abundance. When animals were divided into 3 groups (high, mid, low) based overall weight loss, pre-diet bacterial community structure was found to have the greatest divergence between the high and low weight-loss groups (R = 0.67, p <  0.01), following PERMANOVA and ANOSIM analysis. CONCLUSIONS:Weight-loss in this group of ponies was associated with lower pre-diet faecal bacterial diversity and greater pre-diet acetate concentration. Overall, these data support a role for the faecal microbiome in weight-loss propensity in ponies and provide a baseline for research evaluating elements of the faecal microbiome in predicting weight-loss success in larger cohorts. 10.1186/s12917-020-02295-6
    Fatty acid activation and utilization by Alistipes finegoldii, a representative Bacteroidetes resident of the human gut microbiome. Radka Christopher D,Frank Matthew W,Rock Charles O,Yao Jiangwei Molecular microbiology Members of the Bacteroidetes phylum, represented by Alistipes finegoldii, are prominent anerobic, Gram-negative inhabitants of the gut microbiome. The lipid biosynthetic pathways were analyzed using bioinformatic analyses, lipidomics, metabolic labeling and biochemistry to characterize exogenous fatty acid metabolism. A. finegoldii only produced the saturated fatty acids. The most abundant lipids were phosphatidylethanolamine (PE) and sulfonolipid (SL). Neither phosphatidylglycerol nor cardiolipin are present. PE synthesis is initiated by the PlsX/PlsY/PlsC pathway, whereas the SL pathway is related to sphingolipid biosynthesis. A. finegoldii incorporated medium-chain fatty acids (≤14 carbons) into PE and SL after their elongation, whereas long-chain fatty acids (≥16 carbons) were not elongated. Fatty acids >16 carbons were primarily incorporated into the 2-position of phosphatidylethanolamine at the PlsC step, the only biosynthetic enzyme that utilizes long-chain acyl-ACP. The ability to assimilate a broad-spectrum of fatty acid chain lengths present in the gut environment is due to the expression of two acyl-acyl carrier protein (ACP) synthetases. Acyl-ACP synthetase 1 had a substrate preference for medium-chain fatty acids and synthetase 2 had a substrate preference for long-chain fatty acids. This unique combination of synthetases allows A. finegoldii to utilize both the medium- and long-chain fatty acid nutrients available in the gut environment to assemble its membrane lipids. 10.1111/mmi.14445
    Microbiota Metabolites in Health and Disease. McCarville Justin L,Chen Grischa Y,Cuevas Víctor D,Troha Katia,Ayres Janelle S Annual review of immunology Metabolism is one of the strongest drivers of interkingdom interactions-including those between microorganisms and their multicellular hosts. Traditionally thought to fuel energy requirements and provide building blocks for biosynthetic pathways, metabolism is now appreciated for its role in providing metabolites, small-molecule intermediates generated from metabolic processes, to perform various regulatory functions to mediate symbiotic relationships between microbes and their hosts. Here, we review recent advances in our mechanistic understanding of how microbiota-derived metabolites orchestrate and support physiological responses in the host, including immunity, inflammation, defense against infections, and metabolism. Understanding how microbes metabolically communicate with their hosts will provide us an opportunity to better describe how a host interacts with all microbes-beneficial, pathogenic, and commensal-and an opportunity to discover new ways to treat microbial-driven diseases. 10.1146/annurev-immunol-071219-125715
    Translocation of Viable Gut Microbiota to Mesenteric Adipose Drives Formation of Creeping Fat in Humans. Ha Connie W Y,Martin Anthony,Sepich-Poore Gregory D,Shi Baochen,Wang Yizhou,Gouin Kenneth,Humphrey Gregory,Sanders Karenina,Ratnayake Yasiru,Chan Kelvin S L,Hendrick Gustaf,Caldera J R,Arias Christian,Moskowitz Jacob E,Ho Sui Shannan J,Yang Shaohong,Underhill David,Brady Matthew J,Knott Simon,Kaihara Kelly,Steinbaugh Michael J,Li Huiying,McGovern Dermot P B,Knight Rob,Fleshner Phillip,Devkota Suzanne Cell A mysterious feature of Crohn's disease (CD) is the extra-intestinal manifestation of "creeping fat" (CrF), defined as expansion of mesenteric adipose tissue around the inflamed and fibrotic intestine. In the current study, we explore whether microbial translocation in CD serves as a central cue for CrF development. We discovered a subset of mucosal-associated gut bacteria that consistently translocated and remained viable in CrF in CD ileal surgical resections, and identified Clostridium innocuum as a signature of this consortium with strain variation between mucosal and adipose isolates, suggesting preference for lipid-rich environments. Single-cell RNA sequencing characterized CrF as both pro-fibrotic and pro-adipogenic with a rich milieu of activated immune cells responding to microbial stimuli, which we confirm in gnotobiotic mice colonized with C. innocuum. Ex vivo validation of expression patterns suggests C. innocuum stimulates tissue remodeling via M2 macrophages, leading to an adipose tissue barrier that serves to prevent systemic dissemination of bacteria. 10.1016/j.cell.2020.09.009
    Recent Advances in Function-based Metagenomic Screening. Ngara Tanyaradzwa Rodgers,Zhang Houjin Genomics, proteomics & bioinformatics Metagenomes from uncultured microorganisms are rich resources for novel enzyme genes. The methods used to screen the metagenomic libraries fall into two categories, which are based on sequence or function of the enzymes. The sequence-based approaches rely on the known sequences of the target gene families. In contrast, the function-based approaches do not involve the incorporation of metagenomic sequencing data and, therefore, may lead to the discovery of novel gene sequences with desired functions. In this review, we discuss the function-based screening strategies that have been used in the identification of enzymes from metagenomes. Because of its simplicity, agar plate screening is most commonly used in the identification of novel enzymes with diverse functions. Other screening methods with higher sensitivity are also employed, such as microtiter plate screening. Furthermore, several ultra-high-throughput methods were developed to deal with large metagenomic libraries. Among these are the FACS-based screening, droplet-based screening, and the in vivo reporter-based screening methods. The application of these novel screening strategies has increased the chance for the discovery of novel enzyme genes. 10.1016/j.gpb.2018.01.002
    Inulin Can Alleviate Metabolism Disorders in ob/ob Mice by Partially Restoring Leptin-related Pathways Mediated by Gut Microbiota. Song Xiaofeng,Zhong Liang,Lyu Na,Liu Fei,Li Boxing,Hao Yanan,Xue Yong,Li Jing,Feng Yuqing,Ma Yue,Hu Yongfei,Zhu Baoli Genomics, proteomics & bioinformatics Inulin has been used as a prebiotic to alleviate glucose and lipid metabolism disorders in mice and humans by modulating the gut microbiota. However, the mechanism underlying the alleviation of metabolic disorders by inulin through interactions between the gut microbiota and host cells is unclear. We use ob/ob mice as a model to study the effect of inulin on the cecal microbiota by 16S rRNA gene amplicon sequencing and its interaction with host cells by transcriptomics. The inulin-supplemented diet improved glucose and lipid metabolism disorder parameters in ob/ob mice, alleviating fat accumulation and glucose intolerance. The α diversity of gut microbial community of ob/ob mice was reduced after inulin treatment, while the β diversity tended to return to the level of wild type mice. Interestingly, Prevotellaceae UCG 001 (family Prevotellaceae) was obviously enriched after inulin treatment. A comparative analysis of the gene expression profile showed that the cecal transcriptome was changed in leptin gene deficiency mice, whereas the inulin-supplemented diet partially reversed the changes in leptin gene-related signaling pathways, especially AMPK signaling pathway, where the levels of gene expression became comparable to those in wild type mice. Further analysis indicated that Prevotellaceae UCG 001 was positively correlated with the AMPK signaling pathway, which was negatively correlated with markers of glycolipid metabolism disorders. Our results suggest that the inulin-supplemented diet alleviates glucose and lipid metabolism disorders by partially restoring leptin related pathways mediated by gut microbiota. 10.1016/j.gpb.2019.03.001
    Dietary protein levels and amino acid supplementation patterns alter the composition and functions of colonic microbiota in pigs. Zhao Yumei,Tian Gang,Chen Daiwen,Zheng Ping,Yu Jie,He Jun,Mao Xiangbing,Huang Zhiqing,Luo Yuheng,Luo Junqiu,Yu Bing Animal nutrition (Zhongguo xu mu shou yi xue hui) Different dietary nitrogen (N) patterns may have different effects on gut microbiota. To investigate the effects of different crude protein (CP) levels or essential amino acids (EAA) supplementation patterns on the structure and functions of colonic microbiota, 42 barrows (25 ± 0.39 kg) were randomly assigned to 7 dietary treatments including: diet 1, a high CP diet with balanced 10 EAA; diet 2, a medium CP diet with approximately 2% decreased CP level from diet 1 and balanced 10 EAA; diets 3, 4, 5, 6 and 7, low CP diets with 4% decreased CP level from diet 1. Specifically, diet 3 was only balanced for Lys, Met, Thr and Trp; diets 4, 5 and 6 were further supplemented with Ile, Val and Ile + Val on the basis of diet 3, respectively; and diet 7 was balanced for 10 EAA. Results over a 110-d trial showed that reducing the CP level by 2% or 4% dramatically decreased N intake and excretion ( < 0.05) in the presence of balanced 10 EAA, which was not observed when altering the EAA supplementation patterns in low CP diet (-4%). With balanced 10 EAA, 2% reduction in dietary CP significantly reduced Firmicutes-to-Bacteroidetes (F:B) ratio and significantly elevated the abundance of NK3B31 ( < 0.05); whereas 4% reduction evidently increased the abundances of , and XPB1014 ( < 0.05). Among the 5 low CP diets (-4%), supplementation with Ile, or Val + Ile, or balanced 10 EAA increased F:B ratio and the abundance of . In addition, the predicted functions revealed that different CP levels and EAA balanced patterns dramatically altered the mRNA expression profiles of N-metabolizing genes, the "N and energy metabolism" pathways or the metabolism of some small substances, such as amino acids (AA) and vitamins. Our findings suggested that reducing the dietary CP levels by 2% to 4% with balancing 10 EAA, or only further supplementation with Ile or Val + Ile to a low protein diet (-4%) reduced the N contents entering the hindgut to various degrees, altered the abundances of N-metabolizing bacteria, and improved the abilities of N utilization. 10.1016/j.aninu.2020.02.005
    Toll-like receptor 4 (TLR4) deficient mice are protected from adipose tissue inflammation in aging. Ghosh Amiya K,O'Brien Martin,Mau Theresa,Yung Raymond Aging Adipose tissue (AT) inflammation is a central mechanism for metabolic dysfunction in both diet-induced obesity and age-associated obesity. Studies in diet-induced obesity have characterized the role of Fetuin A (Fet A) in Free Fatty Acids (FFA)-mediated TLR4 activation and adipose tissue inflammation. However, the role of Fet A & TLR4 in aging-related adipose tissue inflammation is unknown. In the current study, analysis of epidymymal fat pads of C57/Bl6 male mice, we found that, in contrast to data from diet-induced obesity models, adipose tissue from aged mice have normal Fet A and TLR4 expression. Interestingly, aged TLR4-deficient mice have diminished adipose tissue inflammation compared to normal controls. We further demonstrated that reduced AT inflammation in old TLR4-deficient mice is linked to impaired ER stress, augmented autophagy activity, and diminished senescence phenomenon. Importantly, old TLR4-deficient mice have improved glucose tolerance compared to age-matched wild type mice, suggesting that the observed reduced AT inflammation in aged TLR4-deficient mice has important physiological consequences. Taken together, our present study establishes novel aspect of aging-associated AT inflammation that is distinct from diet-induced AT inflammation. Our results also provide strong evidence that TLR4 plays a significant role in promoting aging adipose tissue inflammation. 10.18632/aging.101288
    Obesity and type-2 diabetes as inducers of premature cellular senescence and ageing. Burton Dominick G A,Faragher Richard G A Biogerontology Cellular senescence is now considered as a major mechanism in the development and progression of various diseases and this may include metabolic diseases such as obesity and type-2 diabetes. The presence of obesity and diabetes is a major risk factor in the development of additional health conditions, such as cardiovascular disease, kidney disease and cancer. Since senescent cells can drive disease development, obesity and diabetes can potentially create an environment that accelerates cell senescence within other tissues of the body. This can consequently manifest as age-related biological impairments and secondary diseases. Cell senescence in cell types linked with obesity and diabetes, namely adipocytes and pancreatic beta cells will be explored, followed by a discussion on the role of obesity and diabetes in accelerating ageing through induction of premature cell senescence mediated by high glucose levels and oxidised low-density lipoproteins. Particular emphasis will be placed on accelerated cell senescence in endothelial progenitor cells, endothelial cells and vascular smooth muscle cells with relation to cardiovascular disease and proximal tubular cells with relation to kidney disease. A summary of the potential strategies for therapeutically targeting senescent cells for improving health is also presented. 10.1007/s10522-018-9763-7
    Adipose tissue inflammation in aging. Mau Theresa,Yung Raymond Experimental gerontology Adipose tissue has traditionally been viewed as an organ of interest within studies of obesity and diet-associated metabolic disorders. However, as studies reveal the role white adipose tissue plays as an energy storage, a lipid metabolism site, and an adipokine secretor, it has become recognized as an organ of importance for metabolic health in both the young obese and the old obese. Within the realms of aging research, the pursuit of senolytics has taken the field's spotlight, where the clearance of senescent cells has shown to attenuate aspects of age-related disorders. More interestingly, these senolytics have also revealed that these senescent cells, specifically p16 cells, accumulate within adipose tissue, skeletal muscles, and eye (Baker et al., 2011). These results implicate the importance of adipose tissue inflammation in aging and widen the discussion on how senescent cells among other immune and non-immune cells cross paths to influence an organism's lifespan and healthspan. 10.1016/j.exger.2017.10.014
    Convertible visceral fat as a therapeutic target to curb obesity. Giordano Antonio,Frontini Andrea,Cinti Saverio Nature reviews. Drug discovery New therapeutic and preventative strategies are needed to address the growing obesity epidemic. In animal models, brown adipose tissue activation and the associated heat produced contribute to countering obesity and the accompanying metabolic abnormalities. Adult humans also have functional brown fat. Here, we present and discuss the concepts of murine and human white adipose tissue plasticity and the transdifferentiation of white adipocytes into brown adipocytes. Human visceral adipocytes - which are crucial contributors to the burden of obesity and its complications - are particularly susceptible to such transdifferentiation. Therefore, we propose that this process should be a focus of anti-obesity research. Approved drugs that have browning properties as well as future drugs that target molecular pathways involved in white-to-brown visceral adipocyte transdifferentiation may provide new avenues for obesity therapy. 10.1038/nrd.2016.31
    Factors involved in white-to-brown adipose tissue conversion and in thermogenesis: a review. Montanari T,Pošćić N,Colitti M Obesity reviews : an official journal of the International Association for the Study of Obesity Obesity is the result of energy intake chronically exceeding energy expenditure. Classical treatments against obesity do not provide a satisfactory long-term outcome for the majority of patients. After the demonstration of functional brown adipose tissue in human adults, great effort is being devoted to develop therapies based on the adipose tissue itself, through the conversion of fat-accumulating white adipose tissue into energy-dissipating brown adipose tissue. Anti-obesity treatments that exploit endogenous, pharmacological and nutritional factors to drive such conversion are especially in demand. In the present review, we summarize the current knowledge about the various molecules that can be applied in promoting white-to-brown adipose tissue conversion and energy expenditure and the cellular mechanisms involved. 10.1111/obr.12520
    Identification of New Potent Human Uncoupling Protein 1 (UCP1) Agonists Using Virtual Screening and in vitro Approaches. Lu Hong-Yuan,Wang Nan,Li Xiang,Huang Yuan,Wang Jian,Zhao Qing-Chun Molecular informatics Recent studies suggested that activation of Uncoupling Protein 1 (UCP1) has become an appealing therapeutic strategy against obesity and diabetes. In our research, the 3D structure of UCP1 was constructed through homology modelling, refined through molecular dynamics simulation, and evaluated by Ramachandran plot, the molecular docking of UCP1 activators brought about the proposal of an interaction mode inside the UCP1 active site. Remarkably, Reside Lys126 formed hydrogen bond; residues Pro121, Val125, Tyr146, Tyr149 and Arg150 formed hydrophobic interaction, which are key amino acids within UCP1 site. Then a pharmacophore model was generated consisting of three hydrophobic groups, a negative center and an additional hydrophobic group. Pharmacophore-based virutal screening of Specs database yield 5 hits. In vitro assay indicated ZINC 04660290 significantly increased the protein expression of UCP1 and decreased the fat droplet in a dose-dependent manner. Besides, pharmacokinetic properties were predicted for those five compounds through ADME/T prediction. All of these will guide us to design new UCP1 activators for the treatment of obesity and diabetes. 10.1002/minf.201900030
    A miR-327-FGF10-FGFR2-mediated autocrine signaling mechanism controls white fat browning. Fischer Carina,Seki Takahiro,Lim Sharon,Nakamura Masaki,Andersson Patrik,Yang Yunlong,Honek Jennifer,Wang Yangang,Gao Yanyan,Chen Fang,Samani Nilesh J,Zhang Jun,Miyake Masato,Oyadomari Seiichi,Yasue Akihiro,Li Xuri,Zhang Yun,Liu Yizhi,Cao Yihai Nature communications Understanding the molecular mechanisms regulating beige adipocyte formation may lead to the development of new therapies to combat obesity. Here, we report a miRNA-based autocrine regulatory pathway that controls differentiation of preadipocytes into beige adipocytes. We identify miR-327 as one of the most downregulated miRNAs targeting growth factors in the stromal-vascular fraction (SVF) under conditions that promote white adipose tissue (WAT) browning in mice. Gain- and loss-of-function experiments reveal that miR-327 targets FGF10 to prevent beige adipocyte differentiation. Pharmacological and physiological β-adrenergic stimulation upregulates FGF10 levels and promotes preadipocyte differentiation into beige adipocytes. In vivo local delivery of miR-327 to WATs significantly compromises the beige phenotype and thermogenesis. Contrarily, systemic inhibition of miR-327 in mice induces browning and increases whole-body metabolic rate under thermoneutral conditions. Our data provide mechanistic insight into an autocrine regulatory signaling loop that regulates beige adipocyte formation and suggests that the miR-327-FGF10-FGFR2 signaling axis may be a therapeutic targets for treatment of obesity and metabolic diseases. 10.1038/s41467-017-02158-z
    Rho-kinase/AMPK axis regulates hepatic lipogenesis during overnutrition. Huang Hu,Lee Seung-Hwan,Sousa-Lima Inês,Kim Sang Soo,Hwang Won Min,Dagon Yossi,Yang Won-Mo,Cho Sungman,Kang Min-Cheol,Seo Ji A,Shibata Munehiko,Cho Hyunsoo,Belew Getachew Debas,Bhin Jinhyuk,Desai Bhavna N,Ryu Min Jeong,Shong Minho,Li Peixin,Meng Hua,Chung Byung-Hong,Hwang Daehee,Kim Min Seon,Park Kyong Soo,Macedo Maria Paula,White Morris,Jones John,Kim Young-Bum The Journal of clinical investigation Obesity is a major risk factor for developing nonalcoholic fatty liver disease (NAFLD). NAFLD is the most common form of chronic liver disease and is closely associated with insulin resistance, ultimately leading to cirrhosis and hepatocellular carcinoma. However, knowledge of the intracellular regulators of obesity-linked fatty liver disease remains incomplete. Here we showed that hepatic Rho-kinase 1 (ROCK1) drives obesity-induced steatosis in mice through stimulation of de novo lipogenesis. Mice lacking ROCK1 in the liver were resistant to diet-induced obesity owing to increased energy expenditure and thermogenic gene expression. Constitutive expression of hepatic ROCK1 was sufficient to promote adiposity, insulin resistance, and hepatic lipid accumulation in mice fed a high-fat diet. Correspondingly, liver-specific ROCK1 deletion prevented the development of severe hepatic steatosis and reduced hyperglycemia in obese diabetic (ob/ob) mice. Of pathophysiological significance, hepatic ROCK1 was markedly upregulated in humans with fatty liver disease and correlated with risk factors clustering around NAFLD and insulin resistance. Mechanistically, we found that hepatic ROCK1 suppresses AMPK activity and a ROCK1/AMPK pathway is necessary to mediate cannabinoid-induced lipogenesis in the liver. Furthermore, treatment with metformin, the most widely used antidiabetes drug, reduced hepatic lipid accumulation by inactivating ROCK1, resulting in activation of AMPK downstream signaling. Taken together, our findings establish a ROCK1/AMPK signaling axis that regulates de novo lipogenesis, providing a unique target for treating obesity-related metabolic disorders such as NAFLD. 10.1172/JCI63562
    Immunometabolism of regulatory T cells. Newton Ryan,Priyadharshini Bhavana,Turka Laurence A Nature immunology The bidirectional interaction between the immune system and whole-body metabolism has been well recognized for many years. Via effects on adipocytes and hepatocytes, immune cells can modulate whole-body metabolism (in metabolic syndromes such as type 2 diabetes and obesity) and, reciprocally, host nutrition and commensal-microbiota-derived metabolites modulate immunological homeostasis. Studies demonstrating the metabolic similarities of proliferating immune cells and cancer cells have helped give birth to the new field of immunometabolism, which focuses on how the cell-intrinsic metabolic properties of lymphocytes and macrophages can themselves dictate the fate and function of the cells and eventually shape an immune response. We focus on this aspect here, particularly as it relates to regulatory T cells. 10.1038/ni.3466
    Lipotoxicity and the gut-liver axis in NASH pathogenesis. Marra Fabio,Svegliati-Baroni Gianluca Journal of hepatology The pathogenesis of non-alcoholic fatty liver disease, particularly the mechanisms whereby a minority of patients develop a more severe phenotype characterised by hepatocellular damage, inflammation, and fibrosis is still incompletely understood. Herein, we discuss two pivotal aspects of the pathogenesis of NASH. We first analyse the initial mechanisms responsible for hepatocellular damage and inflammation, which derive from the toxic effects of excess lipids. Accumulating data indicate that the total amount of triglycerides stored in hepatocytes is not the major determinant of lipotoxicity, and that specific lipid classes act as damaging agents on liver cells. In particular, the role of free fatty acids such as palmitic acid, cholesterol, lysophosphatidylcholine and ceramides has recently emerged. These lipotoxic agents affect the cell behaviour via multiple mechanisms, including activation of signalling cascades and death receptors, endoplasmic reticulum stress, modification of mitochondrial function, and oxidative stress. In the second part of this review, the cellular and molecular players involved in the cross-talk between the gut and the liver are considered. These include modifications to the microbiota, which provide signals through the intestine and bacterial products, as well as hormones produced in the bowel that affect metabolism at different levels including the liver. Finally, the activation of nuclear receptors by bile acids is analysed. 10.1016/j.jhep.2017.11.014
    Lipotoxicity induces hepatic protein inclusions through TANK binding kinase 1-mediated p62/sequestosome 1 phosphorylation. Cho Chun-Seok,Park Hwan-Woo,Ho Allison,Semple Ian A,Kim Boyoung,Jang Insook,Park Haeli,Reilly Shannon,Saltiel Alan R,Lee Jun Hee Hepatology (Baltimore, Md.) Obesity commonly leads to hepatic steatosis, which often provokes lipotoxic injuries to hepatocytes that cause nonalcoholic steatohepatitis (NASH). NASH, in turn, is associated with the accumulation of insoluble protein aggregates that are composed of ubiquitinated proteins and ubiquitin adaptor p62/sequestosome 1 (SQSTM1). Formation of p62 inclusions in hepatocytes is the critical marker that distinguishes simple fatty liver from NASH and predicts a poor prognostic outcome for subsequent liver carcinogenesis. However, the molecular mechanism by which lipotoxicity induces protein aggregation is currently unknown. Here, we show that, upon saturated fatty acid-induced lipotoxicity, TANK binding kinase 1 (TBK1) is activated and phosphorylates p62. TBK1-mediated p62 phosphorylation is important for lipotoxicity-induced aggregation of ubiquitinated proteins and formation of large protein inclusions in hepatocytes. In addition, cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), upstream regulators of TBK1, are involved in lipotoxic activation of TBK1 and subsequent p62 phosphorylation in hepatocytes. Furthermore, TBK1 inhibition prevented formation of ubiquitin-p62 aggregates not only in cultured hepatocytes, but also in mouse models of obesity and NASH. CONCLUSION:These results suggest that lipotoxic activation of TBK1 and subsequent p62 phosphorylation are critical steps in the NASH pathology of protein inclusion accumulation in hepatocytes. This mechanism can provide an explanation for how hypernutrition and obesity promote the development of severe liver pathologies, such as steatohepatitis and liver cancer, by facilitating the formation of p62 inclusions. (Hepatology 2018). 10.1002/hep.29742
    Obesity. González-Muniesa Pedro,Mártinez-González Miguel-Angel,Hu Frank B,Després Jean-Pierre,Matsuzawa Yuji,Loos Ruth J F,Moreno Luis A,Bray George A,Martinez J Alfredo Nature reviews. Disease primers Excessive fat deposition in obesity has a multifactorial aetiology, but is widely considered the result of disequilibrium between energy intake and expenditure. Despite specific public health policies and individual treatment efforts to combat the obesity epidemic, >2 billion people worldwide are overweight or obese. The central nervous system circuitry, fuel turnover and metabolism as well as adipose tissue homeostasis are important to comprehend excessive weight gain and associated comorbidities. Obesity has a profound impact on quality of life, even in seemingly healthy individuals. Diet, physical activity or exercise and lifestyle changes are the cornerstones of obesity treatment, but medical treatment and bariatric surgery are becoming important. Family history, food environment, cultural preferences, adverse reactions to food, perinatal nutrition, previous or current diseases and physical activity patterns are relevant aspects for the health care professional to consider when treating the individual with obesity. Clinicians and other health care professionals are often ill-equipped to address the important environmental and socioeconomic drivers of the current obesity epidemic. Finally, understanding the epigenetic and genetic factors as well as metabolic pathways that take advantage of 'omics' technologies could play a very relevant part in combating obesity within a precision approach. 10.1038/nrdp.2017.34
    An obesity-associated gut microbiome reprograms the intestinal epigenome and leads to altered colonic gene expression. Qin Yufeng,Roberts John D,Grimm Sara A,Lih Fred B,Deterding Leesa J,Li Ruifang,Chrysovergis Kaliopi,Wade Paul A Genome biology BACKGROUND:The gut microbiome, a key constituent of the colonic environment, has been implicated as an important modulator of human health. The eukaryotic epigenome is postulated to respond to environmental stimuli through alterations in chromatin features and, ultimately, gene expression. How the host mediates epigenomic responses to gut microbiota is an emerging area of interest. Here, we profile the gut microbiome and chromatin characteristics in colon epithelium from mice fed either an obesogenic or control diet, followed by an analysis of the resultant changes in gene expression. RESULTS:The obesogenic diet shapes the microbiome prior to the development of obesity, leading to altered bacterial metabolite production which predisposes the host to obesity. This microbiota-diet interaction leads to changes in histone modification at active enhancers that are enriched for binding sites for signal responsive transcription factors. These alterations of histone methylation and acetylation are associated with signaling pathways integral to the development of colon cancer. The transplantation of obesogenic diet-conditioned microbiota into germ free mice, combined with an obesogenic diet, recapitulates the features of the long-term diet regimen. The diet/microbiome-dependent changes are reflected in both the composition of the recipient animals' microbiome as well as in the set of transcription factor motifs identified at diet-influenced enhancers. CONCLUSIONS:These findings suggest that the gut microbiome, under specific dietary exposures, stimulates a reprogramming of the enhancer landscape in the colon, with downstream effects on transcription factors. These chromatin changes may be associated with those seen during colon cancer development. 10.1186/s13059-018-1389-1
    T cell-mediated regulation of the microbiota protects against obesity. Petersen Charisse,Bell Rickesha,Klag Kendra A,Lee Soh-Hyun,Soto Raymond,Ghazaryan Arevik,Buhrke Kaitlin,Ekiz H Atakan,Ost Kyla S,Boudina Sihem,O'Connell Ryan M,Cox James E,Villanueva Claudio J,Stephens W Zac,Round June L Science (New York, N.Y.) The microbiota influences obesity, yet organisms that protect from disease remain unknown. During studies interrogating host-microbiota interactions, we observed the development of age-associated metabolic syndrome (MetS). Expansion of and loss of Clostridia were key features associated with obesity in this model and are present in humans with MetS. T cell-dependent events were required to prevent disease, and replacement of Clostridia rescued obesity. Inappropriate immunoglobulin A targeting of Clostridia and increased antagonized the colonization of beneficial Clostridia. Transcriptional and metabolic analysis revealed enhanced lipid absorption in the obese host. Colonization of germ-free mice with Clostridia, but not , down-regulated genes that control lipid absorption and reduced adiposity. Thus, immune control of the microbiota maintains beneficial microbial populations that constrain lipid metabolism to prevent MetS. 10.1126/science.aat9351
    Strategies to increase the efficacy of using gut microbiota for the modulation of obesity. Li J,Riaz Rajoka M S,Shao D,Jiang C,Jin M,Huang Q,Yang H,Shi J Obesity reviews : an official journal of the International Association for the Study of Obesity Obesity is one of the most serious global public health challenges of the 21st century. The adjustment of gut microbiota is often recommended as an efficient strategy to treat obesity. This modulation of gut microbiota can be performed by many methods, including dietary intervention, antibiotic application, the use of prebiotics and probiotics, bariatric surgery and faecal microbiota transplantation. In most cases, positive effects have been observed in response to treatment, but invalid and even contrary effects have also been observed in some cases due to factors that are unrelated to intervention methods, such as genetic factors, patient age or gender, environmental microbiota, climate, geography and lifestyle. These factors can cause variation of gut microbial populations and thus should also be taken into consideration when selecting modulation strategies. 10.1111/obr.12590
    Role of the Gut Microbiome in the Pathogenesis of Obesity and Obesity-Related Metabolic Dysfunction. Bouter Kristien E,van Raalte Daniël H,Groen Albert K,Nieuwdorp Max Gastroenterology The potential role of intestinal microbiota in the etiology of various human diseases has attracted massive attention in the last decade. As such, the intestinal microbiota has been advanced as an important contributor in the development of obesity and obesity-related metabolic dysfunctions, amongst others. Experiments in animal models have produced evidence for a causal role of intestinal microbiota in the etiology of obesity and insulin resistance. However, with a few exceptions, such causal relation is lacking for humans and most publications merely report associations between intestinal microbial composition and metabolic disorders such as obesity and type 2 diabetes. Thus, the reciprocal relationship between the bacteria and these metabolic disorders remains a matter of debate. The main objective of this review is to critically assess the driving role of intestinal microbe composition in the etiology, prevention, and treatment of obesity and obesity-related metabolic dysfunction, including type 2 diabetes. 10.1053/j.gastro.2016.12.048
    Effects of dietary fibre and protein content on intestinal fibre degradation, short-chain fatty acid and microbiota composition in a high-fat fructose-rich diet induced obese Göttingen Minipig model. Xu Yetong,Curtasu Mihai Victor,Bendiks Zachary,Marco Maria L,P Nørskov Natalja,Knudsen Knud Erik Bach,Hedemann Mette Skou,Lærke Helle Nygaard Food & function Obesity-related metabolic syndrome has been linked with gut microbiome dysbiosis while dietary fibre (DF) and protein can modify the gut microbial ecosystem and metabolism. After 20-weeks of high-fat fructose-rich diet feeding for the development of obesity, forty-three 30-week old Göttingen Minipigs (31 ± 4.0 kg body weight) were allocated to one of the four diets with low or high DF and protein contents in a two by two factorial design and digesta were collected from the intestinal segments of minipigs after 8 weeks at libitum feeding. High DF content increased (P < 0.001) while high protein content decreased (P = 0.004) the content of non-starch polysaccharides (NSP) in all intestinal segments. Arabinoxylan (AX) as proportion of NSP was higher with high DF (P < 0.001) but decreased from the distal small intestine to the mid colon (P < 0.001). High DF increased the relative abundance of Blautia, Faecalibacterium and Peptococcus in the caecum, the mid colon and faeces, reduced the intestinal concentrations of total short-chain fatty acids (SCFA) (P = 0.020) and acetate (P = 0.011) but slightly increased butyrate pools in the large intestine (P≤ 0.050) compared to low DF. High protein increased the SCFA (P = 0.026) and propionate (P = 0.044) concentrations in the gut. High DF induced a lower increase in the BCFA concentration and proportion throughout the colon (P < 0.001). The butyrate concentrations in plasma from the jugular vein were increased with high DF diets (P = 0.031), whereas the propionate concentrations were increased (P < 0.001) and succinate were decreased (P = 0.001) with high protein diets compared with low protein diets. In conclusion, AX in the high DF diets was continuously degraded up to the mid-colon, associated with enriched butyrate-producing bacteria and slightly improved butyrate production, while protein fermentation was attenuated by high DF and high protein did not show prebiotic effects in this obese minipig model. 10.1039/d0fo02252g
    Cecal versus fecal microbiota in Ossabaw swine and implications for obesity. Panasevich Matthew R,Wankhade Umesh D,Chintapalli Sree V,Shankar Kartik,Rector R Scott Physiological genomics The gut microbiome plays a critical role in the onset and progression of obesity and the metabolic syndrome. However, it is not well documented whether the cecal vs. the fecal microbiome is more relevant when assessing their contributions to these diseases. Here, we amplified the V4 region of the 16S rRNA gene from cecal and fecal samples of female Ossabaw swine fed a low-fat control diet (10.5% fat, n = 4) or Western diet (43.0% fat, 17.8% high fructose corn syrup, 2% cholesterol; n = 3) for 36 wk. Obesity significantly lowered alpha-diversity ( P < 0.05), and there was clear separation in beta-diversity between lean and obese pigs, as well as between cecal and fecal samples ( P < 0.05). Obesity dramatically increased ( P < 0.05) the Firmicutes:Bacteroidetes ratio in fecal samples, and Actinobacteria was higher ( P < 0.05) in fecal vs. cecal samples in obese pigs. Cyanobacteria, Proteobacteria, and Fusobacteria were increased ( P < 0.05), while Spirochaetes, Tenericutes, and Verrucomicrobia were decreased ( P < 0.05) in obese vs. lean pigs. Prevotellaceae was reduced ( P < 0.05) in obese fecal vs. cecal samples. Moreover, cecal samples in obese had greater ( P < 0.05) predicted metabolic capacity for glycan biosynthesis and metabolism and LPS biosynthesis compared with fecal. Obese pigs also had greater ( P < 0.05) capacity for carbohydrate metabolism, which was driven by obese fecal rather than cecal samples and was opposite in lean pigs ( P < 0.05). The observed differences in pro-inflammatory microbiota and their metabolic capacity in cecal vs. fecal samples of obese pigs provide new insight into evaluating the microbiome in the pathogenesis of obesity and metabolic disease. 10.1152/physiolgenomics.00110.2017