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 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 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 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 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 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.

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 Influence of the presence of OB-Re on leptin radioimmunoassay

2001 ◽  
Vol 168 (1) ◽  
pp. 79-86 ◽  
Author(s):  
T Murakami ◽  
S Otani ◽  
T Honjoh ◽  
T Doi ◽  
K Shima
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Serum Levels ◽  
Mouse Serum ◽  
Serum Leptin ◽  
Mouse Placenta ◽  
Pregnant State

Leptin, a hormone derived from adipose tissue, regulates energy homeostasis and body weight. In the mouse, serum leptin levels, when measured by radioimmunoassay (RIA), increase by a factor of more than 50 times during pregnancy, compared with those in the non-pregnant state. It is well known that mouse placenta produces the secretory isoform of the leptin receptor, OB-Re. In order to investigate the issue of whether serum leptin levels are actually increased during pregnancy or whether the increased OB-Re concentration plays a role in this phenomenon, serum leptin levels were determined by the immunoprecipitation of leptin using anti-leptin antibody, and were found to be increased only by about ten times during pregnancy. To investigate the influence of OB-Re on leptin measurement by the RIA procedure, serum leptin levels were measured by the RIA after the addition of OB-Re to the serum. The apparent values of leptin levels increased in parallel with the amount of OB-Re added to the serum. Leptin levels, as determined by the RIA, might therefore provide artificially high values when serum levels of the secretory form of OB-R are high, in cases, for example, such as the last period of pregnancy in mice.

Aging Influences the Value of Serum Leptin as Prostate Cancer Risk Factor

2013 ◽  
Vol 09 (01) ◽  
pp. 10 ◽  
Author(s):  
Mauro Bologna ◽  
Patrizia Sanità ◽  
Carlo Vicentini ◽  
Adriano Angelucci ◽  
◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Adipose Tissue ◽  
Risk Factor ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Prostate Cancer Risk ◽  
Visceral Obesity ◽  
Whole Body ◽  
Serum Leptin ◽  
Inflammatory Status

Depository fat functions as endocrine tissue able to regulate whole-body energy homeostasis. Obesity and aging are independently associated with a deregulation of adipose tissue, resulting in pro-inflammatory status and excessive release of adipokines. These events are under investigation for a possible synergism in determining chronic diseases, including cardiovascular illnesses and several types of cancer. Our data, obtained through an observational study conducted with prostate cancer patients, confirmed the association of leptin, an adipose tissue-derived adipokine, with cancer, and suggested that serum leptin represents a stronger risk factor for prostate cancer (PCa) in older than in younger subjects. In elderly patients, visceral obesity measured by waist to hip ratio provided a better correlation with serum leptin in terms of body mass index (BMI) measurements and appeared to be a more adequate indicator for obesity. The expression of leptin receptor mainly observed in invasive prostate carcinoma tissue and in aggressive prostate cancer cell lines suggests a possible molecular link between persistently high leptin levels, seen in aged obese subjects, and PCa progression.

scholarly journals Perirenal White Adipose Tissue Browning and Epithelial-Mesenchymal Transition, Contributes To Tumor Development in Kidney Cancer

2021 ◽  
Author(s):  
Matias Ferrando ◽  
Flavia Bruna ◽  
Leonardo Romeo ◽  
David Contador ◽  
Daiana Moya-Morales ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Kidney Cancer ◽  
White Adipose Tissue ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Development ◽  
Human Kidney ◽  
Mesenchymal Transition ◽  
Epithelial Cell Lines ◽  
And Control ◽  
Tissue Browning

Abstract Tumor cells can interact with neighboring adipose tissue and adipocyte dedifferentiation appears to be an important aspect of tumorigenesis. We evaluated the size of adipocytes in human adipose explants from normal (hRAN) and kidney cancer (hRAT); changes in the expression of WAT and BAT/beige markers in hRAN and hRAT; and changes in the expression of epithelial-mesenchymal transition (EMT) cell markers; in human kidney tumor (786-O, ACHN and Caki-1) and non-tumor (HK-2) epithelial cell lines incubated with the conditioned media (CMs) of hRAN and hRAT. We observed that hRAT adipocytes showed a significantly minor size compared to hRAN adipocytes. Also, we observed that both Prdm16 and Tbx1 mRNA and the expression of UCP1, TBX1, PPARγ, PCG1α, c/EBPα LAP and c/EBPα LIP was significantly higher in hRAT than hRAN. Finally, we found an increase in vimentin and N-cadherin expression in HK-2 cell incubated for 24 h with hRAT-CMs compared to hRAN- and control-CMs. Furthermore, desmin and N-cadherin expression also increased significantly in 786-O when these cells were incubated with hRAT-CMs compared to the value observed with hRAN- and control-CMs. The results obtained, together with the results previously published by our group, allow us to conclude that perirenal white adipose tissue browning and epithelial-mesenchymal transition, contributes to tumor development in kidney cancer.

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