TY - JOUR
T1 - Melanocortin-4 receptor antagonist TCMCB07 ameliorates cancer- And chronic kidney disease-associated cachexia
AU - Zhu, Xinxia
AU - Callahan, Michael F.
AU - Gruber, Kenneth A.
AU - Szumowski, Marek
AU - Marks, Daniel L.
N1 - Funding Information:
We thank My Linh Nguyen and Tariq Shah for technical assistance. This work was supported by NCI R01 CA184324 (to DLM); NCI 1R43CA150703, 2R44CA150703, and 2R44CA210763 (to KAG); and a research grant from Tensive Controls Inc.
Funding Information:
Conflict of interest: MFC, KAG, and DLM have equity in Tensive Controls Inc. KAG and MFC were salaried officers of Tensive Controls Inc. DLM was the recipient of a subaward from KAG’s NIH Small Business Innovation Research (SBIR) grant 2R44CA150703. Copyright: © 2020, American Society for Clinical Investigation. Submitted: March 25, 2020; Accepted: June 10, 2020; Published: August 10, 2020. Reference information: J Clin Invest. 2020;130(9):4921–4934. https://doi.org/10.1172/JCI138392.
Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI138392
DO - 10.1172/JCI138392
M3 - Article
C2 - 32544087
AN - SCOPUS:85090250778
VL - 130
SP - 4921
EP - 4934
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 9
ER -