Anti-CRF antibody-mediated HPA axis modulation induces selective fat mass loss with lean mass preservation

Zachary A. Krumm; Tariful Islam; Caroline M. Watson; Yong Ran; Yona Levites; Hunter S. Futch; Luming Yin; Edgardo Rodriguez-Lebron; Xuefei Liu; Kazi Farhana Afroz; Ariella Goloborodsky; Thomas B. Ladd; Kristy D. Dillon; Danny Ryu; Jennifer L. Bizon; Jada Lewis; Karen A. Scott; Annette de Kloet; Nicholas T. Seyfried; Eric G. Krause; Karen N. McFarland; Todd E. Golde

doi:10.1172/jci.insight.210525

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by Krumm, Z. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by Islam, T. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by Watson, C. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by Ran, Y. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by Levites, Y. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by Futch, H. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by Yin, L. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by Rodriguez-Lebron, E. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by Liu, X. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by Afroz, K. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by Goloborodsky, A. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by Ladd, T. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by Dillon, K. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by Ryu, D. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by Bizon, J. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by Lewis, J. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by Scott, K. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by de Kloet, A. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by Seyfried, N. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by Krause, E. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by McFarland, K. in: PubMed | Google Scholar

¹Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, United States of America

²Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, United States of America

³Goizueta Brain Health Institute and Alzheimer’s Disease Research Center, School of Medicine, Emory University, Atlanta, United States of America

⁴Center for Neurodegenerative Disease Center, School of Medicine, Emory University, Atlanta, United States of America

⁵Neuroscience Institute, College of Arts and Sciences, Georgia State University, Atlanta, United States of America

⁶Department of Physiological Sciences, College of Veterinary Medicine, Gainesville, United States of America

Find articles by Golde, T. in: PubMed | Google Scholar

JCI Insight. https://doi.org/10.1172/jci.insight.210525.
Copyright © 2026, Krumm et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published October 6, 2026 - Version history

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.

Anti-CRF antibody-mediated HPA axis modulation induces selective fat mass loss with lean mass preservation

Article tools

Metrics

Go to

Anti-CRF antibody-mediated HPA axis modulation induces selective fat mass loss with lean mass preservation

Article tools

Metrics

Go to

Sign up for email alerts