Restoration of leptin responsiveness in diet‐induced obese mice using an optimized leptin analog in combination with exendin‐4 or FGF21
Open accessAbstract
The identification of leptin as a mediator of body weight regulation provided much initial excitement for the treatment of obesity. Unfortunately, leptin monotherapy is insufficient in reversing obesity in rodents or humans. Recent findings suggest that amylin is able to restore leptin sensitivity and when used in combination with leptin enhances body weight loss in obese rodents and humans. However, as the uniqueness of this combination therapy remains unclear, we assessed whether co‐administration of leptin with other weight loss‐inducing hormones equally restores leptin responsiveness in diet‐induced obese (DIO) mice. Accordingly, we report here the design and characterization of a series of site‐specifically enhanced leptin analogs of high potency and sustained action that, when administered in combination with exendin‐4 or fibroblast growth factor 21 (FGF21), restores leptin responsiveness in DIO mice after an initial body weight loss of 30%. Using either combination, body weight loss was enhanced compared with either exendin‐4 or FGF21 monotherapy, and leptin alone was sufficient to maintain the reduced body weight. In contrast, leptin monotherapy proved ineffective when identical weight loss was induced by caloric restriction alone over a comparable time. Accordingly, we find that a hypothalamic counter‐regulatory response to weight loss, assessed using changes in hypothalamic agouti related peptide (AgRP) levels, is triggered by caloric restriction, but blunted by treatment with exendin‐4. We conclude that leptin re‐sensitization requires pharmacotherapy but does not appear to be restricted to a unique signaling pathway. Our findings provide preclinical evidence that high activity, long‐acting leptin analogs are additively efficacious when used in combination with other weight‐lowering agents. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.
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FGF21 administration enhances leptin-mediated decreases in body weight.
“Finally, FGF21 administration enhances leptin-mediated decreases in body weight (96, 131).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [96]
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- Authors
- Müller, T. D., Sullivan, L. M., Habegger, K., Yi, C., Kabra, D., Grant, E., Ottaway, N., Krishna, R., Holland, J., Hembree, J., Perez‐Tilve, D., Pfluger, P. T., DeGuzman, M. J., Siladi, M. E., Kraynov, V. S., Axelrod, D. W., DiMarchi, R., Pinkstaff, J. K., & Tschöp, M. H.
- Affiliations
- Helmholtz Munich (DE)
- Ambrx (United States) (US)
- University of Cincinnati (US)
- Metabolic Disease Institute, Division of Endocrinology, Diabetes & Metabolism Department of Internal Medicine College of Medicine University of Cincinnati Cincinnati OH 45230 USA
- Indiana University Bloomington (US)
- Corresponding author
- Pinkstaff, Jason K.
- Tschöp, Matthias H.
- ORCID
- Venue
- Journal of Peptide Science
- Publisher
- Wiley
- Published
- 2012-05-04
- Volume
- 18
- Issue
- 6
- Pages
- 383-393
- ISSN
- 1075-2617 (ISSN-L)
- 1099-1387
- OpenAlex
- W1943524962
- Cited by
- 156
- References
- 53
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 7 · 2023: 4 · 2022: 9 · 2021: 5 · 2020: 7 · 2019: 14 · 2018: 15 · 2017: 13 · 2016: 14 · 2015: 24 · 2014: 20 · 2013: 10 · 2012: 4
- FWCI
- 8.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Peptide Science (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- leptin resistance, diet-induced obesity, exendin-4, FGF21, combination therapy, weight loss, caloric restriction, agouti-related protein, amylin, obesity pharmacotherapy
- MeSH terms
- Exenatide, Animals, Body Weight, Diet, Drug Combinations, Fibroblast Growth Factors, Mice, Inbred C57BL, Mice, Obese, Models, Molecular, Obesity, Peptides, Polyethylene Glycols, Venoms, Leptin, Mice
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