Leptin responsiveness restored by amylin agonism in diet-induced obesity: Evidence from nonclinical and clinical studies
Open accessAbstract
Body weight is regulated by complex neurohormonal interactions between endocrine signals of long-term adiposity (e.g., leptin, a hypothalamic signal) and short-term satiety (e.g., amylin, a hindbrain signal). We report that concurrent peripheral administration of amylin and leptin elicits synergistic, fat-specific weight loss in leptin-resistant, diet-induced obese rats. Weight loss synergy was specific to amylin treatment, compared with other anorexigenic peptides, and dissociable from amylin's effect on food intake. The addition of leptin after amylin pretreatment elicited further weight loss, compared with either monotherapy condition. In a 24-week randomized, double-blind, clinical proof-of-concept study in overweight/obese subjects, coadministration of recombinant human leptin and the amylin analog pramlintide elicited 12.7% mean weight loss, significantly more than was observed with either treatment alone ( P < 0.01). In obese rats, amylin pretreatment partially restored hypothalamic leptin signaling (pSTAT3 immunoreactivity) within the ventromedial, but not the arcuate nucleus and up-regulated basal and leptin-stimulated signaling in the hindbrain area postrema. These findings provide both nonclinical and clinical evidence that amylin agonism restored leptin responsiveness in diet-induced obesity, suggesting that integrated neurohormonal approaches to obesity pharmacotherapy may facilitate greater weight loss by harnessing naturally occurring synergies.
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Promise has been seen in an approach that combines metreleptin treatment with the amylin analogue pramlintide, which has been suggested to act as a leptin sensitizer.
“Promise has been seen in an approach that combines metreleptin (recombinant human methionyl-leptin) treatment with the amylin analogue, pramlintide, which has been suggested to act as a leptin sensitizer 154 (Table 1A).”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [154]
Amylin reduces food intake.
“Amylin reduces glucose absorption, suppresses glucagon secretion, and reduces food intake (48).”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [48]
Amylin suppresses glucagon secretion.
“Amylin reduces glucose absorption, suppresses glucagon secretion, and reduces food intake (48).”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [48]
Amylin therapy is associated with a durable weight loss of about 5% in humans.
“Amylin therapy is also associated with a durable weight loss of '5% in humans, which establishes it as one of a number of gastrointestinal signals that regulate nutrient intake and disposition.”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [48]
Amylin is a peptide hormone secreted from pancreatic beta cells that has effects on plasma glucose synergistic with insulin.
“Amylin is a peptide hormone secreted from pancreatic b cells that has a number of effects on plasma glucose that are synergistic with insulin.”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [48]
There is true synergy between leptin and amylin, and amylin can restore leptin signal transduction in the hypothalamus of diet-induced obesity rats.
“The data further suggested that there was true synergy between leptin and amylin and that amylin could restore leptin signal transduction in the hypothalamus of DIO (diet-induced obesity) rats.”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [48]
Amylin ameliorates leptin resistance.
“Recently, the hormone amylin has also been shown to ameliorate leptin resistance, although the molecular mechanism has not been fully established (48).”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [48]
In humans, the combination of leptin and amylin resulted in a substantial weight loss of 12.9%, which was significantly greater than that of either agent alone.
“The clinical significance of these findings was also assessed in humans in which the combination of leptin and amylin resulted in a substantial weight loss of 12.9%, which was significantly greater than that of either agent alone (48).”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [48]
In diet-induced rats, doses of leptin that had no discernible effect as monotherapy significantly enhance the response to amylin.
“The possibility that amylin could interact with leptin to achieve even greater weight loss was first assessed in dietinduced rats where it was shown that doses of leptin that had no discernible effect as a monotherapy could significantly enhance the response to amylin (48).”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [48]
Amylin reduces glucose absorption.
“Amylin reduces glucose absorption, suppresses glucagon secretion, and reduces food intake (48).”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [48]
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- Authors
- Roth, J. D., Roland, B. L., Cole, R. L., Trevaskis, J. L., Weyer, C., Koda, J. E., Anderson, C. M., Parkes, D. G., & Baron, A. D.
- Affiliations
- Amylin Pharmaceuticals, Inc., San Diego, CA 92121
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-05-20
- Volume
- 105
- Issue
- 20
- Pages
- 7257-7262
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2438237
- OpenAlex
- W1999851917
- Cited by
- 436
- References
- 42
- Citations by year
- 2026: 11 · 2025: 18 · 2024: 14 · 2023: 12 · 2022: 13 · 2021: 15 · 2020: 15 · 2019: 16 · 2018: 20 · 2017: 24 · 2016: 29 · 2015: 32 · 2014: 28 · 2013: 27 · 2012: 34
- FWCI
- 18.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- 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, pramlintide, diet-induced obesity, area postrema, satiety peptides, obesity pharmacotherapy, anorexigenic peptides
- MeSH terms
- Adipose Tissue, Amyloid, Animals, Body Weight, Disease Models, Animal, Hormones, Hypothalamus, Models, Biological, Obesity, Oxygen Consumption, Leptin, Caloric Restriction, Rats, Islet Amyloid Polypeptide
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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