Rosiglitazone delayed weight loss and anorexia while attenuating adipose depletion in mice with cancer cachexia

Michelle, L.; Tian, Min; Kliewer, Kara; Belury, Martha A.

doi:10.4161/cbt.12.11.18134

Cited by 39 publications

(39 citation statements)

References 31 publications

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“…Tumor mass (1125 § 127 mg) was markedly lower than in our previous studies of late cachexia. 31,32 Compared to the No Tumor group, final tumor-free body weight and muscle mass in the Tumor group were each reduced 13% but were not different from the Pairfed group (Fig. 1B and C).…”

Section: Effects Of Colon-26 Carcinoma On Adipose and Muscle Tissues mentioning

confidence: 92%

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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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Section: Effects Of Colon-26 Carcinoma On Adipose and Muscle Tissues mentioning

confidence: 92%

“…Because C-26 carcinoma may induce anorexia in mice, 31,32 we included a pair-fed group in our study to determine effects of tumor independent of food intake. Cumulative food intake in the Tumor group was significantly lower compared to the No Tumor group beginning on day 11 of the study (Fig.…”

Section: Effects Of Colon-26 Carcinoma On Adipose and Muscle Tissues mentioning

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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“…The role of insulin signaling in preventing cachexia is further stressed by experimental data showing that mice treated with insulin sensitizers (rosiglitazone) 39, 162 and patients treated with insulin ameliorate cachexia symptoms. 163 …”

Section: Introductionmentioning

confidence: 99%

Understanding cachexia as a cancer metabolism syndrome

2016

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Metabolic reprogramming occurs in tumors to foster cancer cell proliferation, survival and metastasis, but as well at a systemic level affecting the whole organism, eventually leading to cancer cachexia. Indeed, as cancer cells rely on external sources of nitrogen and carbon skeleton to grow, systemic metabolic deregulation promoting tissue wasting and metabolites mobilization ultimately supports tumor growth. Cachectic patients experience a wide range of symptoms affecting several organ functions such as muscle, liver, brain, immune system and heart, collectively decreasing patients' quality of life and worsening their prognosis. Moreover, cachexia is estimated to be the direct cause of at least 20% of cancer deaths. The main aspect of cachexia syndrome is the unstoppable skeletal muscle and fat storage wasting, even with an adequate caloric intake, resulting in nutrient mobilization – both directly as lipid and amino acids and indirectly as glucose derived from the exploitation of liver gluconeogenesis – that reaches the tumor through the bloodstream. From a metabolic standpoint, cachectic host develops a wide range of dysfunctions, from increased insulin and IGF-1 resistance to induction of mitochondrial uncoupling proteins and fat tissue browning resulting in an increased energy expenditure and heat generation, even at rest. For a long time, cachexia has been merely considered an epiphenomenon of end-stage tumors. However, in specific tumor types, such as pancreatic cancers, it is now clear that patients present markers of tissue wasting at a stage in which tumor is not yet clinically detectable, and that host amino acid supply is required for tumor growth. Indeed, tumor cells actively promote tissue wasting by secreting specific factors such as parathyroid hormone-related protein and micro RNAs. Understanding the molecular and metabolic mediators of cachexia will not only advance therapeutic approaches against cancer, but also improve patients' quality of life.

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“…Similarly, no effect on body weight gain was recoreded in the same experimental model using pioglitazone although higher pioglitazone dose (100 ppm in a diet) increased food intake and insignificantly periovarial fat weight too [52]. Asp et al [53] reported initial weight loss delay and adipose depletion attenuation in mice with cancer cachexia administered with ROS, which, however, did not persist, food intake eventually declined as well. It seems that ROS cannot prevent weight loss in cancer subjects (which is mostly mediated by inflammatory cytokines) regardless of changes in food intake.…”

Section: Discussionmentioning

confidence: 95%

Rosiglitazone Shows Partial Oncostatic Effect in Rat Mammary Carcinogenesis

Bojková

Kajo²,

Garajová³

et al. 2012

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Peroral antidiabetics from thiazolidinedione (glitazone) group showed oncostatic effects in preclinical models. This study evaluated chemopreventive effects of rosiglitazone in N-methyl-N-nitrosourea-induced mammary carcinogenesis in rats. N-methyl-N-nitrosourea was administered in two intraperitoneal doses each per 50 mg/kg b.w. between 40 th and 51 st postnatal days. Rosiglitazone was administered in a diet at a concentration of 10 ppm and 100 ppm, respectively, 9 days before the first carcinogen dose until the termination of the experiment. During the experiment the animals were weekly weighed and palpated for the presence of mammary tumors and estimation of latency period, tumor frequency per group and animal, and tumor volume were recorded. The experiment was terminated 16 weeks after the first carcinogen dose, basic tumor growth parameters and selected metabolic and hormonal variables were evaluated. Chemoprevention with higher rosiglitazone dose decreased tumor frequency per group by 44%, other tumor parameters (incidence, tumor frequency per animal) were decreased insignificantly (at both doses), latency period was not changed. Rosiglitazone administration decreased cumulative tumor volume, more efficiently at lower dose. Glycaemia and insulinaemia decreased after lower rosigitazone dose administration but glycaemia did not exceed normal values. Higher rosiglitazone dose alleviated some metabolic alterations resulting from cancer progression more effectively but induced a prominent cardiac hypertrophy.

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Rosiglitazone delayed weight loss and anorexia while attenuating adipose depletion in mice with cancer cachexia

Cited by 39 publications

References 31 publications

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

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

Understanding cachexia as a cancer metabolism syndrome

Rosiglitazone Shows Partial Oncostatic Effect in Rat Mammary Carcinogenesis

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