Modulation of adipocyte G-protein expression in cancer cachexia by a lipid-mobilizing factor (LMF)

Islam-Ali, B.S.; Khan, Syrah; Price, Sarah; Tisdale, Michael J.

doi:10.1054/bjoc.2001.1992

Cited by 51 publications

(24 citation statements)

References 14 publications

(12 reference statements)

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“…Dexamethasone has been shown to stimulate adenylate cyclase catalytic activity and response to GTP in fat cell membranes (Lacasa et al, 1988). Zinc-a 2 -glycoprotein has also been shown to cause a three-fold increase in lipolytic response to isoprenaline, arising from changes in GTP-binding proteins (Gproteins), with an increased expression of Gas and a decreased expression of Gai in adipose tissue (Islam-Ali et al, 2001). ), EPA (50 mM) or SR59230A (10 mM) and the various inhibitors alone in a total volume of 2 ml.…”

Section: Discussionmentioning

confidence: 99%

The role of glucocorticoids in the induction of zinc-α2-glycoprotein expression in adipose tissue in cancer cachexia

Russell

Tisdale

2005

Br J Cancer

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Loss of adipose tissue in cancer cachexia in mice bearing the MAC16 tumour arises from an increased lipid mobilisation through increased expression of zinc-a 2 -glycoprotein (ZAG) in white (WAT) and brown (BAT) adipose tissue. Glucocorticoids have been suggested to increase ZAG expression, and this study examines their role in cachexia and the mechanisms involved. In mice bearing the MAC16 tumour, serum cortisol concentrations increased in parallel with weight loss, and the glucocorticoid receptor antagonist RU38486 (25 mg kg À1 ) attenuated both the loss of body weight and ZAG expression in WAT. Dexamethasone (66 mg kg À1 ) administration to normal mice produced a six-fold increase in ZAG expression in both WAT and BAT, which was also attenuated by RU38486. In vitro studies using 3T3-L1 adipocytes showed dexamethasone (1.68 mM) to stimulate lipolysis and increase ZAG expression, and both were attenuated by RU38486 (10 mM), anti-ZAG antibody (1 mgml À1 ), and the b3-adrenoreceptor (b3-AR) antagonist SR59230A (10 mM). Zinc-a 2 -glycoprotein also increased its own expression and this was attenuated by SR59230A, suggesting that it was mediated through the b3-AR. This suggests that glucocorticoids stimulate lipolysis through an increase in ZAG expression, and that they are responsible for the increase in ZAG expression seen in adipose tissue of cachectic mice.

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Section: Discussionmentioning

confidence: 99%

The role of glucocorticoids in the induction of zinc-α2-glycoprotein expression in adipose tissue in cancer cachexia

Russell

Tisdale

2005

Br J Cancer

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“…[10][11][12][13][14][15][16] Elevated rates of lipolysis in cachexia would contribute to loss of total body fat only if lipid utilization were also increased. Indeed, clinical studies have reported elevated rates of whole body fatty acid oxidation in weight losing (10% of initial body weight) cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Adipose tissue lipolysis and energy metabolism in early cancer cachexia in mice

Kliewer

Tian

et al. 2014

Cancer Biology & Therapy

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Keywords: colon-26 adenocarcinoma, early cachexia, energy expenditure, lipid metabolism, lipolysis, thermogenesis Abbreviations: eWAT, epididymal white adipose tissue; iWAT, inguinal white adipose tissue; iBAT, interscapular brown adipose tissue; PKA, protein kinase A; ATGL, adipose triglyceride lipase; HSL, hormone sensitive lipase; UCP, uncoupling protein; PPAR, peroxisome proliferator activated receptor; PGC, peroxisome proliferator activated receptor gamma coactivator; CPT, carnitine palmitoyltransferase; DIO, iodothyronine deiodinase; MuRF, muscle ring finger protein; COX, cytochrome c oxidase subunits; GYK, glycerokinase; PRDM, PR domain zinc finger protein; ACOX, acyl CoA oxidase; CRP, C-reactive protein; LPL, lipoprotein lipase; H&E, hematoxylin and eosin; TEE, total energy expenditure; RER, respiratory exchange ratio.Cancer cachexia is a progressive metabolic disorder that results in depletion of adipose tissue and skeletal muscle. A growing body of literature suggests that maintaining adipose tissue mass in cachexia may improve quality-of-life and survival outcomes. Studies of lipid metabolism in cachexia, however, have generally focused on later stages of the disorder when severe loss of adipose tissue has already occurred. Here, we investigated lipid metabolism in adipose, liver and muscle tissues during early stage cachexia -before severe fat loss -in the colon-26 murine model of cachexia. White adipose tissue mass in cachectic mice was moderately reduced (34-42%) and weight loss was less than 10% of initial body weight in this study of early cachexia. In white adipose depots of cachectic mice, we found evidence of enhanced protein kinase A -activated lipolysis which coincided with elevated total energy expenditure and increased expression of markers of brown (but not white) adipose tissue thermogenesis and the acute phase response. Total lipids in liver and muscle were unchanged in early cachexia while markers of fatty oxidation were increased. Many of these initial metabolic responses contrast with reports of lipid metabolism in later stages of cachexia. Our observations suggest intervention studies to preserve fat mass in cachexia should be tailored to the stage of cachexia. Our observations also highlight a need for studies that delineate the contribution of cachexia stage and animal model to altered lipid metabolism in cancer cachexia and identify those that most closely mimic the human condition.

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“…32 Adipocytes from obese mice also express twofold lower levels of Gas, a stimulatory subunit of the guanosine triphosphate-binding protein, which stimulates adenylyl cyclase. 42 ZAG has been shown to increase the expression of Gas and decrease the expression of the inhibitory G-protein, Gai, in 3T3 adipocytes, 43 suggesting a mechanism by which ZAG could increase lipolytic responsiveness, in addition to the induction of HSL and ATGL. These results show that ZAG caused a major reduction in adipose mass in ob/ob mice.…”

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confidence: 99%

Studies on the antiobesity effect of zinc-α2-glycoprotein in the ob/ob mouse

Russell

Tisdale

2010

Int J Obes

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Objective: To investigate the mechanism of the lipid depletion by zinc-a 2 -glycoprotein (ZAG). Design: Studies were conducted in the ob/ob mouse, or on isolated adipocytes from these animals or their lean counterparts. Results: Treatment of these animals for 15 days with ZAG (100 mg, intravenously, daily) resulted in a reduction of body weight of 6.55 g compared with phosphate-buffered saline-treated controls, without a change in food or water intake, but with a 0.4 1C rise in rectal temperature. ZAG-treated mice had a 30% reduction in carcass fat mass and a twofold increase in weight of brown adipose tissue. Epididymal adipocytes from ZAG-treated mice showed an increased expression of ZAG and hormone-sensitive lipase (HSL), and this was maintained for a further 3 days in the absence of ZAG. There was an increased lipolytic response to isoproterenol, which was retained for 3 days in vitro in the absence of ZAG. Expression of HSL was also increased in subcutaneous and visceral adipose tissue, as was also adipose triglyceride lipase (ATGL). There was a rapid loss of labelled lipid from epididymal adipose tissue of ZAG-treated mice, but not from the other depots, reflecting the difference in sensitivity to lipolytic stimuli. The increased expression of HSL and ATGL may involve the extracellular signal-regulated kinase (ERK) pathway, as the active (phospho) form was upregulated in all adipose depots after ZAG administration, whereas in vitro studies showed induction of HSL and ATGL by ZAG to be attenuated by PD98059, an inhibitor of the ERK pathway. Conclusion: These results suggest that ZAG not only induces direct lipolysis, but also sensitizes adipose tissue to other lipolytic stimuli.

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Modulation of adipocyte G-protein expression in cancer cachexia by a lipid-mobilizing factor (LMF)

Cited by 51 publications

References 14 publications

The role of glucocorticoids in the induction of zinc-α2-glycoprotein expression in adipose tissue in cancer cachexia

The role of glucocorticoids in the induction of zinc-α2-glycoprotein expression in adipose tissue in cancer cachexia

Adipose tissue lipolysis and energy metabolism in early cancer cachexia in mice

Studies on the antiobesity effect of zinc-α2-glycoprotein in the ob/ob mouse

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