DSS-induced colitis is associated with adipose tissue dysfunction and disrupted hepatic lipid metabolism leading to hepatosteatosis and dyslipidemia in mice

AbstractConsidering high prevalence of non-alcoholic fatty liver diseases (NAFLD) in patients with inflammatory bowel disease (IBD), this study aimed to elucidate molecular mechanisms for how intestinal inflammatory conditions are causally linked to hepatic steatosis and dyslipidemia. Both younger and older mice treated with acute or chronic dextran sodium sulfate (DSS) developed colitis, which was evidenced by weight loss, colon length shortening, and elevated disease activity index and inflammation score. They also showed decreased expression of intestinal barrier function-related proteins and elevated plasma lipopolysaccharide level, indicating DSS-induced barrier dysfunction and thereby increased permeability. Interestingly, they displayed phenotypes of hepatic fat accumulation and abnormal blood lipid profiles. This DSS-induced colitis-associated lipid metabolic dysfunction was due to overall disruption of metabolic processes including fatty acid oxidation, lipogenesis, lipolysis, reverse cholesterol transport, bile acid synthesis, and white adipose tissue browning and brown adipose tissue thermogenesis, most of which are mediated by key regulators of energy homeostasis such as FGF21, adiponectin, and irisin, via SIRT1/PGC-1α- and LXRα-dependent pathways. Our study suggests a potential molecular mechanism underlying the comorbidity of NAFLD and IBD, which could provide a key to understanding how the two diseases are pathogenically linked and discovering critical therapeutic targets for their treatment.

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Inhibition of Sam68 triggers adipose tissue browning

Journal of Endocrinology ◽

10.1530/joe-14-0727 ◽

2015 ◽

Vol 225 (3) ◽

pp. 181-189 ◽

Cited By ~ 6

Author(s):

Junlan Zhou ◽

Min Cheng ◽

Chan Boriboun ◽

Mariam M Ardehali ◽

Changfei Jiang ◽

...

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Energy Homeostasis ◽

Molecular Mechanisms ◽

Acid Oxidation ◽

M2 Macrophage ◽

Fat Depots ◽

Reduced Body ◽

Brown Adipose ◽

The Difference

Obesity is associated with insulin resistance and type 2 diabetes; molecular mechanisms that promote energy expenditure can be utilized for effective therapy. Src-associated in mitosis of 68 kDa (Sam68) is potentially significant, because knockout (KO) of Sam68 leads to markedly reduced adiposity. In the present study, we sought to determine the mechanism by which Sam68 regulates adiposity and energy homeostasis. We first found that Sam68 KO mice have a significantly reduced body weight as compared to controls, and the difference is explained entirely by decreased adiposity. Interestingly, these effects were not mediated by a difference in food intake; rather, they were associated with enhanced physical activity. When they were fed a high-fat diet, Sam68 KO mice gained much less body weight and fat mass than their WT littermates did, and they displayed an improved glucose and insulin tolerance. In Sam68 KO mice, the brown adipose tissue (BAT), inguinal, and epididymal depots were smaller, and their adipocytes were less hypertrophied as compared to their WT littermates. The BAT of Sam68 KO mice exhibited reduced lipid stores and expressed higher levels of Ucp1 and key thermogenic and fatty acid oxidation genes. Similarly, depots of inguinal and epididymal white adipose tissue (WAT) in Sam68 KO mice appeared browner, their multilocular Ucp1-positive cells were much more abundant, and the expression of Ucp1, Cidea, Prdm16, and Ppargc1a genes was greater as compared to WT controls, which suggests that the loss of Sam68 also promotes WAT browning. Furthermore, in all of the fat depots of the Sam68 KO mice, the expression of M2 macrophage markers was up-regulated, and that of M1 markers was down-regulated. Thus, Sam68 plays a crucial role in controlling thermogenesis and may be targeted to combat obesity and associated disorders.

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Diverse Effects of Different Akkermansia muciniphila Genotypes on Brown Adipose Tissue Inflammation and Whitening in a High-fat-diet Murine Model

10.21203/rs.2.12409/v1 ◽

2019 ◽

Author(s):

Lulu Deng ◽

Zihao Ou ◽

Dongquan Huang ◽

Chong Li ◽

Zhi Lu ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

High Fat Diet ◽

Liver Steatosis ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Chow Diet ◽

High Fat ◽

Akkermansia Muciniphila ◽

Brown Adipose

Abstract Background The study aimed to investigate the differences of different Akkermansia muciniphila (A.muciniphila) genotypes on metabolic protective effects in mice with high-fat diet and explore possible mechanisms. Methods Male C57BL/6 mice were randomly divided into 6 groups, including high-fat diet (HFD)+ A.muciniphila I/II/PBS group, normal chow diet (NCD)+A.muciniphila I/ II /PBS group, respectively. Dietary intervention and A.muciniphila gavage were performed simultaneously. Blood glucose and lipid metabolism, brown adipose morphology and activities, and intestinal barrier function were examined after the mice were sacrificed. Results A.muciniphila gavage improved the impaired glucose tolerance, hyperlipidemia and liver steatosis in HFD mice, and that A.muciniphila II was not as effective as A.muciniphila I. This phenomenon might be because A.muciniphila I intervention significantly inhibited brown adipose tissue whitening and inflammation induced by HFD, by repairing the intestinal barrier and relieving endotoxemia. A.muciniphila II did not display the same results as A.muciniphila I in HFD mice, but had stronger effects in the NCD mice. Conclusions This study mainly reveals the distinct functions of different A.muciniphila genotypes on diet-induced obesity, suggesting that different A.muciniphila genotypes may play inequitable roles in pathological conditions through distinct action pathways.

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Epigenetic Regulators of White Adipocyte Browning

Epigenomes ◽

10.3390/epigenomes5010003 ◽

2021 ◽

Vol 5 (1) ◽

pp. 3

Author(s):

Ravikanth Nanduri

Keyword(s):

Adipose Tissue ◽

Metabolic Disorders ◽

Energy Homeostasis ◽

Molecular Mechanisms ◽

White Adipocyte ◽

Primary Function ◽

Obesity And Diabetes ◽

Brown Adipose ◽

Beige Adipocytes ◽

Epigenetic Regulators

Adipocytes play an essential role in maintaining energy homeostasis in mammals. The primary function of white adipose tissue (WAT) is to store energy; for brown adipose tissue (BAT), primary function is to release fats in the form of heat. Dysfunctional or excess WAT can induce metabolic disorders such as dyslipidemia, obesity, and diabetes. Preadipocytes or adipocytes from WAT possess sufficient plasticity as they can transdifferentiate into brown-like beige adipocytes. Studies in both humans and rodents showed that brown and beige adipocytes could improve metabolic health and protect from metabolic disorders. Brown fat requires activation via exposure to cold or β-adrenergic receptor (β-AR) agonists to protect from hypothermia. Considering the fact that the usage of β-AR agonists is still in question with their associated side effects, selective induction of WAT browning is therapeutically important instead of activating of BAT. Hence, a better understanding of the molecular mechanisms governing white adipocyte browning is vital. At the same time, it is also essential to understand the factors that define white adipocyte identity and inhibit white adipocyte browning. This literature review is a comprehensive and focused update on the epigenetic regulators crucial for differentiation and browning of white adipocytes.

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Omega-3 Fatty Acids and Adipose Tissue: Inflammation and Browning

Annual Review of Nutrition ◽

10.1146/annurev-nutr-122319-034142 ◽

2020 ◽

Vol 40 (1) ◽

pp. 25-49 ◽

Cited By ~ 3

Author(s):

Nishan Sudheera Kalupahana ◽

Bimba Lakmini Goonapienuwala ◽

Naima Moustaid-Moussa

Keyword(s):

Fatty Acids ◽

Weight Loss ◽

Adipose Tissue ◽

Metabolic Regulation ◽

Energy Homeostasis ◽

Molecular Mechanisms ◽

Whole Body ◽

Omega 3 ◽

Brown Adipose ◽

Body Energy

White adipose tissue (WAT) and brown adipose tissue (BAT) are involved in whole-body energy homeostasis and metabolic regulation. Changes to mass and function of these tissues impact glucose homeostasis and whole-body energy balance during development of obesity, weight loss, and subsequent weight regain. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), which have known hypotriglyceridemic and cardioprotective effects, can also impact WAT and BAT function. In rodent models, these fatty acids alleviate obesity-associated WAT inflammation, improve energy metabolism, and increase thermogenic markers in BAT. Emerging evidence suggests that ω-3 PUFAs can also modulate gut microbiota impacting WAT function and adiposity. This review discusses molecular mechanisms, implications of these findings, translation to humans, and future work, especially with reference to the potential of these fatty acids in weight loss maintenance.

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Influence of Plant Bioactive Compounds on Intestinal Epithelial Barrier in Poultry

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666191226111405 ◽

2020 ◽

Vol 20 (7) ◽

pp. 566-577 ◽

Cited By ~ 2

Author(s):

Amlan Kumar Patra

Keyword(s):

Bioactive Compounds ◽

Barrier Function ◽

Molecular Mechanisms ◽

Digestive Enzyme ◽

Intestinal Barrier ◽

Feed Additives ◽

Interactive Effects ◽

Intestinal Barrier Function ◽

Poultry Production ◽

Poultry Feeding

Natural plant bioactive compounds (PBC) have recently been explored as feed additives to improve productivity, health and welfare of poultry following ban or restriction of in-feed antibiotic use. Depending upon the types of PBC, they possess antimicrobial, digestive enzyme secretion stimulation, antioxidant and many pharmacological properties, which are responsible for beneficial effects in poultry production. Moreover, they may also improve the intestinal barrier function and nutrient transport. In this review, the effects of different PBC on the barrier function, permeability of intestinal epithelia and their mechanism of actions are discussed, focusing on poultry feeding. Dietary PBC may regulate intestinal barrier function through several molecular mechanisms by interacting with different metabolic cascades and cellular transcription signals, which may then modulate expressions of genes and their proteins in the tight junction (e.g., claudins, occludin and junctional adhesion molecules), adherens junction (e.g., E-cadherin), other intercellular junctional proteins (e.g., zonula occludens and catenins), and regulatory proteins (e.g., kinases). Interactive effects of PBC on immunomodulation via expressions of several cytokines, chemokines, complement components, pattern recognition receptors and their transcription factors and cellular immune system, and alteration of mucin gene expressions and goblet cell abundances in the intestine may change barrier functions. The effects of PBC are not consistent among the studies depending upon the type and dose of PBC, physiological conditions and parts of the intestine in chickens. An effective concentration in diets and specific molecular mechanisms of PBC need to be elucidated to understand intestinal barrier functionality in a better way in poultry feeding.

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BAFF Blockade Attenuates Inflammatory Responses and Intestinal Barrier Dysfunction in a Murine Endotoxemia Model

Frontiers in Immunology ◽

10.3389/fimmu.2020.570920 ◽

2020 ◽

Vol 11 ◽

Author(s):

Runze Quan ◽

Chaoyue Chen ◽

Wei Yan ◽

Ying Zhang ◽

Xi Zhao ◽

...

Keyword(s):

Barrier Function ◽

Intestinal Inflammation ◽

Inflammatory Responses ◽

Survival Rates ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Barrier Dysfunction ◽

Protein Levels ◽

Lps Challenge ◽

Endotoxemia Model

B cell-activating factor (BAFF) production is increased in septic patients. However, the specific role of BAFF in sepsis remains unknown. This study was designed to investigate the expression and function of BAFF in an experimental endotoxemia model and to identify the potential mechanisms. We established an endotoxemia mouse (6–8 weeks, 20–22 g) model by administering 30 mg/kg lipopolysaccharide (LPS). BAFF levels in the circulating system and organ tissues were measured 4 and 8 h after LPS injection. Survival rates in the endotoxemia mice were monitored for 72 h after BAFF blockade. The effects of BAFF blockade on systemic and local inflammation, organ injuries, and intestinal barrier function were also evaluated 4 h after LPS treatment. BAFF production was systemically and locally elevated after LPS challenge. BAFF blockade improved the survival rate, systemic inflammation, and multi-organ injuries. Moreover, BAFF blockade attenuated both intestinal inflammation and impaired intestinal permeability. BAFF blockade upregulated ZO-1 and occludin protein levels via the NF-κB/MLCK/MLC signaling pathway. These results suggested that BAFF blockade protects against lethal endotoxemia at least partially by alleviating inflammation, multi-organ injuries, and improving intestinal barrier function and provides a novel focus for further research on sepsis and experimental evidence for clinical therapy.

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DsbA-L deficiency in T cells promotes diet-induced thermogenesis through suppressing IFN-γ production

Nature Communications ◽

10.1038/s41467-020-20665-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Haiyan Zhou ◽

Xinyi Peng ◽

Jie Hu ◽

Liwen Wang ◽

Hairong Luo ◽

...

Keyword(s):

T Cells ◽

Adipose Tissue ◽

T Cell ◽

Energy Homeostasis ◽

Metabolic Diseases ◽

Therapeutic Potential ◽

Whole Body ◽

Brown Adipose ◽

Ifn Γ ◽

Diet Induced Thermogenesis

AbstractAdipose tissue-resident T cells have been recognized as a critical regulator of thermogenesis and energy expenditure, yet the underlying mechanisms remain unclear. Here, we show that high-fat diet (HFD) feeding greatly suppresses the expression of disulfide-bond A oxidoreductase-like protein (DsbA-L), a mitochondria-localized chaperone protein, in adipose-resident T cells, which correlates with reduced T cell mitochondrial function. T cell-specific knockout of DsbA-L enhances diet-induced thermogenesis in brown adipose tissue (BAT) and protects mice from HFD-induced obesity, hepatosteatosis, and insulin resistance. Mechanistically, DsbA-L deficiency in T cells reduces IFN-γ production and activates protein kinase A by reducing phosphodiesterase-4D expression, leading to increased BAT thermogenesis. Taken together, our study uncovers a mechanism by which T cells communicate with brown adipocytes to regulate BAT thermogenesis and whole-body energy homeostasis. Our findings highlight a therapeutic potential of targeting T cells for the treatment of over nutrition-induced obesity and its associated metabolic diseases.

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STAT3 Signalling via the IL-6ST/gp130 Cytokine Receptor Promotes Epithelial Integrity and Intestinal Barrier Function during DSS-Induced Colitis

Biomedicines ◽

10.3390/biomedicines9020187 ◽

2021 ◽

Vol 9 (2) ◽

pp. 187

Author(s):

Lokman Pang ◽

Jennifer Huynh ◽

Mariah G. Alorro ◽

Xia Li ◽

Matthias Ernst ◽

...

Keyword(s):

Barrier Function ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Intestinal Epithelial ◽

Barrier Dysfunction ◽

Epithelial Integrity ◽

Barrier Integrity ◽

Gp130 Receptor ◽

Stat3 Signalling

The intestinal epithelium provides a barrier against commensal and pathogenic microorganisms. Barrier dysfunction promotes chronic inflammation, which can drive the pathogenesis of inflammatory bowel disease (IBD) and colorectal cancer (CRC). Although the Signal Transducer and Activator of Transcription-3 (STAT3) is overexpressed in both intestinal epithelial cells and immune cells in IBD patients, the role of the interleukin (IL)-6 family of cytokines through the shared IL-6ST/gp130 receptor and its associated STAT3 signalling in intestinal barrier integrity is unclear. We therefore investigated the role of STAT3 in retaining epithelial barrier integrity using dextran sulfate sodium (DSS)-induced colitis in two genetically modified mouse models, to either reduce STAT1/3 activation in response to IL-6 family cytokines with a truncated gp130∆STAT allele (GP130∆STAT/+), or by inducing short hairpin-mediated knockdown of Stat3 (shStat3). Here, we show that mice with reduced STAT3 activity are highly susceptible to DSS-induced colitis. Mechanistically, the IL-6/gp130/STAT3 signalling cascade orchestrates intestinal barrier function by modulating cytokine secretion and promoting epithelial integrity to maintain a defence against bacteria. Our study also identifies a crucial role of STAT3 in controlling intestinal permeability through tight junction proteins. Thus, therapeutically targeting the IL-6/gp130/STAT3 signalling axis to promote barrier function may serve as a treatment strategy for IBD patients.

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