A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity
Abstract
Adiponectin secreted from adipocytes binds to adiponectin receptors AdipoR1 and AdipoR2, and exerts antidiabetic effects via activation of AMPK and PPAR-α pathways, respectively. Levels of adiponectin in plasma are reduced in obesity, which causes insulin resistance and type 2 diabetes. Thus, orally active small molecules that bind to and activate AdipoR1 and AdipoR2 could ameliorate obesity-related diseases such as type 2 diabetes. Here we report the identification of orally active synthetic small-molecule AdipoR agonists. One of these compounds, AdipoR agonist (AdipoRon), bound to both AdipoR1 and AdipoR2 in vitro. AdipoRon showed very similar effects to adiponectin in muscle and liver, such as activation of AMPK and PPAR-α pathways, and ameliorated insulin resistance and glucose intolerance in mice fed a high-fat diet, which was completely obliterated in AdipoR1 and AdipoR2 double-knockout mice. Moreover, AdipoRon ameliorated diabetes of genetically obese rodent model db/db mice, and prolonged the shortened lifespan of db/db mice on a high-fat diet. Thus, orally active AdipoR agonists such as AdipoRon are a promising therapeutic approach for the treatment of obesity-related diseases such as type 2 diabetes.
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AdipoRon has been proposed for treatment of type 2 diabetes and other obesity-related disorders in mice.
“AdipoRon has first been proposed for the treatment of type 2 diabetes and other obesity-related disorders in mice [32,106,107,108,137,138].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [106]
AdipoRon could prolong the lifespan of obese treated mice.
“It could even prolong the lifespan of obese treated mice [105,106].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [106]
Adiponectin levels are proportional to metabolic fitness.
“This finding that adiponectin levels are proportional to metabolic fitness has prompted the use of recombinant adiponectin and other adiponectin receptor agonists in several mouse models of obesity.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [130]
Mouse models of obesity and unhealthy obese individuals exhibit lower circulating levels of adiponectin.
“Alternatively, mouse models of obesity and unhealthy obese individuals exhibit lower circulating levels of adiponectin.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [130]
Activation of adiponectin signaling has improved glucose tolerance, insulin sensitivity, and longevity in mice.
“So far, the activation of adiponectin signaling has improved glucose tolerance, insulin sensitivity, and longevity in mice 12, 130.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [130]
Adiponectin receptor analogs have successfully been used in preclinical mouse models but have not yet been used in human patients.
“Adiponectin receptor analogs have successfully been used in preclinical mouse models 130, but have not yet been used in human patients.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [130]
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- Authors
- Okada-Iwabu, M., Yamauchi, T., Iwabu, M., Honma, T., Hamagami, K.-I., Matsuda, K., Yamaguchi, M., Tanabe, H., Kimura-Someya, T., Shirouzu, M., Ogata, H., Tokuyama, K., Ueki, K., Nagano, T., Tanaka, A., Yokoyama, S., & Kadowaki, T.
- Affiliations
- The University of Tokyo (JP)
- RIKEN (JP)
- University of Tsukuba (JP)
- Corresponding author
- Yamauchi, Toshimasa
- Kadowaki, Takashi
- ORCID
- Venue
- Nature
- Published
- 2013-10-30
- Volume
- 503
- Issue
- 7477
- Pages
- 493-499
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2044386584
- Cited by
- 757
- References
- 43
- Citations by year
- 2026: 48 · 2025: 52 · 2024: 72 · 2023: 54 · 2022: 60 · 2021: 64 · 2020: 62 · 2019: 55 · 2018: 51 · 2017: 62 · 2016: 66 · 2015: 57 · 2014: 47 · 2013: 3
- FWCI
- 41.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (24790908, 24249053, 24700694, 23689048)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- adiponectin, AdipoR1, AdipoR2, AdipoRon, small molecule agonists, type 2 diabetes, obesity, insulin resistance, impaired glucose tolerance, AMPK, PPARα, high-fat diet, db/db mice, lifespan extension, oral drug delivery, adiponectin receptor agonist, drug discovery screening, chemical library screening
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Adenylate Kinase, Administration, Oral, Animals, Diabetes Mellitus, Type 2, Drug Evaluation, Preclinical, Enzyme Activation, Inflammation, Insulin Resistance, Liver, Longevity, Mitochondria, Muscles, Obesity, Piperidines, Transcription Factors, Triglycerides, Signal Transduction, Glucose Intolerance, Oxidative Stress, Muscle Fibers, Skeletal, PPAR alpha, Dyslipidemias, Mice, Adiponectin, Adipose Tissue, White, Receptors, Adiponectin, Small Molecule Libraries, Diet, High-Fat
About these checks
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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