Enhanced ZAG production by subcutaneous adipose tissue is linked to weight loss in gastrointestinal cancer patients

Mráček, Tomáš; Stephens, Nathan; Gao, Dan; Bao, Yi; Ross, James A.; Rydén, Mikael; Trayhurn, Paul; Fearon, Kenneth C. H.; Chen, Bing

doi:10.1038/sj.bjc.6606083

Cited by 104 publications

(118 citation statements)

References 40 publications

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“…Similar to the loss in muscle mass, the most rapid loss of fat in patients with colorectal liver metastases occurs within 2 mo of death (19). In addition to the loss of fat mass, patients with cancer cachexia experience adipose tissue remodeling characterized by the shrinkage of adipocytes and an increase in interstitial spaces (21). Similar to humans, MoCR mice had a loss of fat mass, reduced adipocyte size, and an increased proportion of nonadipocyte tissue.…”

Section: R861mentioning

confidence: 83%

Physiological characterization of a mouse model of cachexia in colorectal liver metastases

Murphy

Struk

Malcontenti‐Wilson

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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(cachexia) is severe in patients with colorectal liver metastases because of the large increase in resting energy expenditure but remains understudied because of a lack of suitable preclinical models. Our aim was to characterize a novel preclinical model of cachexia in colorectal liver metastases. We tested the hypothesis that mice with colorectal liver metastases would exhibit cachexia, as evidenced by a reduction in liver-free body mass, muscle mass, and physiological impairment. Twelve-week-old male CBA mice received an intrasplenic injection of Ringer solution (sham) or murine colorectal cancer cells (MoCR) to induce colorectal liver metastases. At end-point (20 -29 days), the livers of MoCR mice were infiltrated completely with metastases, and MoCR mice had reduced liver-free body mass, muscle mass, and epididymal fat mass compared with sham controls (P Ͻ 0.03). MoCR mice exhibited impaired rotarod performance and grip strength (P Ͻ 0.03). Histochemical analyses of tibialis anterior muscles from MoCR mice revealed muscle fiber atrophy and reduced oxidative enzyme activity (P Ͻ 0.001). Adipose tissue remodeling was evident in MoCR mice, with reduced adipocyte diameter and greater infiltration of nonadipocyte tissue (P Ͻ 0.05). These findings reveal the MoCR mouse model exhibits significant cachexia and is a suitable preclinical model of cachexia in colorectal liver metastases. This model should be used for identifying effective treatments for cachexia to improve quality of life and reduce mortality in patients with colorectal liver metastases. muscle wasting; cancer cachexia; muscle weakness; colorectal liver metastases CANCER CACHEXIA IS DEFINED as a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support, leading to progressive functional impairment (8). Cachexia occurs in up to 80% of patients with advanced cancers of the gastrointestinal tract, colon, lung, breast, sarcoma, and prostate (33). It is also present early in the progression of gastrointestinal, pancreatic, and lung cancers (33). Cachexia reduces mobility and functional independence and causes severe fatigue, which together reduce overall quality of life (26). Cachexia can also increase the risk of postoperative complications, impair the response to antineoplastic treatments, and result in the eventual failure of respiratory and cardiac muscle function that causes 20 -30% of all cancer-related deaths (33). Unfortunately, there is no Food and Drug Administration-approved treatment for cancer cachexia, and this is due, at least in part, to a lack of suitable preclinical models that closely mimic the human condition for maximizing translational outcomes (24).Colorectal cancer is the third most common cancer worldwide and is the fourth-most common cause of cancer-related death (9). The most frequent complication of colorectal cancer is the development of liver metastases, which occurs in 70% of cases and is the main cause ...

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Section: R861mentioning

confidence: 83%

Physiological characterization of a mouse model of cachexia in colorectal liver metastases

Murphy

Struk

Malcontenti‐Wilson

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…However, in agreement with Raiszadeh et al, the present data do not support the notion that IL-6 is present in sweat in detectable levels and we suggest that measurement of IL-6 in sweat is not a valid or reliable measurement of systemic IL-6. Moreover, of 180 proteins identified in sweat, only albumin, zinc α2 glycoprotein, gelsolin, apolipoprotein D and clusterin 1 were present in both sweat and plasma (Raiszadeh et al 2012), indicating that future work aimed at using sweat as a potential vehicle for biomarkers or disease should focus on these proteins, as they have already been linked to a number of diseases and pathological conditions (Ceperuelo-Mallafré et al 2009;Dubois et al 2010;Hassan et al 2008;Mracek et al 2011;Rydén et al 2012;Yang et al 2013). …”

Section: )mentioning

confidence: 99%

The detection and measurement of interleukin-6 in venous and capillary blood samples, and in sweat collected at rest and during exercise

et al. 2014

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“…In cachectic cancer patients ZAG mRNA showed a negative correlation with body mass index (BMI), but a positive correlation with weight loss and serum glycerol levels (4). In contrast ZAG mRNA levels in WAT have been shown to be down regulated in obesity and correlated negatively with fat mass, BMI, plasma insulin and leptin (5).…”

mentioning

confidence: 99%

“…Later studies showed that ZAG was also produced in normal tissues including liver, brown adipose tissue (BAT) and white adipose tissue (WAT) (3), so that ZAG can be classified as an adipokine. Moreover, in both cachectic mice (3) and humans (4) expression of ZAG mRNA in WAT was found to be increased 10-fold (3) and 2.7-fold (4) respectively.…”

mentioning

confidence: 99%

Role of β-adrenergic receptors in the anti-obesity and anti-diabetic effects of zinc-α2-glycoprotien (ZAG)

Russell

Tisdale

2012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Objectives:The goal of the current study is to determine whether the -adrenoreceptor (-AR) plays a role in the anti-obesity and anti-diabetic effects of zinc-2-glycoprotein (ZAG). Material and Methods:This has been investigated in CHO-K1 cells transfected with the human 1-, 2-, 3-AR and in ob/ob mice. Cyclic AMP assays were carried out along with binding studies. Ob/ob mice were treated with ZAG and glucose transportation and insulin were examined in the presence or absence of propranonol.Results: ZAG bound to the 3-AR with higher affinity (Kd 46+1nM) than the 2-AR (Kd 71+3nM) while there was no binding to the 1-AR, and this correlated with the increases in cyclic AMP in CHO-K1 cells transfected with the various -AR and treated with ZAG. Treatment of ob/ob mice with ZAG increased protein expression of 3-AR in gastrocnemius muscle, and in white and brown adipose tissue, but had no effect on expression of 1-and 2-AR. A reduction of body weight was seen and urinary glucose excretion, increase in body temperature, reduction in maximal plasma glucose and insulin levels in the oral glucose tolerance test, and stimulation of glucose transport into skeletal muscle and adipose tissue, was completely attenuated by the non-specific -AR antagonist propranolol. Conclusion:The results suggest that the effects of ZAG on body weight and insulin sensitivity in ob/ob mice are manifested through a -3AR, or possibly a 2-AR.

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Enhanced ZAG production by subcutaneous adipose tissue is linked to weight loss in gastrointestinal cancer patients

Cited by 104 publications

References 40 publications

Physiological characterization of a mouse model of cachexia in colorectal liver metastases

Physiological characterization of a mouse model of cachexia in colorectal liver metastases

The detection and measurement of interleukin-6 in venous and capillary blood samples, and in sweat collected at rest and during exercise

Role of β-adrenergic receptors in the anti-obesity and anti-diabetic effects of zinc-α2-glycoprotien (ZAG)

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