Adiponectin and AdipoR1 Regulate PGC-1α and Mitochondria by Ca2+ and AMPK/SIRT1
Abstract
Adiponectin is an anti-diabetic adipokine. Its receptors possess a seven-transmembrane topology with the amino terminus located intracellularly, which is the opposite of G-protein-coupled receptors. Here we provide evidence that adiponectin induces extracellular Ca(2+) influx by adiponectin receptor 1 (AdipoR1), which was necessary for subsequent activation of Ca(2+)/calmodulin-dependent protein kinase kinase beta (CaMKKbeta), AMPK and SIRT1, increased expression and decreased acetylation of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), and increased mitochondria in myocytes. Moreover, muscle-specific disruption of AdipoR1 suppressed the adiponectin-mediated increase in intracellular Ca(2+) concentration, and decreased the activation of CaMKK, AMPK and SIRT1 by adiponectin. Suppression of AdipoR1 also resulted in decreased PGC-1alpha expression and deacetylation, decreased mitochondrial content and enzymes, decreased oxidative type I myofibres, and decreased oxidative stress-detoxifying enzymes in skeletal muscle, which were associated with insulin resistance and decreased exercise endurance. Decreased levels of adiponectin and AdipoR1 in obesity may have causal roles in mitochondrial dysfunction and insulin resistance seen in diabetes.
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AMPK upregulates expression of enzymes involved in reducing oxidative stress, particularly stress resulting from increased FAs.
“Additionally, AMPK upregulates the expression of enzymes involved in reducing oxidative stress, particularly stress resulting from increased FAs”
From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [104]
AdipoR1 is tightly linked to activation of AMPK pathways, while AdipoR2 seems to be associated with activation of PPAR-α pathways.
“AdipoR1 is tightly linked to activation of AMP-activated protein kinase (AMPK) pathways, while AdipoR2 seems to be associated with activation of peroxisome proliferator-activated receptor (PPAR)-α pathways [9,11].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [11]
PGC-1α increases the activity of several transcription factors, thus stimulating expression of target genes leading to an increase of mitochondrial biogenesis and a shift towards an oxidative metabolism.
“In turn, PGC-1α increases the activity of several transcriptions factors (TF), thus stimulating the expression of target genes leading to an increase of mitochondrial biogenesis and a shift towards an oxidative metabolism [11] (Figure 2).”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [11]
Mice with muscle-specific disruption of AdipoR1 exhibited a local decrease in oxidative-stress-detoxifying enzymes.
“Mice with muscle-specific disruption of AdipoR1 also exhibited a local decrease in oxidative-stress-detoxifying enzymes [11].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [11]
Mice with muscle-specific disruption of AdipoR1 exhibited decreased PGC-1α expression and activity, decreased mitochondrial content and function, as well as decreased oxidative type 1 myofibers and oxidative-stress detoxifying enzymes. All these abnormalities were associated with decreased insulin sensitivity in muscle and reduced endurance capacity as assessed by treadmill running.
“Likewise, mice with muscle-specific disruption of AdipoR1 exhibited decreased PGC-1α expression and activity, decreased mitochondrial content and function, as well as decreased oxidative type 1 myofibers and oxidative-stress detoxifying enzymes. All these abnormalities were associated with decreased insulin sensitivity in muscle and reduced endurance capacity as assessed by treadmill running [11].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [11]
Upon phosphorylation, PGC-1α is recognized as a deacetylation target by SIRT1.
“Upon phosphorylation, PGC-1α is recognized as a deacetylation target by SIRT1 (Canto & Auwerx, 2009; Iwabu et al, 2010).”
From Mitochondrial response to nutrient availability and its role in metabolic disease (2014) · cites this paper as Iwabu et al, 2010
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- Authors
- Iwabu, M., Yamauchi, T., Okada-Iwabu, M., Sato, K., Nakagawa, T., Funata, M., Yamaguchi, M., Namiki, S., Nakayama, R., Tabata, M., Ogata, H., Kubota, N., Takamoto, I., Hayashi, Y. K., Yamauchi, N., Waki, H., Fukayama, M., Nishino, I., Tokuyama, K., Ueki, K., Oike, Y., Ishii, S., Hirose, K., Shimizu, T., Touhara, K., & Kadowaki, T.
- Affiliations
- The University of Tokyo (JP)
- Kumamoto University (JP)
- University of Tsukuba (JP)
- National Center of Neurology and Psychiatry (JP)
- Corresponding author
- Yamauchi, Toshimasa
- Kadowaki, Takashi
- ORCID
- Venue
- Nature
- Published
- 2010-04
- Volume
- 464
- Issue
- 7293
- Pages
- 1313-1319
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1993132387
- Cited by
- 971
- References
- 46
- Citations by year
- 2026: 35 · 2025: 35 · 2024: 57 · 2023: 69 · 2022: 68 · 2021: 70 · 2020: 61 · 2019: 63 · 2018: 52 · 2017: 52 · 2016: 60 · 2015: 52 · 2014: 57 · 2013: 71 · 2012: 71
- FWCI
- 51.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (21680035, 20229008, 21390278, 22790244, 19002011)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- adiponectin, AdipoR1, PGC-1α, mitochondrial biogenesis, calcium signaling, CaMKKβ, AMPK, SIRT1, skeletal muscle, insulin resistance, type 2 diabetes, obesity, oxidative stress, exercise endurance, mitochondrial dysfunction, adipokine receptors
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Calcium, Cell Line, Glucose, Homeostasis, Insulin, Insulin Resistance, Mitochondria, Oocytes, Physical Conditioning, Animal, Transcription Factors, Xenopus laevis, Trans-Activators, Oxidative Stress, Muscle, Skeletal, Calcium Signaling, Muscle Cells, Mice, Adiponectin, Receptors, Adiponectin, Calcium-Calmodulin-Dependent Protein Kinase Kinase, AMP-Activated Protein Kinases, Sirtuin 1
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