Anti-CRF antibody-mediated HPA axis modulation induces selective fat mass loss with lean mass preservation
The hypothalamic-pituitary-adrenal (HPA) axis integrates central neural processing and responses to stress with endocrine and metabolic responses. We utilized a monoclonal antibody binding corticotrophin-releasing factor (anti-CRF) to achieve durable HPA axis modulation. In mice, anti-CRF treatment decreased plasma corticosterone, food-intake, body weight and fat mass, but preserved lean mass and improved metabolic parameters including insulin sensitization. These body composition effects were observed in middle aged mice on normal chow or high fat diet, aged mice, and Mc4r -/- and ob/ob mice. Single-dose studies demonstrated impacts on weight gain and body composition lasting beyond the period of pharmacological target engagement. Multi-organ transcriptomic and proteomic analyses revealed organ-specific effects of anti-CRF and are consistent with altered glucocorticoid receptor (GR) signaling as a mediator of the observed phenotypes. These studies support anti-CRF-mediated HPA-axis modulation as a metabolic and anti-obesity therapeutic approach distinct from incretins.
Authors
- Jada M. Lewis (ORCID: https://orcid.org/0000-0003-0004-6597)
- Karen A. Scott (ORCID: https://orcid.org/0000-0002-4133-423X)
- Tariful Islam (ORCID: https://orcid.org/0000-0002-6459-5301)
- Jennifer L. Bizon (ORCID: https://orcid.org/0000-0002-9517-5844)
- Yona Levites (ORCID: https://orcid.org/0000-0001-6925-4525)
- Hunter S. Futch (ORCID: https://orcid.org/0000-0002-5260-5736)
- Thomas B. Ladd
- Zachary A. Krumm (ORCID: https://orcid.org/0000-0002-8902-8960)
- Nicholas T. Seyfried (ORCID: https://orcid.org/0000-0002-4507-624X)
- Caroline M Watson (ORCID: https://orcid.org/0000-0001-6574-0833)
- Karen N. McFarland (ORCID: https://orcid.org/0000-0002-9952-8678)
- Annette D. de Kloet (ORCID: https://orcid.org/0000-0002-7213-6957)
- Danny Ryu
- Eric G. Krause (ORCID: https://orcid.org/0000-0002-2718-3113)
- Kazi Farhana Afroz (ORCID: https://orcid.org/0000-0002-1650-249X)
- Todd Eliot Golde (ORCID: https://orcid.org/0000-0003-1867-7071)
- Kristy D. Dillon
- Edgardo Rodríguez-Lebrón
- Yong Ran (ORCID: https://orcid.org/0000-0002-9748-4392)
- Xuefei Liu
- Luming Yin
- Ariella Goloborodsky
Institutions
- Emory University (US)
- Georgia State University (US)
- German Center for Neurodegenerative Diseases (DE)
- McKnight Brain Research Foundation (US)
- Institute for Neurodegenerative Disorders (US)
- Department of Physiological Sciences (RU)
Publication Details
- Journal
- JCI Insight
- Published
- 2026-10-06
- DOI
- https://doi.org/10.1172/jci.insight.210525
- Primary Topic
- Regulation of Appetite and Obesity
- Type
- article
- Field-Weighted Citation Impact
- 0.00