Ghrelin ameliorates tumor-induced adipose tissue atrophy and inflammation <i>via</i> Ghrelin receptor-dependent and -independent pathways

Abstract

// Haiming Liu 1 , 2 , * , Jiaohua Luo 3 , 4 , * , Bobby Guillory 3 , Ji-an Chen 3 , 5 , Pu Zang 3 , 6 , Jordan K. Yoeli 3 , Yamileth Hernandez 3 , Ian (In-gi) Lee 1 , 2 , Barbara Anderson 1 , 2 , Mackenzie Storie 1 , 2 , Alison Tewnion 1 and Jose M. Garcia 1 , 2 , 3 1 Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA 2 Gerontology and Geriatric Medicine, University of Washington Department of Medicine, Seattle, WA, USA 3 Division of Endocrinology, Diabetes and Metabolism, MCL, Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Department of Medicine, Baylor College of Medicine, Houston, TX, USA 4 Department of Environmental Hygiene, College of Preventive Medicine, Army Medical University, Chongqing, China 5 Department of Health Education, College of Preventive Medicine, Army Medical University, Chongqing, China 6 Department of Endocrinology, Nanjing Jinling Hospital, Nanjing, China * These authors contributed equally to this work Correspondence to: Jose M. Garcia, email: jose.garcia@va.gov Keywords: cachexia; cancer; muscle; ghrelin; adipose tissue Received: January 29, 2020&emsp;&emsp;&emsp;&emsp; Accepted: July 21, 2020&emsp;&emsp;&emsp;&emsp; Published: September 01, 2020 ABSTRACT Adipose tissue (AT) atrophy is a hallmark of cancer cachexia contributing to increased morbidity/mortality. Ghrelin has been proposed as a treatment for cancer cachexia partly by preventing AT atrophy. However, the mechanisms mediating ghrelin&#x2019;s effects are incompletely understood, including the extent to which its only known receptor, GHSR-1a, is required for these effects. This study characterizes the pathways involved in AT atrophy in the Lewis Lung Carcinoma (LLC)-induced cachexia model and those mediating the effects of ghrelin in Ghsr +/+ and Ghsr &#x2013;/&#x2013; mice. We show that LLC causes AT atrophy by inducing anorexia, and increasing lipolysis, AT inflammation, thermogenesis and energy expenditure. These changes were greater in Ghsr &#x2013;/&#x2013; . Ghrelin administration prevented LLC-induced anorexia only in Ghsr +/+ , but prevented WAT lipolysis, inflammation and atrophy in both genotypes, although its effects were greater in Ghsr +/+ . LLC-induced increases in BAT inflammation, WAT and BAT thermogenesis, and energy expenditure were not affected by ghrelin. In conclusion, ghrelin ameliorates WAT inflammation, fat atrophy and anorexia in LLC-induced cachexia. GHSR-1a is required for ghrelin&#x2019;s orexigenic effect but not for its anti-inflammatory or fat-sparing effects.