Oncotarget: Ghrelin ameliorates tumor-induced adipose tissue atrophy and inflammation

Oncotarget Volume 11, Issue 35 published "Ghrelin ameliorates tumor-induced adipose tissue atrophy and inflammation via Ghrelin receptor-dependent and -independent pathways" by Liu et. al which reported that Ghrelin has been proposed as a treatment for cancer cachexia partly by preventing AT atrophy.

This study characterizes the pathways involved in AT atrophy in the Lewis Lung Carcinoma -induced cachexia model and those mediating the effects of ghrelin in Ghsr / and Ghsr–/– mice.

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.

Dr. Jose M. Garcia from The Veterans Affairs Puget Sound Health Care System, The University of Washington Department of Medicine, as well as The Baylor College of Medicine said, "Cachexia, defined as an involuntary loss of muscle and adipose tissue, is present in 15–65% of cancer patients depending on the tumor type, and it is strongly associated with poor outcomes."

Accelerated loss of adipose tissue plays an important role in cancer cachexia contributing significantly to the increased morbidity and mortality.

Ghrelin has also been proposed as a promising target for cancer cachexia and it has been shown to prevent fat atrophy in tumor-bearing animals and in patients with cancer cachexia.

To the researcher's knowledge, the extent to which ghrelin's effects on adipose tissue atrophy and metabolism in cancer cachexia are mediated by GHSR-1a is not known.

Figure 6: Indirect calorimetry measurements by CLAMS. (A) HK+V: heat-killed + vehicle; T+V: tumor + vehicle; T+G: tumor + ghrelin. (A–B) Energy expenditure (EE) adjusted by LBM (without tumor) is expressed as kcal/h/kg (A) during 72 hours before sacrificing (2 weeks of ghrelin treatment); (B) average daily EE over the 72 hours before sacrificing. (C–D) Ambulatory activity (C) during 72 hours before sacrificing (counts/6 h). (D) Average daily ambulatory activity over the 72 hours before sacrificing (counts/day). (E–F) Respiratory Quotient (RQ) is calculated by VCO2/VO2 (E) during 72 hours before sacrificing (RQ/6 h); (F) average daily RQ over the 72 hours before sacrificing (RQ/day). Two-way ANOVA was performed to detect genotype and treatment differences. ^*p < 0.05 compared to HK+V within the same genotype. Genotype effects are shown in p-values above the corresponding figures (p < 0.05). N = 4 for HK+V groups and N = 6 for the rest of the groups. Data are shown as mean ± SE.

The objectives of the current study were:

1) To characterize the pathways involved in adipose tissue atrophy in the LLC-induced cachexia model, and

2) To determine the pathways mediating the effects of ghrelin on adipose tissue and the relative contribution of GHSR-1a.

The Garcia Research Team concluded in their Oncotarget Research Paper that ghrelin prevents LLC tumor-induced body weight and fat loss by a combination of GHSR-1a-dependent mechanisms including preventing anorexia, and other mechanisms that are partly GHSR-1a-independent such as WAT lipolysis.

The increase in inflammation in AT induced by tumor implantation is prevented by ghrelin only in WAT; however, tumor-induced WAT browning and increased BAT inflammation, uncoupling and whole-body energy expenditure are not prevented by ghrelin even when the presence of GHSR-1a appears to contribute to maintaining energy balance in the present study.

Tumor-induced WAT browning and BAT thermogenesis are associated with significant increases in REE and these seem to be independent of inflammation given that downregulating it does not prevent these changes.

These results are clinically relevant because they show that ghrelin ameliorates WAT inflammation, lipolysis and fat atrophy in CACS in spite of not having a discernible effect on energy expenditure, WAT browning or BAT inflammation and thermogenesis.

This data fills an important gap in the knowledge regarding the mechanisms of action of ghrelin in cancer cachexia and should inform the design of future preclinical and clinical studies targeting this pathway.

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DOI - https://doi.org/10.18632/oncotarget.27705

Full text - https://www.oncotarget.com/article/27705/text/

Correspondence to - Jose M. Garcia - jose.garcia@va.gov

Keywords - cachexia, cancer, muscle, ghrelin, adipose tissue

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