Tumor-induced anorexia and weight loss are mediated by the TGF-β superfamily cytokine MIC-1

Johnen, Heiko; Lin, Shu; Kuffner, Támara; Brown, David A.; Tsai, Vicky Wang-Wei; Bauskin, Asne R.; Wu, Liyun; Pankhurst, Greg J.; Jiang, Lele; Junankar, Simon; Hunter, Mark; Fairlie, W. Douglas; Lee, Nicola J.; Enriquez, Ronaldo F.; Baldock, Paul A.; Corey, Eva; Apple, Fred S.; Murakami, MaryAnn M.; Lin, En Ju; Wang, Chuansong; During, Matthew J.; Sainsbury, Amanda; Herzog, Herbert; Breit, Samuel N.

doi:10.1038/nm1677

Cited by 495 publications

(533 citation statements)

References 22 publications

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“…processes and cancer (7,10,12). Recent data indicated a direct role for MIC-1 in energy homeostasis regulation in cachectic conditions making it a potentially interesting candidate molecule to modulate food intake and/or body adiposity (14). Here, we show that human obesity is associated, similarly to cancer (8-10) and inflammatory conditions of different etiology (7), with significantly higher serum MIC-1 levels.…”

Section: Discussionmentioning

confidence: 53%

“…MIC-1 was also identified as a predictor of cardiovascular events in a cohort of previously healthy women (11,12) and as an early mediator of the injury response in kidney and lung (13). Recently, a key role of increased MIC-1 concentrations in the induction of cancer-related anorexia and weight loss in animals and humans was described (14).…”

Section: Introductionmentioning

confidence: 99%

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Increased serum concentrations of macrophage inhibitory cytokine-1 in patients with obesity and type 2 diabetes mellitus: the influence of very low calorie diet

Dostálová

Roubíček²,

Bartlova³

et al. 2009

European Journal of Endocrinology

138

136

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Objective: Macrophage inhibitory cytokine-1 (MIC-1) is a novel regulator of energy homeostasis. We explored whether alterations in MIC-1 levels contribute to metabolic disturbances in patients with obesity and/or obesity and type 2 diabetes mellitus (T2DM). Design: We measured serum MIC-1 levels and its mRNA expression in subcutaneous and visceral adipose tissue of 17 obese nondiabetic women, 14 obese women with T2DM and 23 healthy lean women. We also explored the relationship of MIC-1 with anthropometric and biochemical parameters and studied the influence of 2-week very low calorie diet (VLCD) on serum MIC-1 levels. Methods: Serum MIC-1 levels were measured by ELISA and its mRNA expression was determined by RT-PCR. Results: Both obese and T2DM group had significantly elevated serum MIC-1 levels relative to controls. T2DM group had significantly higher serum MIC-1 levels relative to obese group. Serum MIC-1 positively correlated with body weight, body fat, and serum levels of triglycerides, glucose, HbAlc, and C-reactive protein and it was inversely related to serum high-density lipoprotein cholesterol. Fat mRNA MIC-1 expression did not significantly differ between lean and obese women but it was significantly higher in subcutaneous than in visceral fat in both groups. VLCD significantly increased serum MIC-1 levels in obese but not T2DM group. Conclusion: Elevated MIC-1 levels in patients with obesity are further increased by the presence of T2DM. We suggest that in contrast to patients with cancer cachexia, increased MIC-1 levels in obese patients and diabetic patients do not induce weight loss.

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Section: Discussionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Increased serum concentrations of macrophage inhibitory cytokine-1 in patients with obesity and type 2 diabetes mellitus: the influence of very low calorie diet

Dostálová

Roubíček²,

Bartlova³

et al. 2009

European Journal of Endocrinology

138

136

View full text Add to dashboard Cite

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“…injection, mice were deeply anaesthetized with ketamine/xylazine (100 and 20 mg/kg from Parke Davis-Pfizer, Sydney, Australia and Bayer AG, Leverkusen, Germany, respectively) and perfused via the left ventricle and right carotid artery with 25 ml phosphate buffered saline following by ice-cold 4% paraformaldehyde in phosphate buffered saline. Our previous experience with another molecule that regulates food intake, macrophage inhibitory cytokine-1 (MIC-1) (Johnen et al, 2007), revealed that this 30 min time point is important for determining specific neurons in the brain that are activated after peripheral administration of MIC-1. However, to more comprehensively investigate the activation of c-Fos in response to i.p.…”

Section: Immunohistochemistry For Determination Of Pp-induced Changesmentioning

confidence: 99%

Y4 receptors and pancreatic polypeptide regulate food intake via hypothalamic orexin and brain-derived neurotropic factor dependent pathways

et al. 2010

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Gut-derived peptides are known to regulate food intake by activating specific receptors in the brain, but the target nuclei and neurons influenced are largely unknown. Here we show that peripherally administered pancreatic polypeptide (PP) stimulates neurons in key nuclei of the hypothalamus critical for appetite and satiety regulation. In the lateral hypothalamic area (LHA), also known as the feeding center, neurons expressing the orexigenic neuropeptide orexin co-localize with the early neuronal activation marker c-Fos upon i.p. injection of PP into mice. In the ventromedial hypothalamus (VMH), also known as the satiety center, neurons activated by PP, as indicated by induction of c-Fos immunoreactivity, express the anorexigenic brain-derived neurotrophic factor (BDNF). Activation of neurons in the LHA and VMH in response to PP occurs via a Y4 receptor-dependent process as it is not seen in Y4 receptor knockout mice. We further demonstrate that in response to i.p. PP, orexin mRNA expression in the LHA is down-regulated, with Y4 receptors being critical for this effect as it is not seen in Y4 receptor knockout mice, whereas BDNF mRNA expression is up-regulated in the VMH in response to i.p. PP in the fasted, but not in the non-fasted state. Taken together these data suggest that PP can regulate food intake by suppressing orexigenic pathways by down-regulation of orexin and simultaneously increasing anorexigenic pathways by upregulating BDNF.

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“…In prostate cancer bone metastases, MIC-1 induced osteoclast activation (Wakchoure et al, 2009). In mice bearing human prostate cancer xenografts, elevated MIC-1 concentrations were associated with marked weight, fat, and lean tissue loss that was mediated by decreased food intake and was reversed by an antibody to MIC-1 (Johnen et al, 2007). In addition, normal mice administered systemic MIC-1, and transgenic mice overexpressing MIC-1, showed hypophagia and reduced body weight (Johnen et al, 2007).…”

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confidence: 99%

Plasma MIC-1 correlates with systemic inflammation but is not an independent determinant of nutritional status or survival in oesophago-gastric cancer

et al. 2010

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BACKGROUND: Macrophage inhibitory cytokine-1(MIC-1) is a potential modulator of systemic inflammation and nutritional depletion, both of which are adverse prognostic factors in oesophago-gastric cancer (OGC). METHODS: Plasma MIC-1, systemic inflammation (defined as plasma C-reactive protein (CRP) of X10 mg l -1 or modified Glasgow prognostic score (mGPS) of X1), and nutritional status were assessed in newly diagnosed OGC patients (n ¼ 293). Healthy volunteers (n ¼ 35) served as controls. RESULTS: MIC-1 was elevated in patients (median ¼ 1371 pg ml -1 ; range 141 -39 053) when compared with controls (median ¼ 377 pg ml -1 ; range 141 -3786; Po0.001). Patients with gastric tumours (median ¼ 1592 pg ml -1 ; range 141 -12 643) showed higher MIC-1 concentrations than patients with junctional (median ¼ 1337 pg ml -1 ; range 383 -39 053) and oesophageal tumours (median ¼ 1180 pg ml -1 ; range 258 -31 184; P ¼ 0.015). Patients showed a median weight loss of 6.4% (range 0.0 -33.4%), and 42% of patients had an mGPS of X1 or plasma CRP of X10 mg l -1 (median ¼ 9 mg l -1 ; range 1 -200). MIC-1 correlated positively with disease stage (r 2 ¼ 0.217; Po0.001), age (r 2 ¼ 0.332; Po0.001), CRP (r 2 ¼ 0.314; Po0.001), and mGPS (r 2 ¼ 0.336; Po0.001), and negatively with Karnofsky Performance Score (r 2 ¼ À0.269; Po0.001). However, although MIC-1 correlated weakly with dietary intake (r 2 ¼ 0.157; P ¼ 0.031), it did not correlate with weight loss, BMI, or anthropometry. Patients with MIC-1 levels in the upper quartile showed reduced survival (median ¼ 204 days; 95% CI 157 -251) when compared with patients with MIC-1 levels in the lower three quartiles (median ¼ 316 days; 95% CI 259 -373; P ¼ 0.036), but MIC-1 was not an independent prognostic indicator. CONCLUSIONS: There is no independent link between plasma MIC-1 levels and depleted nutritional status or survival in OGC.

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Tumor-induced anorexia and weight loss are mediated by the TGF-β superfamily cytokine MIC-1

Cited by 495 publications

References 22 publications

Increased serum concentrations of macrophage inhibitory cytokine-1 in patients with obesity and type 2 diabetes mellitus: the influence of very low calorie diet

Increased serum concentrations of macrophage inhibitory cytokine-1 in patients with obesity and type 2 diabetes mellitus: the influence of very low calorie diet

Y4 receptors and pancreatic polypeptide regulate food intake via hypothalamic orexin and brain-derived neurotropic factor dependent pathways

Plasma MIC-1 correlates with systemic inflammation but is not an independent determinant of nutritional status or survival in oesophago-gastric cancer

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