The role of IL-1 in adipose browning and muscle wasting in CKD-associated cachexia

AbstractCytokines such as IL-6, TNF-α and IL-1β trigger inflammatory cascades which may play a role in the pathogenesis of chronic kidney disease (CKD)-associated cachexia. CKD was induced by 5/6 nephrectomy in mice. We studied energy homeostasis in Il1β−/−/CKD, Il6−/−/CKD and Tnfα−/−/CKD mice and compared with wild type (WT)/CKD controls. Parameters of cachexia phenotype were completely normalized in Il1β−/−/CKD mice but were only partially rescued in Il6−/−/CKD and Tnfα−/−/CKD mice. We tested the effects of anakinra, an IL-1 receptor antagonist, on CKD-associated cachexia. WT/CKD mice were treated with anakinra (2.5 mg/kg/day, IP) or saline for 6 weeks and compared with WT/Sham controls. Anakinra normalized food intake and weight gain, fat and lean mass content, metabolic rate and muscle function, and also attenuated molecular perturbations of energy homeostasis in adipose tissue and muscle in WT/CKD mice. Anakinra decreased serum and muscle expression of IL-6, TNF-α and IL-1β in WT/CKD mice. Anakinra attenuated browning of white adipose tissue in WT/CKD mice. Moreover, anakinra normalized gastrocnemius weight and fiber size as well as attenuated muscle fat infiltration in WT/CKD mice. This was accompanied by correcting the increased muscle wasting signaling pathways while promoting the decreased myogenesis process in gastrocnemius of WT/CKD mice. We performed qPCR analysis for the top 20 differentially expressed muscle genes previously identified via RNAseq analysis in WT/CKD mice versus controls. Importantly, 17 differentially expressed muscle genes were attenuated in anakinra treated WT/CKD mice. In conclusion, IL-1 receptor antagonism may represent a novel targeted treatment for adipose tissue browning and muscle wasting in CKD.

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The role of IL-1 in adipose browning and muscle wasting in CKD-associated cachexia

10.21203/rs.3.rs-156249/v1 ◽

2021 ◽

Author(s):

Wai W Cheung ◽

Ronghao Zheng ◽

Sheng Hao ◽

Zhen Wang ◽

Alex Gonzalez ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Homeostasis ◽

Muscle Wasting ◽

Differentially Expressed ◽

Wild Type ◽

Tnf Α ◽

Fiber Size ◽

Muscle Genes ◽

Muscle Fat Infiltration

Abstract Cytokines such as IL-6, TNF-α and IL-1β trigger inflammatory cascades which may play a role in the pathogenesis of chronic kidney disease (CKD)-associated cachexia. CKD was induced by 5/6 nephrectomy in mice. We studied energy homeostasis in Il1β −/−/CKD, Il6−/−/CKD and Tnfα −/−/CKD mice and compared with wild type (WT)/CKD controls. Parameters of cachexia phenotype were completely normalized in Il1β −/−/CKD mice but were only partially rescued in Il6−/−/CKD and Tnfα −/−/CKD mice. We tested the effects of anakinra, an IL-1 receptor antagonist, on CKD-associated cachexia. WT/CKD mice were treated with anakinra (2.5 mg.kg.day, IP) or saline for 6 weeks and compared with WT/sham controls. Anakinra normalized food intake and weight gain, fat and lean mass content, metabolic rate and muscle function, and also attenuated molecular perturbations of energy homeostasis in adipose tissue and muscle in WT/CKD mice. Anakinra attenuated browning of white adipose tissue in WT/CKD mice. Moreover, anakinra normalized gastrocnemius weight and fiber size as well as attenuated muscle fat infiltration in WT/CKD mice. This was accompanied by correcting the increased muscle wasting signaling pathways while promoting the decreased myogenesis process in gastrocnemius of WT/CKD mice. We performed qPCR analysis for the top 20 differentially expressed muscle genes previously identified via RNAseq analysis in WT/CKD mice versus controls. Importantly, 17 differentially expressed muscle genes were attenuated in anakinra treated WT/CKD mice. In conclusion, IL-1 receptor antagonism may represent a novel targeted treatment for adipose tissue browning and muscle wasting in CKD.

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The role of IL-1 in adipose browning and muscle wasting in CKD-associated cachexia

10.1101/2021.02.05.429984 ◽

2021 ◽

Author(s):

Wai W Cheung ◽

Ronghao Zheng ◽

Sheng Hao ◽

Zhen Wang ◽

Alex Gonzalez ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Homeostasis ◽

Muscle Wasting ◽

Differentially Expressed ◽

Wild Type ◽

Tnf Α ◽

Fiber Size ◽

Muscle Genes ◽

Muscle Fat Infiltration

ABSTRACTCytokines such as IL-6, TNF-α and IL-1β trigger inflammatory cascades which may play a role in the pathogenesis of chronic kidney disease (CKD)-associated cachexia. CKD was induced by 5/6 nephrectomy in mice. We studied energy homeostasis in Il1β−/−/CKD, Il6−/−/CKD and Tnfα−/−/CKD mice and compared with wild type (WT)/CKD controls. Parameters of cachexia phenotype were completely normalized in Il1β−/−/CKD mice but were only partially rescued in Il6−/−/CKD and Tnfα−/−/CKD mice. We tested the effects of anakinra, an IL-1 receptor antagonist, on CKD-associated cachexia. WT/CKD mice were treated with anakinra (2.5 mg.kg.day, IP) or saline for 6 weeks and compared with WT/sham controls. Anakinra normalized food intake and weight gain, fat and lean mass content, metabolic rate and muscle function, and also attenuated molecular perturbations of energy homeostasis in adipose tissue and muscle in WT/CKD mice. Anakinra attenuated browning of white adipose tissue in WT/CKD mice. Moreover, anakinra normalized gastrocnemius weight and fiber size as well as attenuated muscle fat infiltration in WT/CKD mice. This was accompanied by correcting the increased muscle wasting signaling pathways while promoting the decreased myogenesis process in gastrocnemius of WT/CKD mice. We performed qPCR analysis for the top 20 differentially expressed muscle genes previously identified via RNAseq analysis in WT/CKD mice versus controls. Importantly, 17 differentially expressed muscle genes were attenuated in anakinra treated WT/CKD mice. In conclusion, IL-1 receptor antagonism may represent a novel targeted treatment for adipose tissue browning and muscle wasting in CKD.

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A Leptin Receptor Antagonist Attenuates Adipose Tissue Browning and Muscle Wasting in Infantile Nephropathic Cystinosis-Associated Cachexia

Cells ◽

10.3390/cells10081954 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1954

Author(s):

Alex Gonzalez ◽

Wai W. Cheung ◽

Elliot A. Perens ◽

Eduardo A. Oliveira ◽

Arieh Gertler ◽

...

Keyword(s):

Adipose Tissue ◽

Receptor Antagonist ◽

Energy Homeostasis ◽

Muscle Wasting ◽

Leptin Receptor ◽

Nephropathic Cystinosis ◽

Muscle Genes ◽

Muscle Fat Infiltration ◽

And Control ◽

Tissue Browning

Mice lacking the functional cystinosin gene (Ctns−/−), a model of infantile nephropathic cystinosis (INC), exhibit the cachexia phenotype with adipose tissue browning and muscle wasting. Elevated leptin signaling is an important cause of chronic kidney disease-associated cachexia. The pegylated leptin receptor antagonist (PLA) binds to but does not activate the leptin receptor. We tested the efficacy of this PLA in Ctns−/− mice. We treated 12-month-old Ctns−/− mice and control mice with PLA (7 mg/kg/day, IP) or saline as a vehicle for 28 days. PLA normalized food intake and weight gain, increased fat and lean mass, decreased metabolic rate and improved muscle function. It also attenuated perturbations of energy homeostasis in adipose tissue and muscle in Ctns−/− mice. PLA attenuated adipose tissue browning in Ctns−/− mice. PLA increased gastrocnemius weight and fiber size as well as attenuated muscle fat infiltration in Ctns−/− mice. This was accompanied by correcting the increased expression of muscle wasting signaling while promoting the decreased expression of myogenesis in gastrocnemius of Ctns−/− mice. PLA attenuated aberrant expressed muscle genes that have been associated with muscle atrophy, increased energy expenditure and lipolysis in Ctns−/− mice. Leptin antagonism may represent a viable therapeutic strategy for adipose tissue browning and muscle wasting in INC.

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Urokinase-type plasminogen activator receptor is associated with the development of adipose tissue

Thrombosis and Haemostasis ◽

10.1160/th10-02-0101 ◽

2010 ◽

Vol 104 (12) ◽

pp. 1124-1132 ◽

Cited By ~ 11

Author(s):

Hiroyuki Matsuno ◽

Eri Kawashita ◽

Kiyotaka Okada ◽

Hidetaka Suga ◽

Shigeru Ueshima ◽

...

Keyword(s):

Adipose Tissue ◽

Plasminogen Activator ◽

Adipocyte Differentiation ◽

Cellular Adhesion ◽

Wild Type ◽

Tissue Mass ◽

Type Plasminogen Activator ◽

Urokinase Type Plasminogen Activator ◽

Plasminogen Activator Receptor

SummaryUrokinase-type plasminogen activator receptor (uPAR) plays a role in cellular responses which include cellular adhesion, differentiation, proliferation and migration. The aim of this study was to clarify the role of uPAR on the development of adipose tissue. To clarify the role of uPAR on adipogenesis, we examined the effect of uPAR overexpression and uPAR deficiency on the adipocyte differentiation. Adipocyte differentiation was induced by incubation of 3T3-L1 cells with differentiation media containing insulin, dexamethasone, and 1-methyl-3-isobutylxanthin. uPAR overexpression by transfection of uPAR expression vector induced adipocyte differentiation. In addition, we examined the difference in adipocyte differentiation of mesenchymal stem cells from wild-type mice and uPAR knockout (uPAR-/-) mice. The uPAR deficiency attenuated differentiation media-induced adipocyte differentiation. Moreover, we found that the inhibition of phosphatidylinositol 3-kinase (PI3K) pathway attenuated uPAR overexpression-induced adipocyte differentiation, and uPAR overexpression induced the activation of Akt. We also found that an increase of the adipose tissue mass in uPAR-/- mice was less than that observed in wild-type mice. The present results suggest that uPAR plays a pivotal role in the development of adipose tissue through PI3K/Akt pathway.

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Role of Nitric Oxide in the Pathogenesis of Encephalomyocarditis Virus-Induced Diabetes in Mice

Journal of Virology ◽

10.1128/jvi.00205-09 ◽

2009 ◽

Vol 83 (16) ◽

pp. 8004-8011 ◽

Cited By ~ 5

Author(s):

Young-Sun Lee ◽

Na Li ◽

Seungjin Shin ◽

Hee-Sook Jun

Keyword(s):

Virus Infection ◽

Encephalomyocarditis Virus ◽

Wild Type ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Diabetes In Mice ◽

Tnf Α ◽

Deficient Mice

ABSTRACT The D variant of encephalomyocarditis virus (EMC-D virus) causes diabetes in mice by destroying pancreatic β cells. In mice infected with a low dose of EMC-D virus, macrophages play an important role in β-cell destruction by producing soluble mediators such as interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), and nitric oxide (NO). To investigate the role of NO and inducible NO synthase (iNOS) in the development of diabetes in EMC-D virus-infected mice, we infected iNOS-deficient DBA/2 mice with EMC-D virus (2 × 102 PFU/mouse). Mean blood glucose levels in EMC-D virus-infected iNOS-deficient mice and wild-type mice were 205.5 and 466.7 mg/dl, respectively. Insulitis and macrophage infiltration were reduced in islets of iNOS-deficient mice compared with wild-type mice at 3 days after EMC-D virus infection. Apoptosis of β cells was decreased in iNOS-deficient mice, as evidenced by reduced numbers of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells. There were no differences in mRNA expression of antiapoptotic molecules Bcl-2, Bcl-xL, Bcl-w, Mcl-1, cIAP-1, and cIAP-2 between wild-type and iNOS-deficient mice, whereas expression of proapoptotic Bax and Bak mRNAs was significantly decreased in iNOS-deficient mice. Expression of IL-1β and TNF-α mRNAs was significantly decreased in both islets and macrophages of iNOS-deficient mice compared with wild-type mice after EMC-D virus infection. Nuclear factor κB was less activated in macrophages of iNOS-deficient mice after virus infection. We conclude that NO plays an important role in the activation of macrophages and apoptosis of pancreatic β cells in EMC-D virus-infected mice and that deficient iNOS gene expression inhibits macrophage activation and β-cell apoptosis, contributing to prevention of EMC-D virus-induced diabetes.

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Adiponectin is required to mediate rimonabant-induced improvement of insulin sensitivity but not body weight loss in diet-induced obese mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90824.2008 ◽

2009 ◽

Vol 296 (4) ◽

pp. R929-R935 ◽

Cited By ~ 29

Author(s):

Stéphanie Migrenne ◽

Amélie Lacombe ◽

Anne-Laure Lefèvre ◽

Marie-Pierre Pruniaux ◽

Etienne Guillot ◽

...

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Energy Homeostasis ◽

Hepatic Glucose Production ◽

Body Weight Loss ◽

Metabolic Effects ◽

Wild Type ◽

High Fat ◽

Wild Type Littermate

The increase in adiponectin levels in obese patients with untreated dyslipidemia and its mRNA expression in adipose tissue of obese animals are one of the most interesting consequences of rimonabant treatment. Thus, part of rimonabant's metabolic effects could be related to an enhancement of adiponectin secretion and its consequence on the modulation of insulin action, as well as energy homeostasis. The present study investigated the effects of rimonabant in adiponectin knockout mice (Ad−/−) exposed to diet-induced obesity conditions. Six-week-old Ad−/− male mice and their wild-type littermate controls (Ad+/+) were fed a high-fat diet for 7 mo. During the last month, animals were administered daily either with vehicle or rimonabant by mouth (10 mg/kg). High-fat feeding induced weight gain by about 130% in both wild-type and Ad−/− mice. Obesity was associated with hyperinsulinemia and insulin resistance. Treatment with rimonabant led to a significant and similar decrease in body weight in both Ad+/+ and Ad−/− mice compared with vehicle-treated animals. In addition, rimonabant significantly improved insulin sensitivity in Ad+/+ mice compared with Ad+/+ vehicle-treated mice by decreasing hepatic glucose production and increasing glucose utilization index in both visceral and subcutaneous adipose tissue. In contrast, rimonabant failed to improve insulin sensitivity in Ad−/− mice, despite the loss in body weight. Rimonabant's effect on body weight appeared independent of the adiponectin pathway, whereas adiponectin seems required to mediate rimonabant-induced improvement of insulin sensitivity in rodents.

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Adipose Tissue-Derived Signatures for Obesity and Type 2 Diabetes: Adipokines, Batokines and MicroRNAs

Journal of Clinical Medicine ◽

10.3390/jcm8060854 ◽

2019 ◽

Vol 8 (6) ◽

pp. 854 ◽

Cited By ~ 29

Author(s):

Min-Woo Lee ◽

Mihye Lee ◽

Kyoung-Jin Oh

Keyword(s):

Type 2 Diabetes ◽

Adipose Tissue ◽

Energy Homeostasis ◽

Metabolic Disturbances ◽

Endocrine Organ ◽

Brown Adipose ◽

Exosomal Mirnas ◽

Exosomal Mirna

Obesity is one of the main risk factors for type 2 diabetes mellitus (T2DM). It is closely related to metabolic disturbances in the adipose tissue that primarily functions as a fat reservoir. For this reason, adipose tissue is considered as the primary site for initiation and aggravation of obesity and T2DM. As a key endocrine organ, the adipose tissue communicates with other organs, such as the brain, liver, muscle, and pancreas, for the maintenance of energy homeostasis. Two different types of adipose tissues—the white adipose tissue (WAT) and brown adipose tissue (BAT)—secrete bioactive peptides and proteins, known as “adipokines” and “batokines,” respectively. Some of them have beneficial anti-inflammatory effects, while others have harmful inflammatory effects. Recently, “exosomal microRNAs (miRNAs)” were identified as novel adipokines, as adipose tissue-derived exosomal miRNAs can affect other organs. In the present review, we discuss the role of adipose-derived secretory factors—adipokines, batokines, and exosomal miRNA—in obesity and T2DM. It will provide new insights into the pathophysiological mechanisms involved in disturbances of adipose-derived factors and will support the development of adipose-derived factors as potential therapeutic targets for obesity and T2DM.

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Indoleamine 2,3-Dioxygenase 2 Deficiency Exacerbates Imiquimod-Induced Psoriasis-Like Skin Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms21155515 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5515

Author(s):

Kento Fujii ◽

Yasuko Yamamoto ◽

Yoko Mizutani ◽

Kuniaki Saito ◽

Mariko Seishima

Keyword(s):

Immune Responses ◽

Immune Cells ◽

Skin Inflammation ◽

Kynurenine Pathway ◽

Immune Functions ◽

Wild Type ◽

Indoleamine 2,3 Dioxygenase ◽

Tnf Α ◽

In The Wild

Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme known to suppress immune responses, and several reports have showed that it is associated with psoriasis. IDO2 is an isoform of IDO1, recently identified as a catalytic enzyme in the tryptophan-kynurenine pathway, which is expressed in dendritic cells and monocytes. The expression of IDO2 in immune cells suggests that IDO2 may contribute to immune functions. However, the role of IDO2 in the pathogenesis of psoriasis remains unclear. In this study, to elucidate the role of IDO2 in psoriasis, we assessed imiquimod (IMQ)-induced psoriasis-like dermatitis in IDO2 knockout (KO) mice. Skin inflammation, evaluated by scoring erythema, scaling, and ear thickness, was significantly worse in the IDO2 KO mice than in the wild-type (WT) mice. The mRNA expression levels of TNF-α, IL-23p19, and IL-17A, key cytokines involved in the development of psoriasis, were also increased in the IDO2 KO mice. Furthermore, immunohistochemistry revealed that the number of Ki67-positive cells in the epidermis and CD4-, CD8-, and IL-17-positive lymphocytes infiltrating the dermis were significantly increased in the IDO2 KO mice. These results suggest that IDO2 might decrease IL-17 expression, thereby resulting in the suppression of skin inflammation in IMQ-induced psoriasis-like dermatitis.

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Anti-inflammatory effects of exercise training in adipose tissue do not require FGF21

Journal of Endocrinology ◽

10.1530/joe-17-0190 ◽

2017 ◽

Vol 235 (2) ◽

pp. 97-109 ◽

Cited By ~ 9

Author(s):

Jay W Porter ◽

Joe L Rowles ◽

Justin A Fletcher ◽

Terese M Zidon ◽

Nathan C Winn ◽

...

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

Citrate Synthase ◽

Metabolic Effects ◽

Relative Mass ◽

Fibroblast Growth Factor 21 ◽

Wild Type ◽

Anti Inflammatory ◽

Running Wheels

Exercise enhances insulin sensitivity; it also improves adipocyte metabolism and reduces adipose tissue inflammation through poorly defined mechanisms. Fibroblast growth factor 21 (FGF21) is a pleiotropic hormone-like protein whose insulin-sensitizing properties are predominantly mediated via receptor signaling in adipose tissue (AT). Recently, FGF21 has also been demonstrated to have anti-inflammatory properties. Meanwhile, an association between exercise and increased circulating FGF21 levels has been reported in some, but not all studies. Thus, the role that FGF21 plays in mediating the positive metabolic effects of exercise in AT are unclear. In this study, FGF21-knockout (KO) mice were used to directly assess the role of FGF21 in mediating the metabolic and anti-inflammatory effects of exercise on white AT (WAT) and brown AT (BAT). Male FGF21KO and wild-type mice were provided running wheels or remained sedentary for 8 weeks (n = 9–15/group) and compared for adiposity, insulin sensitivity (i.e., HOMA-IR, Adipo-IR) and AT inflammation and metabolic function (e.g., mitochondrial enzyme activity, subunit content). Adiposity and Adipo-IR were increased in FGF21KO mice and decreased by EX. The BAT of FGF21KO animals had reduced mitochondrial content and decreased relative mass, both normalized by EX. WAT and BAT inflammation was elevated in FGF21KO mice, reduced in both genotypes by EX. EX increased WAT Pgc1alpha gene expression, citrate synthase activity, COX I content and total AMPK content in WT but not FGF21KO mice. Collectively, these findings reveal a previously unappreciated anti-inflammatory role for FGF21 in WAT and BAT, but do not support that FGF21 is necessary for EX-mediated anti-inflammatory effects.

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