scholarly journals Butyrate Protects against Diet-Induced NASH and Liver Fibrosis and Suppresses Specific Non-Canonical TGF-β Signaling Pathways in Human Hepatic Stellate Cells

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1954
Author(s):  
Eveline Gart ◽  
Wim van Duyvenvoorde ◽  
Karin Toet ◽  
Martien P. M. Caspers ◽  
Lars Verschuren ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Liver Fibrosis ◽  
Signaling Pathways ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Adipose Tissue Inflammation ◽  
Gut Permeability ◽  
Tissue Inflammation ◽  
Plasma Leptin

In obesity-associated non-alcoholic steatohepatitis (NASH), persistent hepatocellular damage and inflammation are key drivers of fibrosis, which is the main determinant of NASH-associated mortality. The short-chain fatty acid butyrate can exert metabolic improvements and anti-inflammatory activities in NASH. However, its effects on NASH-associated liver fibrosis remain unclear. Putative antifibrotic effects of butyrate were studied in Ldlr-/-.Leiden mice fed an obesogenic diet (HFD) containing 2.5% (w/w) butyrate for 38 weeks and compared with a HFD-control group. Antifibrotic mechanisms of butyrate were further investigated in TGF-β-stimulated primary human hepatic stellate cells (HSC). HFD-fed mice developed obesity, insulin resistance, increased plasma leptin levels, adipose tissue inflammation, gut permeability, dysbiosis, and NASH-associated fibrosis. Butyrate corrected hyperinsulinemia, lowered plasma leptin levels, and attenuated adipose tissue inflammation, without affecting gut permeability or microbiota composition. Butyrate lowered plasma ALT and CK-18M30 levels and attenuated hepatic steatosis and inflammation. Butyrate inhibited fibrosis development as demonstrated by decreased hepatic collagen content and Sirius-red-positive area. In TGF-β-stimulated HSC, butyrate dose-dependently reduced collagen deposition and decreased procollagen1α1 and PAI1 protein expression. Transcriptomic analysis and subsequent pathway and upstream regulator analysis revealed deactivation of specific non-canonical TGF-β signaling pathways Rho-like GTPases and PI3K/AKT and other important pro-fibrotic regulators (e.g., YAP/TAZ, MYC) by butyrate, providing a potential rationale for its antifibrotic effects. In conclusion, butyrate protects against obesity development, insulin resistance-associated NASH, and liver fibrosis. These antifibrotic effects are at least partly attributable to a direct effect of butyrate on collagen production in hepatic stellate cells, involving inhibition of non-canonical TGF-β signaling pathways.

scholarly journals IL-1 family members in the pathogenesis and treatment of metabolic disease: Focus on adipose tissue inflammation and insulin resistance

Cytokine ◽  
2015 ◽  
Vol 75 (2) ◽  
pp. 280-290 ◽  
Author(s):  
Dov B. Ballak ◽  
Rinke Stienstra ◽  
Cees J. Tack ◽  
Charles A. Dinarello ◽  
Janna A. van Diepen
Keyword(s):  
Metabolic Disease ◽  
Insulin Resistance ◽  
Adipose Tissue ◽  
Family Members ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Disease Focus

scholarly journals Adipose tissue inflammation and metabolic dysfunction: a clinical perspective

2013 ◽  
Vol 15 (1) ◽  
Author(s):  
Charmaine S. Tam ◽  
Leanne M. Redman
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Low Grade ◽  
Metabolic Dysfunction ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Proinflammatory Mediators ◽  
Low Grade Inflammation

AbstractObesity is characterized by a state of chronic low-grade inflammation due to increased immune cells, specifically infiltrated macrophages into adipose tissue, which in turn secrete a range of proinflammatory mediators. This nonselective low-grade inflammation of adipose tissue is systemic in nature and can impair insulin signaling pathways, thus, increasing the risk of developing insulin resistance and type 2 diabetes. The aim of this review is to provide an update on clinical studies examining the role of adipose tissue in the development of obesity-associated complications in humans. We will discuss adipose tissue inflammation during different scenarios of energy imbalance and metabolic dysfunction including obesity and overfeeding, weight loss by calorie restriction or bariatric surgery, and conditions of insulin resistance (diabetes, polycystic ovarian syndrome).

scholarly journals Glucose-6-Phosphate Dehydrogenase Deficiency Improves Insulin Resistance With Reduced Adipose Tissue Inflammation in Obesity

Diabetes ◽  
2016 ◽  
Vol 65 (9) ◽  
pp. 2624-2638 ◽  
Author(s):  
Mira Ham ◽  
Sung Sik Choe ◽  
Kyung Cheul Shin ◽  
Goun Choi ◽  
Ji-Won Kim ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Dehydrogenase Deficiency ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Glucose 6 Phosphate Dehydrogenase

scholarly journals Macrophage VLDLR mediates obesity-induced insulin resistance with adipose tissue inflammation

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Kyung Cheul Shin ◽  
Injae Hwang ◽  
Sung Sik Choe ◽  
Jeu Park ◽  
Yul Ji ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation

scholarly journals The role of uncoupling protein 2 in macrophages and its impact on obesity-induced adipose tissue inflammation and insulin resistance

2020 ◽  
Vol 295 (51) ◽  
pp. 17535-17548
Author(s):  
Xanthe A. M. H. van Dierendonck ◽  
Tiphaine Sancerni ◽  
Marie-Clotilde Alves-Guerra ◽  
Rinke Stienstra
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Macrophage Activation ◽  
Uncoupling Protein ◽  
Uncoupling Protein 2 ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Obesity And Diabetes ◽  
Adipose Tissue Macrophages

The development of a chronic, low-grade inflammation originating from adipose tissue in obese subjects is widely recognized to induce insulin resistance, leading to the development of type 2 diabetes. The adipose tissue microenvironment drives specific metabolic reprogramming of adipose tissue macrophages, contributing to the induction of tissue inflammation. Uncoupling protein 2 (UCP2), a mitochondrial anion carrier, is thought to separately modulate inflammatory and metabolic processes in macrophages and is up-regulated in macrophages in the context of obesity and diabetes. Here, we investigate the role of UCP2 in macrophage activation in the context of obesity-induced adipose tissue inflammation and insulin resistance. Using a myeloid-specific knockout of UCP2 (Ucp2ΔLysM), we found that UCP2 deficiency significantly increases glycolysis and oxidative respiration, both unstimulated and after inflammatory conditions. Strikingly, fatty acid loading abolished the metabolic differences between Ucp2ΔLysM macrophages and their floxed controls. Furthermore, Ucp2ΔLysM macrophages show attenuated pro-inflammatory responses toward Toll-like receptor-2 and -4 stimulation. To test the relevance of macrophage-specific Ucp2 deletion in vivo, Ucp2ΔLysM and Ucp2fl/fl mice were rendered obese and insulin resistant through high-fat feeding. Although no differences in adipose tissue inflammation or insulin resistance was found between the two genotypes, adipose tissue macrophages isolated from diet-induced obese Ucp2ΔLysM mice showed decreased TNFα secretion after ex vivo lipopolysaccharide stimulation compared with their Ucp2fl/fl littermates. Together, these results demonstrate that although UCP2 regulates both metabolism and the inflammatory response of macrophages, its activity is not crucial in shaping macrophage activation in the adipose tissue during obesity-induced insulin resistance.

Alterations of the classic pathway of complement in adipose tissue of obesity and insulin resistance

2007 ◽  
Vol 292 (5) ◽  
pp. E1433-E1440 ◽  
Author(s):  
Jinhui Zhang ◽  
Wendy Wright ◽  
David A. Bernlohr ◽  
Samuel W. Cushman ◽  
Xiaoli Chen
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Epididymal Adipose Tissue ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Insulin Resistant ◽  
Obese Rats ◽  
Initial Activation ◽  
Adipose Cells ◽  
Classic Pathway

Adipose tissue inflammation has recently been linked to the pathogenesis of obesity and insulin resistance. C1 complex comprising three distinct proteins, C1q, C1r, and C1s, involves the key initial activation of the classic pathway of complement and plays an important role in the initiation of inflammatory process. In this study, we investigated adipose expression and regulation of C1 complement subcomponents and C1 activation regulator decorin in obesity and insulin resistance. Expression of C1q in epididymal adipose tissue was increased consistently in ob/ob mice, Zucker obese rats, and high fat-diet-induced obese (HF-DIO) mice. Decorin was found to increase in expression in Zucker obese rats and HF-DIO mice but decrease in ob/ob mice. After TZD administration, C1q and decorin expression was reversed in Zucker obese rats and HF-DIO mice. Increased expression of C1 complement and decorin was observed in both primary adipose and stromal vascular cells isolated from Zucker obese rats. Upregulation of C1r and C1s expression was also perceived in adipose cells from insulin-resistant humans. Furthermore, expression of C1 complement and decorin is dysregulated in TNF-α-induced insulin resistance in 3T3-L1 adipocytes and cultured rat adipose cells as they become insulin resistant after 24-h culture. These data suggests that both adipose and immune cells are the sources for abnormal adipose tissue production of C1 complement and decorin in obesity. Our findings also demonstrate that excessive activation of the classic pathway of complement commonly occurs in obesity, suggesting its possible role in adipose tissue inflammation and insulin resistance.

Loss of iRhom2 accelerates fat gain and insulin resistance in diet-induced obesity despite reduced adipose tissue inflammation

Metabolism ◽  
2020 ◽  
Vol 106 ◽  
pp. 154194 ◽  
Author(s):  
Joseph Skurski ◽  
Christie M. Penniman ◽  
Ramasatyaveni Geesala ◽  
Garima Dixit ◽  
Priyanjali Pulipati ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Diet Induced Obesity
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