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Alcohol intake aggravates adipose browning and muscle atrophy in cancer-associated cachexia.

ABSTRACT: Cancer is commonly associated with cachexia, a paraneoplastic syndrome characterized by body weight loss, muscle wasting, adipose tissue atrophy and inflammation. Chronic alcohol consumption increases the risk of multiple types of cancer, and enhances cancer-associated cachexia (CAC), but the underlying mechanisms remain poorly defined. To test, C57BL/6 mice were fed with 0% or 20% (w/v) alcohol for 3 months, then inoculated with B16BL6 melanoma cells subcutaneously in the right side of the hip and continued to feed with/without alcohol for 3 or 4 weeks. Alcohol intake upregulated ALDH1A1 expression and elevated retinoic acid (RA) content in inguinal white adipose tissue (iWAT), which led to enhanced iWAT browning and brown adipose tissue (BAT) activation, accelerating fat loss. Moreover, alcohol increased muscle loss through augmenting muscle protein degradation, cell apoptosis and inflammation. In addition, alcohol reduced satellite cell density and impaired myogenesis in skeletal muscle. Taken together, alcohol aggravates cancer-associated cachexia at least partially through elevating adipose browning and muscle atrophy.

SUBMITTER: Wang B

PROVIDER: S-EPMC5725030 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Alcohol intake aggravates adipose browning and muscle atrophy in cancer-associated cachexia.

Wang Bo B Zhang Faya F Zhang Hui H Wang Zhixiu Z Ma Yan-Nan YN Zhu Mei-Jun MJ Du Min M

Oncotarget 20171101 59

Cancer is commonly associated with cachexia, a paraneoplastic syndrome characterized by body weight loss, muscle wasting, adipose tissue atrophy and inflammation. Chronic alcohol consumption increases the risk of multiple types of cancer, and enhances cancer-associated cachexia (CAC), but the underlying mechanisms remain poorly defined. To test, C57BL/6 mice were fed with 0% or 20% (w/v) alcohol for 3 months, then inoculated with B16BL6 melanoma cells subcutaneously in the right side of the hip ...[more]

PMID: 29245988

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Project description:BackgroundCtns-/- mice, a mouse model of infantile nephropathic cystinosis, exhibit hypermetabolism with adipose tissue browning and profound muscle wasting. Ctns-/- mice are 25(OH)D3 and 1,25(OH)2 D3 insufficient. We investigated whether vitamin D repletion could ameliorate adipose tissue browning and muscle wasting in Ctns-/- mice.MethodsTwelve-month-old Ctns-/- mice and wild-type controls were treated with 25(OH)D3 and 1,25(OH)2 D3 (75 μg/kg/day and 60 ng/kg/day, respectively) or an ethylene glycol vehicle for 6 weeks. Serum chemistry and parameters of energy homeostasis were measured. We quantitated total fat mass and studied expression of molecules regulating adipose tissue browning, energy metabolism, and inflammation. We measured lean mass content, skeletal muscle fibre size, in vivo muscle function (grip strength and rotarod activity), and expression of molecules regulating muscle metabolism. We also analysed the transcriptome of skeletal muscle in Ctns-/- mice using RNAseq.ResultsSupplementation of 25(OH)D3 and 1,25(OH)2 D3 normalized serum concentration of 25(OH)D3 and 1,25(OH)2 D3 in Ctns-/- mice, respectively. Repletion of vitamin D partially or fully normalized food intake, weight gain, gain of fat, and lean mass, improved energy homeostasis, and attenuated perturbations of uncoupling proteins and adenosine triphosphate content in adipose tissue and muscle in Ctns-/- mice. Vitamin D repletion attenuated elevated expression of beige adipose cell biomarkers (UCP-1, CD137, Tmem26, and Tbx1) as well as aberrant expression of molecules implicated in adipose tissue browning (Cox2, Pgf2α, and NF-κB pathway) in inguinal white adipose tissue in Ctns-/- mice. Vitamin D repletion normalized skeletal muscle fibre size and improved in vivo muscle function in Ctns-/- mice. This was accompanied by correcting the increased muscle catabolic signalling (increased protein contents of IL-1β, IL-6, and TNF-α as well as an increased gene expression of Murf-2, atrogin-1, and myostatin) and promoting the decreased muscle regeneration and myogenesis process (decreased gene expression of Igf1, Pax7, and MyoD) in skeletal muscles of Ctns-/- mice. Muscle RNAseq analysis revealed aberrant gene expression profiles associated with reduced muscle and neuron regeneration, increased energy metabolism, and fibrosis in Ctns-/- mice. Importantly, repletion of 25(OH)D3 and 1,25(OH)2 D3 normalized the top 20 differentially expressed genes in Ctns-/- mice.ConclusionsWe report the novel findings that correction of 25(OH)D3 and 1,25(OH)2 D3 insufficiency reverses cachexia and may improve quality of life by restoring muscle function in an animal model of infantile nephropathic cystinosis. Mechanistically, vitamin D repletion attenuates adipose tissue browning and muscle wasting in Ctns-/- mice via multiple cellular and molecular mechanisms.

Dataset Information

Alcohol intake aggravates adipose browning and muscle atrophy in cancer-associated cachexia.

Publications

Alcohol intake aggravates adipose browning and muscle atrophy in cancer-associated cachexia.

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