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Int. J. Mol. Sci. 2017, 18(5), 986; doi:10.3390/ijms18050986

Oral Treatment with the Ghrelin Receptor Agonist HM01 Attenuates Cachexia in Mice Bearing Colon-26 (C26) Tumors

1
Institute of Veterinary Physiology, University of Zurich, 8057 Zurich, Switzerland
2
Zurich Center for Human Integrative Physiology, University of Zurich, 8057 Zurich, Switzerland
3
Helsinn Healthcare SA, 6912 Pazzallo–Lugano, Switzerland
*
Author to whom correspondence should be addressed.
Academic Editor: Suzanne L. Dickson
Received: 28 February 2017 / Revised: 3 April 2017 / Accepted: 29 April 2017 / Published: 5 May 2017
(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)
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Abstract

The gastrointestinal hormone ghrelin reduces energy expenditure and stimulates food intake. Ghrelin analogs are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to investigate whether oral treatment with the non-peptidergic ghrelin receptor agonist HM01 counteracts CACS in colon-26 (C26) tumor-bearing mice. The C26 tumor model is characterized by pronounced body weight (BW) loss and muscle wasting in the absence of severe anorexia. We analyzed the time course of BW loss, body composition, muscle mass, bone mineral density, and the cytokines interleukin-6 (IL-6) and macrophage-inhibitory cytokine-1 (MIC-1). Moreover, we measured the expression of the muscle degradation markers muscle RING-finger-protein-1 (MuRF-1) and muscle atrophy F-box (MAFbx). After tumor inoculation, MIC-1 levels increased earlier than IL-6 and both cytokines were elevated before MuRF-1/MAFbx expression increased. Oral HM01 treatment increased BW, fat mass, and neuronal hypothalamic activity in healthy mice. In tumor-bearing mice, HM01 increased food intake, BW, fat mass, muscle mass, and bone mineral density while it decreased energy expenditure. These effects appeared to be independent of IL-6, MIC-1, MuRF-1 or MAFbx, which were not affected by HM01. Therefore, HM01 counteracts cachectic body weight loss under inflammatory conditions and is a promising compound for the treatment of cancer cachexia in the absence of severe anorexia. View Full-Text
Keywords: muscle wasting; bone mineral density; food intake; energy expenditure; macrophage-inhibitory cytokine-1 (MIC-1)/growth differentiation factor-15 (GDF15) muscle wasting; bone mineral density; food intake; energy expenditure; macrophage-inhibitory cytokine-1 (MIC-1)/growth differentiation factor-15 (GDF15)
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Villars, F.O.; Pietra, C.; Giuliano, C.; Lutz, T.A.; Riediger, T. Oral Treatment with the Ghrelin Receptor Agonist HM01 Attenuates Cachexia in Mice Bearing Colon-26 (C26) Tumors. Int. J. Mol. Sci. 2017, 18, 986.

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