Expression of uncoupling proteins-1, -2 and -3 mRNA is induced by an adenocarcinoma-derived lipid-mobilizing factor

Chen, Bing; Russell, Stewart; Beckett, Emily; Collins, Peter William; Taylor, Susan; Barraclough, Roger; Tisdale, Michael J.; Williams, Gareth

doi:10.1038/sj.bjc.6600101

Cited by 69 publications

(53 citation statements)

References 39 publications

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“…There was a significant increase in [ ted mice compared with PBS controls, but no difference in gastrocnemius muscle, brain, kidney or heart. This distribution correlates with what would be expected from a decrease in lipid in plasma and WAT, and an increase in lipid in liver (Bing et al, 2002).…”

Section: Resultssupporting

confidence: 58%

“…LMF has been shown not only to initiate lipolysis, but also to prime adipose tissue towards lipolytic stimuli by increasing Gas expression with a reciprocal decrease in Gai (Islam-Ali et al, 2001b). This together with the increase in UCP1 mRNA in BAT (Bing et al, 2002) after LMF suggests a role also in the disposal of excess lipid. Large amounts of micro-droplets of lipid have been shown to be deposited in hepatocytes after LMF administration (Bing et al, 2002), suggesting that lipid is mobilised at a faster rate than it can be metabolised in BAT, and that excess lipid is stored in the liver.…”

Section: Discussionmentioning

confidence: 71%

“…This together with the increase in UCP1 mRNA in BAT (Bing et al, 2002) after LMF suggests a role also in the disposal of excess lipid. Large amounts of micro-droplets of lipid have been shown to be deposited in hepatocytes after LMF administration (Bing et al, 2002), suggesting that lipid is mobilised at a faster rate than it can be metabolised in BAT, and that excess lipid is stored in the liver.…”

Section: Discussionmentioning

confidence: 92%

“…The primary effect of LMF is on lipid mobilisation and utilisation through an increased rate of lipolysis (Hirai et al, 1998), and through stimulation of increased expression of mRNA for uncoupling protein 1 (UCP1) in BAT and uncoupling protein 2 (UCP2) in BAT, skeletal muscle and liver (Bing et al, 2002). The effect of LMF on the ability of mice to deal with administered lipid was investigated by intragastric intubation with [ 14 C carboxy] triolein 48 h after treatment with either LMF or PBS and the absorption into various organs was monitored over a 6 h period (Figure 4).…”

Section: Resultsmentioning

confidence: 99%

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Effect of a tumour-derived lipid-mobilising factor on glucose and lipid metabolism in vivo

Russell

Tisdale

2002

Br J Cancer

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Treatment of ex-breeder male NMRI mice with lipid mobilising factor isolated from the urine of cachectic cancer patients, caused a significant increase in glucose oxidation to CO 2, compared with control mice receiving phosphate buffered saline. Glucose utilisation by various tissues was determined by the 2-deoxyglucose tracer technique and shown to be elevated in brain, heart, brown adipose tissue and gastrocnemius muscle. The tissue glucose metabolic rate was increased almost threefold in brain, accounting for the ability of lipid mobilising factor to decrease blood glucose levels. Lipid mobilising factor also increased overall lipid oxidation, as determined by the production of Loss of whole body fat is a prominent feature of cancer cachexia, with losses of up to 85% being reported (Fearon, 1992) in lung cancer patients, who had lost 30% of their pre-illness stable weight. Most studies suggest that loss of fat arises as a result of an increased lipolysis, together with increased whole body fatty acid oxidation. Thus increased plasma concentrations of glycerol, free fatty acids (FFA) and triglycerides were observed in a heterogeneous group of cancer patients with an average loss of 13% of their original body weight (Legaspi et al, 1987). Basal fatty acid turnover was elevated by 25% above that for controls, and was found to be similar to the rate observed for patients with severe burns. Lipolysis was increased by 40% in patients in whom complete triglyceride hydrolysis without re-esterification was observed, and there was a 20% increase in fatty acid oxidation.Upregulation of catabolism, rather than defects in anabolism, appear to be most important in the loss of lipid from human adipose tissue in cancer cachexia. Thus Thompson et al (1993) have shown a two-fold increase in the relative level of mRNA for triglyceride lipase, while the relative levels of mRNA for lipoprotein lipase (LPL) and fatty acid synthase were not significantly different between cancer patients and controls. This suggests that cytokines such as tumour necrosis factor-a (TNF-a), interleukin-1 (IL-1), interleukin-6 (IL-6), interferon-g (IFN-g) and leukaemiainhibitory factor (LIF), which have been proposed to decrease adipose tissue mass by decreasing synthesis of triglycerides through inhibition of LPL (Berg et al, 1994) probably play a minor role in the loss of lipid from human adipose tissue. It therefore seems more likely that lipid mobilisation in cancer cachexia can be attributed to tumour catabolic factors, such as lipid mobilising factor (LMF), which acts directly on adipose tissue with the release of FFA and glycerol in a manner similar to that of lipolytic hormones (Beck and Tisdale, 1987). LMF has been purified from the urine of patients with cancer cachexia using a combination of ion exchange, exclusion and hydrophobic interaction chromatographies (Todorov et al, 1998). Unlike polypeptide hormones stimulating lipolysis which are basic, LMF is acidic and showed homology in amino acid sequence, electrophoretic mobility and immunore...

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Section: Resultssupporting

confidence: 58%

Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

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Effect of a tumour-derived lipid-mobilising factor on glucose and lipid metabolism in vivo

Russell

Tisdale

2002

Br J Cancer

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“…39 In vitro, ZAG induces expression of UCP-1 protein 40 and oxygen uptake 34 in primary cultures of brown adipocytes. Treatment with ZAG has also been shown to increase UCP-2 and -3 mRNA levels in skeletal muscle in mice, 37,38 and UCP-2 and -3 protein expression in murine myotubes. 40 Hence, by upregulating UCPs in brown adipose tissue and muscle, ZAG may provide a mechanism for the utilization of excess fatty acids liberated from enhanced lipolysis.…”

Section: Zag: a Lipid-mobilizing Factormentioning

confidence: 99%

Zinc-α2-glycoprotein: an adipokine modulator of body fat mass?

et al. 2010

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The importance of white adipose tissue in the control of energy balance is now firmly recognized. In addition to fuel storage, adipocytes secrete an array of proteins factors (adipokines), which regulate multiple physiological and metabolic processes as well as influence body fat accumulation. Zinc-a2-glycoprotein (ZAG), a lipid mobilizing factor initially characterized as a tumor product associated with cachexia, has recently been identified as a novel adipokine. Although the exact role of ZAG in adipose tissue remains to be clarified, there is evidence that ZAG expression appears to be inversely related to adiposity, being upregulated in cachexia whereas reduced in obesity. Investigations on the regulation of ZAG give insights into its potential function in adipose tissue with a link to lipid mobilization and an anti-inflammatory action. Recent work shows that ZAG stimulates adiponectin secretion by human adipocytes. Data from genetic studies suggest that ZAG may be a candidate gene for body weight regulation; this is supported by the demonstration that ZAG-knockout mice are susceptible to weight gain, whereas transgenic mice overexpressing ZAG exhibit weight loss. The present review summarizes these new perspectives of ZAG and the potential mechanisms by which it might modulate adipose tissue mass and function.

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Cancer Cachexia

Eid¹,

Njeim²,

Khuri³

et al. 2022

Holland‐Frei Cancer Medicine

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Overview Cachexia is a systemic wasting syndrome of progressive muscle and, usually, adipose loss, multi‐organ dysfunction, and wide metabolic derangement, often exacerbated by anorexia and diminished nutritional intake. More than half of all cancer patients develop cachexia, which directly causes profound morbidity and substantially reduced survival. New large‐scale high‐dimensional clinical and experimental studies are revealing unexpected ground truths that cachexia frequently occurs in early stages of many cancers; has several distinct clinical phenotypes; increases complications of and reduces response to cancer‐directed therapies. More precise tools for early assessment, diagnosis, and multi‐modal interventions, including quantitative image‐based body composition analysis, molecular biomarkers, and new targeted therapeutics are in advanced development. These advances, with rapidly expanding basic research into causal molecular mechanisms, are transforming our fundamental understanding of this complex disease as being integral with cancer biology, treatment response, and patient outcomes.

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Expression of uncoupling proteins-1, -2 and -3 mRNA is induced by an adenocarcinoma-derived lipid-mobilizing factor

Cited by 69 publications

References 39 publications

Effect of a tumour-derived lipid-mobilising factor on glucose and lipid metabolism in vivo

Effect of a tumour-derived lipid-mobilising factor on glucose and lipid metabolism in vivo

Zinc-α2-glycoprotein: an adipokine modulator of body fat mass?

Cancer Cachexia

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