Ghrelin ameliorates tumor-induced adipose tissue atrophy and inflammation via Ghrelin receptor-dependent and -independent pathways

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'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-/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-/-. 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 LLCinduced cachexia. GHSR-1a is required for ghrelin's orexigenic effect but not for its anti-inflammatory or fat-sparing effects.

“A LEAP 2 conclusions? Targeting the ghrelin system to treat obesity and diabetes”

“…GHSR-null mice exhibit reduced exercise tolerance when run on treadmills [ 183 ]. Also, pharmacological antagonism of GHSR and GHSR-deletion worsen anorexia/cachexia and accelerate death in tumor-bearing rodents [ 194 , 195 ]. Given these findings, activating the ghrelin system could be a viable pharmacological approach to promote food intake and defend against hypoglycemia, body weight loss, poor exercise endurance, and death during extreme nutritional challenges including severe caloric restriction and cachexia [ 4 , 183 ].…”

Growth hormone secretagogue receptor‐1a mediates ghrelin's effects on attenuating tumour‐induced loss of muscle strength but not muscle mass

“…The procedures of tumour implantation (TI) and ghrelin intervention were described previously. 7 , 15 Briefly, Lewis lung carcinoma (LLC) cells (1 × 10 6 cells American Type Culture Collection, Manassas, VA) were implanted subcutaneously into the right flank of mice in tumour‐bearing groups, while the mice in control groups were injected with equal volume and number of heat‐killed LLC cells (HK) in the same area. When the tumour was palpable (~1 cm in diameter, about 7 days after TI), the tumour‐bearing mice were treated with either acylated ghrelin (Anaspect, Fremont, CA) at a dose of 0.8 mg/kg (tumour + ghrelin, T + G) or saline solution (tumour + vehicle, T + V), s.q., twice daily, at 8 a.m. and 5 p.m., for approximately 14 days; while mice in HK groups received saline solution (15 mcl, HK + V), s.q., twice/day for 2 weeks until the endpoint (21 days after TI).…”

“…Our dose selection was based on our group's experience and that of other groups. 7 , 15 , 39 In brief, the dose selected for this study has been shown to be well‐tolerated and to induce a 5–10% weight gain and a ~10% increase in food intake. 39 These changes are clinically relevant because they are similar to those seen in recent human trials where ghrelin mimetics are being used.…”

Ghrelin and its role in gastrointestinal tract tumors (Review)

“…Its orexigenic role is well established ( 5 , 67 , 68 ); however, ghrelin also serves a function in inflammatory processes ( 69 ). The presence of ghrelin and its receptors on human leucocytes (T lymphocytes and macrophages) was noted as early as 2004 ( 70 ), with proven anti-inflammatory effects in both animal and human studies, in acute ( 71 – 74 ) and chronic settings ( 75 – 78 ), as well as in a neoplastic context ( 79 ). Ghrelin receptors have also been identified in cardiac tissue ( 80 ), where they modulate cardiac function and healing by influencing myocardial contraction ( 81 ), perfusion ( 82 ) and post-myocardial infarction-changes ( 41 , 72 , 83 ).…”