Melanocortin-4 receptor antagonist TCMCB07 ameliorates cancer- and chronic kidney disease–associated cachexia
Xinxia Zhu, … , Marek Szumowski, Daniel L. Marks
Xinxia Zhu, … , Marek Szumowski, Daniel L. Marks
Published June 16, 2020
Citation Information: J Clin Invest. 2020;130(9):4921-4934. https://doi.org/10.1172/JCI138392.
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Research Article Metabolism

Melanocortin-4 receptor antagonist TCMCB07 ameliorates cancer- and chronic kidney disease–associated cachexia

Abstract

Cachexia, a devastating wasting syndrome characterized by severe weight loss with specific losses of muscle and adipose tissue, is driven by reduced food intake, increased energy expenditure, excess catabolism, and inflammation. Cachexia is associated with poor prognosis and high mortality and frequently occurs in patients with cancer, chronic kidney disease, infection, and many other illnesses. There is no effective treatment for this condition. Hypothalamic melanocortins have a potent and long-lasting inhibitory effect on feeding and anabolism, and pathophysiological processes increase melanocortin signaling tone, leading to anorexia, metabolic changes, and eventual cachexia. We used 3 rat models of anorexia and cachexia (LPS, methylcholanthrene sarcoma, and 5/6 subtotal nephrectomy) to evaluate efficacy of TCMCB07, a synthetic antagonist of the melanocortin-4 receptor. Our data show that peripheral treatment using TCMCB07 with intraperitoneal, subcutaneous, and oral administration increased food intake and body weight and preserved fat mass and lean mass during cachexia and LPS-induced anorexia. Furthermore, administration of TCMCB07 diminished hypothalamic inflammatory gene expression in cancer cachexia. These results suggest that peripheral TCMCB07 treatment effectively inhibits central melanocortin signaling and therefore stimulates appetite and enhances anabolism, indicating that TCMCB07 is a promising drug candidate for treating cachexia.

Authors

Xinxia Zhu, Michael F. Callahan, Kenneth A. Gruber, Marek Szumowski, Daniel L. Marks

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Figure 2

Central administration of TCMCB07 that is similar to AgRP treatment attenuates anorexia and body weight loss in rats with cancer cachexia.

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Central administration of TCMCB07 that is similar to AgRP treatment atte...
(A) Schematic of experimental design. Tumor donors were generated approximately 16 days before tumor implantation. Brain unilateral ventricle cannulation was performed, and animals were allowed to recover for a minimum of 7 days before tumor implantation. Fresh tumor tissue from donors was implanted into F344 rats. Daily food intake and body weights were measured after tumor implantation. Injections of saline or TCMCB07 i.c.v. were performed between days 8 and 11 after tumor implantation. Body composition (initial and terminal) was measured by MRI. (B) Daily food intake in tumor-bearing rats receiving i.c.v. injection once daily with saline (n = 6) or TCMCB07 (1.5 nmol/rat/d, n = 11). (C) In a separate experiment, tumor-bearing rats received i.c.v. injection once daily with saline (n = 8) or AgRP (1 nmol/rat/d, n = 8) between days 10 and 13 after tumor implantation. (D and E) Cumulative food intake before and after compound treatment. (F and G) Body weight gain (%, tumor-free net gain normalized to baseline) before and after treatment. (H and I) Tumors were dissected and weighed after animals were euthanized on day 12 or day 14. (J and K) Fat mass and (L and M) lean mass were determined by MRI on day 0 and day 12 or day 14, and gain was calculated (%, net gain normalized to baseline). All data in B and C are expressed as mean ± SEM for each group. All data in D–M are expressed with each dot representing 1 sample. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, 2-way ANOVA (B–G); unpaired Student’s t test (H–M).