The DOI matches its Crossref record; 61 of the 61 references it cites were found in a registry or an index.
Adiponectin Activates AMP-activated Protein Kinase in Muscle Cells via APPL1/LKB1-dependent and Phospholipase C/Ca2+/Ca2+/Calmodulin-dependent Protein Kinase Kinase-dependent Pathways
Open accessAbstract
The binding of the adaptor protein APPL1 to adiponectin receptors is necessary for adiponectin-induced AMP-activated protein kinase (AMPK) activation in muscle, yet the underlying molecular mechanism remains unknown. Here we show that in muscle cells adiponectin and metformin induce AMPK activation by promoting APPL1-dependent LKB1 cytosolic translocation. APPL1 mediates adiponectin signaling by directly interacting with adiponectin receptors and enhances LKB1 cytosolic localization by anchoring this kinase in the cytosol. Adiponectin also activates another AMPK upstream kinase Ca2+/calmodulin-dependent protein kinase kinase by activating phospholipase C and subsequently inducing Ca2+ release from the endoplasmic reticulum, which plays a minor role in AMPK activation. Our results show that in muscle cells adiponectin is able to activate AMPK via two distinct mechanisms as follows: a major pathway (the APPL1/LKB1-dependent pathway) that promotes the cytosolic localization of LKB1 and a minor pathway (the phospholipase C/Ca2+/Ca2+/calmodulin-dependent protein kinase kinase-dependent pathway) that stimulates Ca2+ release from intracellular stores.
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“At the cellular level, in myocytes, leptin exerts a proliferative effect by reducing the expression of myostatin, a negative regulator of muscle growth, and increasing the expression of cyclin D1 and proliferating cell nuclear antigen (PCNA), both of which are involved in cell cycle progression and proliferation”
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 [102]
In the citing paper
“AMPK activation is also mediated through the adaptor protein containing the PH domain, PTB domain, and leucine zipper motif-1 (APPL1)/liver kinase B1 (LKB1) pathway, where APPL1 interacts directly with AdipoR1 and promotes the cytoplasmic localization of LKB1, a key upstream kinase that activates AMPK”
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 [102]
In the citing paper
“The binding of globular adiponectin (gApN) to AdipoR1 induces Ca2+ influx and activates Ca2+/calmodulin-dependent protein kinase kinase (CaMKK), which in turn phosphorylates and activates AMPK”
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 [102]
In the citing paper
“When ApN links to AdipoR1, it induces the binding of the adaptor protein APPL1, which functions as an anchoring protein tethering LKB1 [41].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [41]
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Metadata
- Authors
- Zhou, L., Deepa, S. S., Etzler, J. C., Ryu, J., Mao, X., Fang, Q., Liu, D. D., Torres, J. M., Jia, W., Lechleiter, J. D., Liu, F., & Dong, L. Q.
- Affiliations
- Shanghai Jiao Tong University (CN)
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Dong, Lily Q.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-08
- Volume
- 284
- Issue
- 33
- Pages
- 22426-22435
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2755964
- OpenAlex
- W1973591364
- Cited by
- 212
- References
- 60
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 9 · 2023: 9 · 2022: 13 · 2021: 16 · 2020: 15 · 2019: 15 · 2018: 14 · 2017: 6 · 2016: 12 · 2015: 9 · 2014: 18 · 2013: 18 · 2012: 10
- FWCI
- 5.77
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (PPG AG19316, P01AG019316, T32AG021890)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK76902, R01 DK69930, R01DK069930, R01DK076902)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- adiponectin, AMPK, APPL1, LKB1, muscle cells, adiponectin receptors, metformin, phospholipase C, calcium signaling, endoplasmic reticulum calcium release, cytosolic translocation, AMPK activation
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Animals, Calcium, Carrier Proteins, Humans, Models, Biological, Muscles, Subcellular Fractions, Protein Serine-Threonine Kinases, Microscopy, Confocal, Adaptor Proteins, Signal Transducing, Mice, Adiponectin, Calcium-Calmodulin-Dependent Protein Kinase Kinase, AMP-Activated Protein Kinases
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