Autophagy Suppresses CCL2 to Preserve Appetite and Prevent Lethal Cachexia

Ibrahim, Maria, Gomez-Jenkins, Maria, Scheinfeld, Adina, Zhao, Zhengqiao, Lopes, Eduardo Cararo, Sawant, Akshada, Hu, Zhixian, Dharani, Aditya, Sun, Michael, Siddiqui, Sarah, Mirek, Emily T, Abram-Saliba, Johan, Lattime, Edmund C, Su, Xiaoyang, Janowitz, Tobias, Goncalves, Marcus D, Dunn, Steven M, Pritykin, Yuri, Anthony, Tracy G, Rabinowitz, Joshua D, White, Eileen (February 2025) Autophagy Suppresses CCL2 to Preserve Appetite and Prevent Lethal Cachexia. bioRxiv. ISSN 2692-8205 (Submitted)

PDF 10.1101.2025.02.20.638910.pdf - Submitted Version Available under License Creative Commons Public Domain Dedication. Download (34MB)

Abstract

Macroautophagy (autophagy hereafter) captures intracellular components and delivers them to lysosomes for degradation and recycling 1 . In adult mice, autophagy sustains metabolism to prevent wasting by cachexia and to survive fasting, and also suppresses inflammation, liver steatosis, neurodegeneration, and lethality 2,3 . Defects in autophagy contribute to metabolic, inflammatory and degenerative diseases, however, the specific mechanisms involved were unclear 4 . Here we profiled metabolism and inflammation in adult mice with conditional, whole-body deficiency in an essential autophagy gene and found that autophagy deficiency altered fuel usage, and reduced ambulatory activity, energy expenditure, and food intake, and elevated circulating GDF15, CXCL10, and CCL2. While deletion of Gdf15 or Cxcl10 provided no or mild benefit, deletion of Ccl2 restored food intake, suppressed cachexia and rescued lethality of autophagy-deficient mice. To test if appetite suppression by CCL2 was responsible for lethal cachexia we performed single nucleus RNA sequencing of the hypothalamus, the center of appetite control in the brain. Notably, we found that autophagy deficiency was specifically toxic to PMCH and HCRT neurons that produce orexigenic neuropeptides that promote food intake, which was rescued by deficiency in CCL2. Finally, the restoration of food intake via leptin deficiency prevented lethal cachexia in autophagy-deficient mice. Our findings demonstrate a novel mechanism where autophagy prevents induction of a cachexia factor, CCL2, which damages neurons that maintain appetite, the destruction of which may be central to degenerative wasting conditions.

Item Type:	Paper
Subjects:	diseases & disorders diseases & disorders > nutritional and metabolic diseases diseases & disorders > nutritional and metabolic diseases > cachexia
CSHL Authors:	Janowitz, Tobias
Communities:	CSHL labs > Janowitz lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	24 February 2025
Date Deposited:	14 Mar 2025 18:32
Last Modified:	14 Mar 2025 18:32
PMCID:	PMC11888218
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41816

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