scholarly journals Targeting interleukin-1 for reversing fat browning and muscle wasting in infantile nephropathic cystinosis

2021 ◽  
Author(s):  
Wai W Cheung ◽  
Sheng Hao ◽  
Ronghao Zheng ◽  
Zhen Wang ◽  
Alex Gonzalez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Lean Mass ◽  
Muscle Function ◽  
Muscle Wasting ◽  
Nephropathic Cystinosis ◽  
Mass Content ◽  
Aberrant Expression ◽  
Fiber Size ◽  
Tissue Browning

ABSTRACTBackgroundCtns−/− mice, a mouse model of infantile nephropathic cystinosis, exhibit hypermetabolism with adipose tissue browning and profound muscle wasting. Inflammatory cytokines such as IL-1 trigger inflammatory cascades and play an important role in the pathogenesis of cachexia. Anakinra is an FDA-approved IL-1 receptor antagonist that blocks IL-1 signaling and may provide targeted novel therapy.MethodsCtns−/− mice were bred to Il6−/− and Il1β−/− mice. Ctns−/− mice and wild type control were treated with anakinra (2.5 mg.kg.day, IP) or saline as vehicle for 6 weeks. We quantitated total fat mass and studied expression of molecules regulating adipose tissue browning. We measured gastrocnemius weight, total lean mass content, muscle function (grip strength and rotarod activity), muscle fiber size, muscle fatty infiltration and expression of molecules regulating muscle metabolism. We also evaluated the effects of anakinra on the muscle transcriptome.ResultsIl-1β deficiency or treatment with anakinra normalized food intake and weight gain, fat and lean mass content, metabolic rate and muscle function in Ctns−/− mice. Anakinra also diminished molecular perturbations of energy homeostasis in adipose tissue and muscle, specifically, aberrant expression of beige adipose cell biomarkers (UCP-1, CD137, Tmem26 and Tbx1) and molecules implicated in adipocyte tissue browning (Cox2/Pgf2α, Tlr2, Myd88 and Traf6) in inguinal white adipose tissue in Ctns−/− mice. Moreover, anakinra normalized gastrocnemius weight and fiber size as well as attenuated muscle fat infiltration in Ctns−/− mice. This was accompanied by correction of the increased muscle wasting signaling pathways (increased protein content of ERK1/2, JNK, p38 MAPK and NF-κB p65 and gene expression of Atrogin-1 and Myostatin) and the decreased myogenesis process (decreased gene expression of MyoD and Myogenin) in gastrocnemius of Ctns−/− mice. Finally, anakinra normalized or attenuated 12 of those top 20 differentially expressed muscle genes in Ctns−/− mice.ConclusionsAnakinra attenuates adipose tissue browning and muscle wasting in Ctns−/− mice. IL-1 receptor blockade may represent a novel targeted treatment for cachexia in patients with infantile nephropathic cystinosis.

scholarly journals Vitamin D repletion ameliorates adipose tissue browning and muscle wasting in infantile nephropathic cystinosis‐associated cachexia

2019 ◽  
Vol 11 (1) ◽  
pp. 120-134 ◽  
Author(s):  
Wai W. Cheung ◽  
Sheng Hao ◽  
Zhen Wang ◽  
Wei Ding ◽  
Ronghao Zheng ◽  
...  
Keyword(s):  
Vitamin D ◽  
Adipose Tissue ◽  
Muscle Wasting ◽  
Nephropathic Cystinosis ◽  
Tissue Browning

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

Cells ◽  
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.

scholarly journals Muscle wasting and adipose tissue browning in infantile nephropathic cystinosis

2015 ◽  
Vol 7 (2) ◽  
pp. 152-164 ◽  
Author(s):  
Wai W. Cheung ◽  
Stephanie Cherqui ◽  
Wei Ding ◽  
Mary Esparza ◽  
Ping Zhou ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Muscle Wasting ◽  
Nephropathic Cystinosis ◽  
Tissue Browning

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

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.

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

2021 ◽  
Vol 11 (1) ◽  
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 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.

scholarly journals The Effect of TNF and Non-TNF-Targeted Biologics on Body Composition in Rheumatoid Arthritis

2021 ◽  
Vol 10 (3) ◽  
pp. 487
Author(s):  
Gaelle Vial ◽  
Céline Lambert ◽  
Bruno Pereira ◽  
Marion Couderc ◽  
Sandrine Malochet-Guinamand ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Body Composition ◽  
Adipose Tissue ◽  
Lean Mass ◽  
Muscle Function ◽  
The Body ◽  
Fat Free Mass ◽  
Tnf Inhibitor ◽  
Time Interaction ◽  
Few Data

Rheumatoid arthritis (RA) is associated with a decrease in lean mass and stability or even an increase in fat and ectopic adipose tissue. A few data are available on body composition changes under treatment, and data are still controversial. Body composition was assessed before initiation of biologic disease-modifying antirheumatic drug (bDMARD) and after 6 and 12 months of stable treatment. Eighty-three RA patients were included (75% of women, mean age 58.5 ± 10.8 years) of whom 47 patients treated with TNF inhibitor (TNFi), 18 with non-TNF-targeted biologic (Non-TNFi), and 18 with conventional DMARD (cDMARD) alone. In the TNFi group, total lean mass, fat-free mass index, and skeletal muscle mass index significantly increased at 1 year. An increase in subcutaneous adipose tissue (SAT) without change for the visceral or body fat composition was associated. These changes were associated with an improvement in strength and walking test. In non-TNFi or cDMARD groups, no significant changes for body composition or muscle function were observed at 1 year. However, no significant differences for treatment x time interaction were noted between group treatments. In active RA patients starting first bDMARD, treatment with TNFi over 1 year was associated with favorable changes of the body composition and muscle function.

scholarly journals Thermoneutrality induces skeletal muscle myopathy via brown adipose tissue in an IRF4- and myostatin-dependent manner

2018 ◽  
Author(s):  
Xingxing Kong ◽  
Peng Zhou ◽  
Ting Yao ◽  
Lawrence Kazak ◽  
Danielle Tenen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Exercise Capacity ◽  
Mitochondrial Function ◽  
Muscle Function ◽  
List Type ◽  
Wild Type ◽  
Brown Adipose

SummarySkeletal muscle and brown adipose tissue (BAT) share a common lineage and have been functionally linked, as exercise increases browning through the actions of various myokines. It is unknown, however, whether BAT can affect skeletal muscle function. Our prior work has shown that loss of the transcription factor IRF4 in BAT (BATI4KO) reduces adaptive thermogenesis. Here, we note that these mice also have reduced exercise capacity relative to wild-type littermates, associated with diminished mitochondrial function, ribosomal protein synthesis, and mTOR signaling in muscle, in addition to the signature ultrastructural abnormalities of tubular aggregate myopathy. Within brown adipose tissue, loss of IRF4 caused the induction of a myogenic gene expression signature, which includes an increase in the secreted factor myostatin, a known inhibitor of muscle function. Reduction of myostatin activity by the injection of neutralizing antibodies or soluble ActRIIB receptor rescued the exercise capacity of BATI4KO mice. Additionally, overexpression of IRF4 in brown adipocytes reduced serum myostatin and increased mitochondrial function and exercise capacity in muscle. A physiological role for this system is suggested by the observation that mice housed at thermoneutrality show lower exercise capacity with increased serum myostatin; both of these abnormalities are corrected by surgical removal of BAT. Collectively, our data point to an unsuspected level of BAT-muscle cross-talk driven by IRF4 and myostatin.HighlightsMice lacking IRF4 in BAT have a decrease in exercise capacity, accompanied by histological, ultrastructural, signaling, gene expression, and bioenergetic evidence of myopathy in white vastus.Loss of IRF4 promotes the expression of a myogenic signature in BAT, including the myokine myostatin.Neutralization of serum myostatin rescues the ability of BATI4KO mice to exercise normally, while overexpression of IRF4 in BAT allows mice to run better than wild-type counterparts.Thermoneutrality reduces the level of IRF4 in BAT of WT mice, resulting in a myopathic phenotype that can be reversed by surgical excision of BAT.

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

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.

scholarly journals Differential Effects of 25-Hydroxyvitamin D3 versus 1α 25-Dihydroxyvitamin D3 on Adipose Tissue Browning in CKD-Associated Cachexia

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3382
Author(s):  
Robert H. Mak ◽  
Uwe Querfeld ◽  
Alex Gonzalez ◽  
Sujana Gunta ◽  
Wai W. Cheung
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Muscle Wasting ◽  
Resting Metabolic Rate ◽  
Dihydroxyvitamin D3 ◽  
Differential Effects ◽  
Muscle Fibrosis ◽  
Tissue Browning

Patients with chronic kidney disease (CKD) often have low serum concentrations of 25(OH)D3 and 1,25(OH)2D3. We investigated the differential effects of 25(OH)D3 versus 1,25(OH)2D3 repletion in mice with surgically induced CKD. Intraperitoneal supplementation of 25(OH)D3 (75 μg/kg/day) or 1,25(OH)2D3 (60 ng/kg/day) for 6 weeks normalized serum 25(OH)D3 or 1,25(OH)2D3 concentrations in CKD mice, respectively. Repletion of 25(OH)D3 normalized appetite, significantly improved weight gain, increased fat and lean mass content and in vivo muscle function, as well as attenuated elevated resting metabolic rate relative to repletion of 1,25(OH)2D3 in CKD mice. Repletion of 25(OH)D3 in CKD mice attenuated adipose tissue browning as well as ameliorated perturbations of energy homeostasis in adipose tissue and skeletal muscle, whereas repletion of 1,25(OH)2D3 did not. Significant improvement of muscle fiber size and normalization of fat infiltration of gastrocnemius was apparent with repletion of 25(OH)D3 but not with 1,25(OH)2D3 in CKD mice. This was accompanied by attenuation of the aberrant gene expression of muscle mass regulatory signaling, molecular pathways related to muscle fibrosis as well as muscle expression profile associated with skeletal muscle wasting in CKD mice. Our findings provide evidence that repletion of 25(OH)D3 exerts metabolic advantages over repletion of 1,25(OH)2D3 by attenuating adipose tissue browning and muscle wasting in CKD mice.

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