MINI REVIEW article
Front. Endocrinol.
Sec. Adrenal Endocrinology
Volume 16 - 2025 | doi: 10.3389/fendo.2025.1647028
CRF1 AND ACTH INHIBITORS ARE A PROMISING APPROACH TO TREAT OBESITY AND LEPTIN AND INSULIN RESISTANCE
Provisionally accepted
- 1Reproductive Health Research Institute (RHRI), Santiago, Chile
- 2Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden
- 3Karolinska Institutet, Stockholm, Sweden
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Evidence synthesis:. Obesity is a state of subtle hypercortisolism accompanied by leptin and insulin resistance. Serum total cortisol concentration is normal or slightly subnormal in obese subjects. However, they have high cortisol production rates. Reduced concentrations of serum cortisol-binding globulin caused by hyperinsulinemia explain this paradox. Elevated free cortisol levels act on the adipose cells of these patients due to excess adrenal cortisol secretion, as well as to high adipocyte expression of 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1). CRF1 and ACTH blockers (such as crinecerfont and atumelnant, respectively) may replace leptin action on the adrenal axis by reducing adrenal cortisol excess in individuals with obesity. Context:. Individuals with obesity experience a subtle hypercortisolism secondary to leptin resistance. Weight loss is commonly followed by a weight rebound, likely provoked by residual leptin resistance. Since leptin inhibits the adrenal axis, leptin resistance induces a hypersecretion of cortisol, promoting chronic, pathological lipolysis of white adipose tissue. The latter situation leads to lean organ steatosis, muscle and liver insulin resistance, and -cell apoptosis. So, there is an urgent need to restore adrenal inhibition in obese individuals. Evidence acquisition. We searched PubMed articles and included them if relevant. Conclusions.: Individuals with obesity and high levels of adipose insulin resistance may benefit from CRF1/ACTH inhibitors, reducing ACTH secretion or its action. A reduction in their adipose resistance index may lead to diminished lean organ steatosis and reduced appetite due to a decrease in orexigenic signals, mainly free cortisol and insulin.
Keywords: Crinecerfont, Atumelnant, leptin resistance, Insulin Resistance, ACTH Inhibitors, Hypercortisolism
Received: 14 Jun 2025; Accepted: 08 Sep 2025.
Copyright: © 2025 Contreras and Falhammar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Patricio Homero Contreras, Reproductive Health Research Institute (RHRI), Santiago, Chile
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