NLRP3 inflammasome mediates white adipose tissue browning after burn

A hallmark after burn is the stress and inflammatory-induced hypermetabolic response. Recently, we and others found that browning of white adipose tissue (WAT) is a critical component of this complex detrimental response. Although browning and inflammation have been independently delineated to occur after injury, their interaction is currently not well defined. One of the master regulators of inflammation and adipose tissue remodeling after burns is nucleotide-binding and oligomerization domain, leucine rich repeat and pyrin domain containing 3 (NLRP3) inflammasome. The aim of this this study was to determine whether NLRP3 modulates and activates WAT browning after burn. To obtain molecular and mechanistic insights, we used an NLRP3 knockout (NLRP3−/−) murine burn model. We demonstrated that genetic deletion of NLRP3 promoted persistent and augmented browning in adipocytes, evidenced by increased gene expression of peroxisome proliferator-activated receptor γ and CIDEA at 3 days (5.74 vs. 0.29, P < 0.05; 26.0 vs. 0.71, P < 0.05) and uncoupling protein 1 ( UCP1) and PGC1α at 7 days (7,406 vs. 3,894, P < 0.05; 20.6 vs. 2.52, P < 0.01) and enhanced UCP1 staining and multilocularity. Additionally, the main regulator of postburn WAT browning, IL-6, was elevated in the plasma acutely after burn in NLRP3−/− compared with wild-type counterparts (478.9 vs. 67.1 pg/mL, P < 0.05 at 3 days). These results suggest that NLRP3 has antibrowning effects and that blocking NLRP3 increases thermogenesis and augments browning via increased levels of IL-6. Our findings provide insights into targeting innate inflammatory systems for regulation of adaptive thermogenesis, a critical response after burns and other hypermetabolic conditions.

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Trans-10, cis-12 conjugated linoleic acid causes inflammation and delipidation of white adipose tissue in mice: a microarray and histological analysis

Physiological Genomics ◽

10.1152/physiolgenomics.00076.2006 ◽

2006 ◽

Vol 27 (3) ◽

pp. 282-294 ◽

Cited By ~ 71

Author(s):

P. Christopher LaRosa ◽

Jess Miner ◽

Yuannan Xia ◽

You Zhou ◽

Steve Kachman ◽

...

Keyword(s):

Adipose Tissue ◽

Linoleic Acid ◽

Conjugated Linoleic Acid ◽

White Adipose Tissue ◽

Binding Protein ◽

Uncoupling Protein ◽

Peroxisome Proliferator ◽

Functional Responses ◽

Peroxisome Proliferator Activated Receptor ◽

Transcript Levels

A combined histological and microarray analysis of the white adipose tissue (WAT) of mice fed trans-10, cis-12 conjugated linoleic acid (t10c12 CLA) was performed to better define functional responses. Mice fed t10c12 CLA for 14 days lost 85% of WAT mass, 95% of adipocyte lipid droplet volume, and 15 or 47% of the number of adipocytes and total cells, respectively. Microarray profiling of replicated pools ( n = 2 per day × diet) of control and treated mice ( n = 140) at seven time points after 1–17 days of t10c12 CLA feeding found between 2,682 and 4,216 transcript levels changed by twofold or more. Transcript levels for genes involved in glucose and fatty acid import or biosynthesis were significantly reduced. Highly expressed transcripts for lipases were significantly reduced but still abundant. Increased levels of mRNAs for two key thermogenesis proteins, uncoupling protein 1 and carnitine palmitoyltransferase 1, may have increased energy expenditures. Significant reductions of mRNAs for major adipocyte regulatory factors, including peroxisome proliferator activated receptor-γ, sterol regulatory binding protein 1, CAAT/enhancer binding protein-α, and lipin 1 were correlated with the reduced transcript levels for key metabolic pathways in the WAT. A prolific inflammation response was indicated by the 2- to 100-fold induction of many cytokine transcripts, including those for IL-6, IL-1β, TNF ligands, and CXC family members, and an increased density of macrophages. The mRNA changes suggest that a combination of cell loss, increased energy expenditure, and residual transport of lipids out of the adipocytes may account for the cumulative mass loss observed.

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Current Progress in Adipose Tissue Biology: Implications in Obesity and Its Comorbidities

The Indonesian Biomedical Journal ◽

10.18585/inabj.v12i2.1171 ◽

2020 ◽

Vol 12 (2) ◽

pp. 85-101

Author(s):

Anna Meiliana ◽

Nurrani Mustika Dewi ◽

Andi Wijaya

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Uncoupling Protein ◽

Common Factor ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Protein Levels ◽

Brown Adipose ◽

Key Factor ◽

Beige Fat

BACKGROUND: Obesity has been decades become a highly interest study, accompanied by the realization that adipose tissue (AT) plays a major role in the regulation of metabolic function.CONTENT: In past few years, adipocytes classification, development, and differentiation has been significant changes. The white adipose tissue (WAT) can transform to a phenotype like brown adipose (BAT) type and function. Exercise and cold induction were the most common factor for fat browning; however batokines such as fibroblast growth factor (FGF)-21, interleukin (IL)-6, Slit homolog 2 protein (SLIT2)-C, and Meteorin-like protein (METRNL) perform a beneficial browning action by increasing peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α protein levels, a key factor to stimulate mitochondrial biogenesis and uncoupling Protein 1 (UCP1) transcription, thus change the WAT phenotype into beige.SUMMARY: AT recently known as a complex organ, not only bearing a storage function but as well as the master regulator of energy balance and nutritional homeostasis; brown and beige fat express constitutively high levels of thermogenic genes and raise our expectation on new strategies for fighting obesity and metabolic disorders.KEYWORDS: obesity, white adipose tissue, brown adipose tissue, beige adipose tissue, inflammation, IR, metabolic disease

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Unripe Rubus coreanus Miquel Extract Containing Ellagic Acid Promotes Lipolysis and Thermogenesis In Vitro and In Vivo

Molecules ◽

10.3390/molecules25245954 ◽

2020 ◽

Vol 25 (24) ◽

pp. 5954

Author(s):

Kyeong Jo Kim ◽

Eui-Seon Jeong ◽

Ki Hoon Lee ◽

Ju-Ryun Na ◽

Soyi Park ◽

...

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

White Adipose Tissue ◽

Ellagic Acid ◽

Uncoupling Protein ◽

Hormone Sensitive Lipase ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Rubus Coreanus ◽

Associated Proteins

Previously, we demonstrated that a 5% ethanol extract of unripe Rubus coreanus (5-uRCK) and ellagic acid has hypocholesterolemic and antiobesity activity, at least partially mediated by the downregulation of adipogenic and lipogenic gene expression in high-fat diet (HFD)-fed animals. The present study investigated the thermogenic and lipolytic antiobesity effects of 5-uRCK and ellagic acid in HFD-induced obese C57BL/6 mice and explored its mechanism of action. Mice fed an HFD received 5-uRCK or ellagic acid as a post-treatment or pretreatment. Both post-treated and pretreated mice showed significant reductions in body weight and adipose tissue mass compared to the HFD-fed mice. The protein levels of lipolysis-associated proteins, such as adipose triglyceride lipase (ATGL), phosphorylated hormone-sensitive lipase (p-HSL), and perilipin1 (PLIN1), were significantly increased in both the 5-uRCK- and ellagic acid-treated mouse epididymal white adipose tissue (eWAT). Additionally, thermogenesis-associated proteins, such as peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyl transferase-1 (CPT1), uncoupling protein 1 (UCP1), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), in inguinal white adipose tissue (ingWAT) were clearly increased in both the 5-uRCK- and ellagic acid-treated mice compared to HFD-fed mice. These results suggest that 5-uRCK and ellagic acid are effective for suppressing body weight gain and enhancing the lipid profile.

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Cinnamaldehyde Ameliorates Diet-Induced Obesity in Mice by Inducing Browning of White Adipose Tissue

Cellular Physiology and Biochemistry ◽

10.1159/000479268 ◽

2017 ◽

Vol 42 (4) ◽

pp. 1514-1525 ◽

Cited By ~ 22

Author(s):

Jiacheng Zuo ◽

Dandan Zhao ◽

Na Yu ◽

Xin Fang ◽

Qianqian Mu ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Uncoupling Protein ◽

Health Concern ◽

Standard Diet ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Diet Induced Obesity ◽

Obesity In Mice ◽

Pr Domain

Background/Aims: Obesity has become a major health concern with few effective medications. Cinnamaldehyde (CA) has been reported to exhibit anti-diabetic and anti-inflammatory properties. However, whether CA shows anti-obesity activity remains unknown. Therefore, the present study aimed to investigate the potential anti-obesity effects of CA on mice fed a high-fat diet (HFD) and to explore the possible mechanisms involved. Methods: Male C57BL/6J mice fed an HFD for 12 weeks were supplemented with CA (40 mg/kg/day) via gavage for an additional 8 weeks. Mice fed a standard diet were used as normal controls. Results: The results revealed that CA treatment decreased body weight, fat mass, food intake, and serum lipid, free fatty acid and leptin levels. CA administration also improved insulin sensitivity in HFD-induced obese mice. Additionally, CA inhibited the hypertrophy of adipose tissue and induced browning of white adipose tissue. Uncoupling protein 1 (UCP1) was expressed in white adipose tissue after the oral administration of CA. Furthermore, CA enhanced the expression of the peroxisome proliferator-activated receptor γ (PPARγ), PR domain-containing 16 (PRDM16) and PPARγ coactivator 1α (PGC-1α) proteins in both brown and white adipose tissues. Conclusions: The results suggest that CA exhibits therapeutic potency against obesity by inducing the browning of white adipose tissue in HFD-fed mice.

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Bilirubin remodels murine white adipose tissue by reshaping mitochondrial activity and the coregulator profile of peroxisome proliferator–activated receptor α

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013700 ◽

2020 ◽

Vol 295 (29) ◽

pp. 9804-9822 ◽

Cited By ~ 10

Author(s):

Darren M. Gordon ◽

Kari L. Neifer ◽

Abdul-Rizaq Ali Hamoud ◽

Charles F. Hawk ◽

Andrea L. Nestor-Kalinoski ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Target Genes ◽

Uncoupling Protein ◽

Mitochondrial Activity ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Obesity And Diabetes ◽

Selective Ligand ◽

Related Proteins

Activation of lipid-burning pathways in the fat-storing white adipose tissue (WAT) is a promising strategy to improve metabolic health and reduce obesity, insulin resistance, and type II diabetes. For unknown reasons, bilirubin levels are negatively associated with obesity and diabetes. Here, using mice and an array of approaches, including MRI to assess body composition, biochemical assays to measure bilirubin and fatty acids, MitoTracker-based mitochondrial analysis, immunofluorescence, and high-throughput coregulator analysis, we show that bilirubin functions as a molecular switch for the nuclear receptor transcription factor peroxisome proliferator–activated receptor α (PPARα). Bilirubin exerted its effects by recruiting and dissociating specific coregulators in WAT, driving the expression of PPARα target genes such as uncoupling protein 1 (Ucp1) and adrenoreceptor β 3 (Adrb3). We also found that bilirubin is a selective ligand for PPARα and does not affect the activities of the related proteins PPARγ and PPARδ. We further found that diet-induced obese mice with mild hyperbilirubinemia have reduced WAT size and an increased number of mitochondria, associated with a restructuring of PPARα-binding coregulators. We conclude that bilirubin strongly affects organismal body weight by reshaping the PPARα coregulator profile, remodeling WAT to improve metabolic function, and reducing fat accumulation.

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Acetylation of Histone and Modification of Gene Expression via HDAC Inhibitors Affects the Obesity

Biomedical & Pharmacology Journal ◽

10.13005/bpj/2110 ◽

2021 ◽

Vol 14 (1) ◽

pp. 153-161

Author(s):

Deepika Sharma ◽

Swati Sharma ◽

Preeti Chauhan

Keyword(s):

Adipose Tissue ◽

Energy Expenditure ◽

White Adipose Tissue ◽

Uncoupling Protein ◽

Peroxisome Proliferator ◽

Inner Mitochondrial Membrane ◽

Adipose Tissues ◽

Peroxisome Proliferator Activated Receptor ◽

Main Site ◽

Brown Adipose

Obesity is due to imbalance between energy intake and energy expenditure. Adipose tissues are the main site for the fat storage as well as for dissipation. There are two types of adipose tissues: white adipose tissue, which store fat as triglyceride, brown adipose tissue, which burns the fat into energy through the thermogenesis due to uncoupling protein1 present in inner mitochondrial membrane. Histone acylation causes changes in the chromatin structure without causing any change in the deoxyribonucleic acidsequence and thus regulate gene expression.Histonedeacetylase causes the deacylation of histone and interfere with function of histone. Thus histonedeacetylase inhibitors alter the expression of thermogenic gene encoding uncoupling protein 1, peroxisome proliferator activated receptor γ and also causes browning or beiging of white adipose tissue and increases the energy expenditure.

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Contribution of PGC-1α to Obesity- and Caloric Restriction-Related Physiological Changes in White Adipose Tissue

International Journal of Molecular Sciences ◽

10.3390/ijms22116025 ◽

2021 ◽

Vol 22 (11) ◽

pp. 6025

Author(s):

Masaki Kobayashi ◽

Yusuke Deguchi ◽

Yuka Nozaki ◽

Yoshikazu Higami

Keyword(s):

Adipose Tissue ◽

Caloric Restriction ◽

White Adipose Tissue ◽

Mitochondrial Gene ◽

Energy Resource ◽

Peroxisome Proliferator ◽

Physiological Changes ◽

Mitochondrial Gene Expression ◽

Peroxisome Proliferator Activated Receptor ◽

White Adipocytes

Peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) regulates mitochondrial DNA replication and mitochondrial gene expression by interacting with several transcription factors. White adipose tissue (WAT) mainly comprises adipocytes that store triglycerides as an energy resource and secrete adipokines. The characteristics of WAT vary in response to systemic and chronic metabolic alterations, including obesity or caloric restriction. Despite a small amount of mitochondria in white adipocytes, accumulated evidence suggests that mitochondria are strongly related to adipocyte-specific functions, such as adipogenesis and lipogenesis, as well as oxidative metabolism for energy supply. Therefore, PGC-1α is expected to play an important role in WAT. In this review, we provide an overview of the involvement of mitochondria and PGC-1α with obesity- and caloric restriction-related physiological changes in adipocytes and WAT.

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Evidence for the Regulatory Role of Lipocalin 2 in High-Fat Diet-Induced Adipose Tissue Remodeling in Male Mice

Endocrinology ◽

10.1210/en.2013-1289 ◽

2013 ◽

Vol 154 (10) ◽

pp. 3525-3538 ◽

Cited By ~ 33

Author(s):

Hong Guo ◽

Merlijn Bazuine ◽

Daozhong Jin ◽

Merry M. Huang ◽

Samuel W. Cushman ◽

...

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

Adipocyte Differentiation ◽

Tissue Remodeling ◽

Peroxisome Proliferator ◽

Lipocalin 2 ◽

Peroxisome Proliferator Activated Receptor ◽

Adipose Tissue Remodeling ◽

Fat Depot

Lipocalin 2 (Lcn2) has previously been characterized as an adipokine/cytokine playing a role in glucose and lipid homeostasis. In this study, we investigate the role of Lcn2 in adipose tissue remodeling during high-fat diet (HFD)-induced obesity. We find that Lcn2 protein is highly abundant selectively in inguinal adipose tissue. During 16 weeks of HFD feeding, the inguinal fat depot expanded continuously, whereas the expansion of the epididymal fat depot was reduced in both wild-type (WT) and Lcn2−/− mice. Interestingly, the depot-specific effect of HFD on fat mass was exacerbated and appeared more pronounced and faster in Lcn2−/− mice than in WT mice. In Lcn2−/− mice, adipocyte hypertrophy in both inguinal and epididymal adipose tissue was more profoundly induced by age and HFD when compared with WT mice. The expression of peroxisome proliferator-activated receptor-γ protein was significantly down-regulated, whereas the gene expression of extracellular matrix proteins was up-regulated selectively in epididymal adipocytes of Lcn2−/− mice. Consistent with these observations, collagen deposition was selectively higher in the epididymal, but not in the inguinal adipose depot of Lcn2−/− mice. Administration of the peroxisome proliferator-activated receptor-γ agonist rosiglitazone (Rosi) restored adipogenic gene expression. However, Lcn2 deficiency did not alter the responsiveness of adipose tissue to Rosi effects on the extracellular matrix expression. Rosi treatment led to the further enlargement of adipocytes with improved metabolic activity in Lcn2−/− mice, which may be associated with a more pronounced effect of Rosi treatment in reducing TGF-β in Lcn2−/− adipose tissue. Consistent with these in vivo observations, Lcn2 deficiency reduces the adipocyte differentiation capacity of stromal-vascular cells isolated from HFD-fed mice in these cells. Herein Rosi treatment was again able to stimulate adipocyte differentiation to a similar extent in WT and Lcn2−/− inguinal and epididymal stromal-vascular cells. Thus, combined, our data indicate that Lcn2 has a depot-specific role in HFD-induced adipose tissue remodeling.

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Analysis of Tks4 Knockout Mice Suggests a Role for Tks4 in Adipose Tissue Homeostasis in the Context of Beigeing

Cells ◽

10.3390/cells8080831 ◽

2019 ◽

Vol 8 (8) ◽

pp. 831 ◽

Cited By ~ 1

Author(s):

Virag Vas ◽

Tamás Háhner ◽

Gyöngyi Kudlik ◽

Dávid Ernszt ◽

Krisztián Kvell ◽

...

Keyword(s):

Adipose Tissue ◽

Uncoupling Protein ◽

Growth Factor Receptor ◽

Cellular Level ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Kinase Substrate ◽

Downstream Signaling ◽

Brown Adipose ◽

Morphological Differences

Obesity and adipocyte malfunction are related to and arise as consequences of disturbances in signaling pathways. Tyrosine kinase substrate with four Src homology 3 domains (Tks4) is a scaffold protein that establishes a platform for signaling cascade molecules during podosome formation and epidermal growth factor receptor (EGFR) signaling. Several lines of evidence have also suggested that Tks4 has a role in adipocyte biology; however, its roles in the various types of adipocytes at the cellular level and in transcriptional regulation have not been studied. Therefore, we hypothesized that Tks4 functions as an organizing molecule in signaling networks that regulate adipocyte homeostasis. Our aims were to study the white and brown adipose depots of Tks4 knockout (KO) mice using immunohistology and western blotting and to analyze gene expression changes regulated by the white, brown, and beige adipocyte-related transcription factors via a PCR array. Based on morphological differences in the Tks4-KO adipocytes and increased uncoupling protein 1 (UCP1) expression in the white adipose tissue (WAT) of Tks4-KO mice, we concluded that the beigeing process was more robust in the WAT of Tks4-KO mice compared to the wild-type animals. Furthermore, in the Tks4-KO WAT, the expression profile of peroxisome proliferator-activated receptor gamma (PPARγ)-regulated adipogenesis-related genes was shifted in favor of the appearance of beige-like cells. These results suggest that Tks4 and its downstream signaling partners are novel regulators of adipocyte functions and PPARγ-directed white to beige adipose tissue conversion.

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Enhanced Fatty Acid Flux Triggered by Adiponectin Overexpression

Endocrinology ◽

10.1210/en.2011-1339 ◽

2012 ◽

Vol 153 (1) ◽

pp. 113-122 ◽

Cited By ~ 23

Author(s):

Shoba Shetty ◽

Maria A. Ramos-Roman ◽

You-Ree Cho ◽

Jonathan Brown ◽

Jorge Plutzky ◽

...

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

Free Fatty Acid ◽

Uncoupling Protein ◽

Retinol Binding Protein ◽

Peroxisome Proliferator ◽

Tissue Mass ◽

Triglyceride Synthesis ◽

Peroxisome Proliferator Activated Receptor ◽

Brown Adipose

Adiponectin overexpression in mice increases insulin sensitivity independent of adiposity. Here, we combined stable isotope infusion and in vivo measurements of lipid flux with transcriptomic analysis to characterize fatty acid metabolism in transgenic mice that overexpress adiponectin via the aP2-promoter (ADNTg). Compared with controls, fasted ADNTg mice demonstrated a 31% reduction in plasma free fatty acid concentrations (P = 0.008), a doubling of ketones (P = 0.028), and a 68% increase in free fatty acid turnover in plasma (15.1 ± 1.5 vs. 25.3 ± 6.8 mg/kg · min, P = 0.011). ADNTg mice had 2-fold more brown adipose tissue mass, and triglyceride synthesis and turnover were 5-fold greater in this organ (P = 0.046). Epididymal white adipose tissue was slightly reduced, possibly due to the approximately 1.5-fold increase in the expression of genes involved in oxidation (peroxisome proliferator-activated receptor α, peroxisome proliferator-activated receptor-γ coactivator 1α, and uncoupling protein 3). In ADNTg liver, lipogenic gene expression was reduced, but there was an unexpected increase in the expression of retinoid pathway genes (hepatic retinol binding protein 1 and retinoic acid receptor beta and adipose Cyp26A1) and liver retinyl ester content (64% higher, P < 0.02). Combined, these data support a physiological link between adiponectin signaling and increased efficiency of triglyceride synthesis and hydrolysis, a process that can be controlled by retinoids. Interactions between adiponectin and retinoids may underlie adiponectin's effects on intermediary metabolism.

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