| 2018 |
ADCY3 localizes to the primary cilia of neurons, and MC4R colocalizes with ADCY3 at the primary cilia of a subset of hypothalamic neurons. Obesity-associated MC4R mutations impair ciliary localization of MC4R, and inhibition of adenylyl cyclase signaling at the primary cilia of these neurons increases body weight, placing ADCY3-dependent cAMP signaling at neuronal primary cilia as a common pathway underlying genetic causes of obesity. |
Confocal colocalization imaging in hypothalamic neurons, pharmacological inhibition of adenylyl cyclase in vivo, genetic mouse models with obesity-associated MC4R mutations |
Nature genetics |
High |
29311635
|
| 2018 |
Homozygous and compound heterozygous loss-of-function mutations in ADCY3 cause severe monogenic obesity in humans, establishing ADCY3 as a mediator of energy homeostasis. Functional characterization of these mutations confirmed loss of adenylate cyclase 3 activity. |
Human genetic sequencing, functional characterization of mutations in patient-derived samples |
Nature genetics |
High |
29311637
|
| 2018 |
A splice-acceptor-site variant in ADCY3 decreases ADCY3 RNA expression and is associated with markedly increased risk of obesity and type 2 diabetes, confirming ADCY3 loss-of-function as pathogenic for metabolic disease. |
Population genetics, splice-site variant identification, RNA expression analysis in carriers |
Nature genetics |
Medium |
29311636
|
| 2013 |
ADCY3 overexpression increases cAMP levels and activates the cAMP/PKA/CREB pathway, leading to increased MMP2 and MMP9 mRNA expression and activity. PKA inhibitor treatment decreased MMP2 and MMP9 expression in ADCY3-overexpressing cells, placing ADCY3 upstream of PKA and CREB in this signaling cascade. ADCY3 expression is regulated by promoter CpG methylation. |
Overexpression and shRNA knockdown in HEK293 and SNU-216 cells, PKA inhibitor treatment, cAMP measurement, luciferase reporter assay, tumor xenograft model, bisulfite sequencing |
Oncotarget |
Medium |
24113161
|
| 2012 |
In Drosophila M pacemaker neurons, adenylate cyclase AC3 (ortholog of mammalian ADCY3) specifically mediates PDF neuropeptide receptor (PDF-R) signaling to produce cAMP increases. Genetic disruption of AC3 selectively abolishes PDF-induced cAMP responses in M cells without affecting other Gs-coupled GPCR signaling. The AKAP-like scaffolding protein Nervy also reduces PDF responses when knocked down, suggesting PDF-R/AC3 are organized into a 'circadian signalosome'. AC3 is not required for PDF signaling in E pacemaker cells, demonstrating cell-type-specific coupling. |
Live imaging of intact fly brains with cAMP reporters, transgenic RNAi knockdown, genetic rescue experiments, behavioral analysis |
PLoS biology |
High |
22679392
|
| 2024 |
ADCY3 localizes dynamically to neuronal primary cilia in the mouse brain in a region- and age-dependent manner. ARL13B+ cilia become relatively rare with age in hypothalamic feeding centers, while ADCY3 becomes a prominent cilia marker in the mature adult brain, indicating dynamic changes in cilia protein composition during postnatal development. |
Immunofluorescence imaging of mouse brain sections across postnatal ages and brain regions, quantification of cilia marker proportions |
Cells |
Medium |
38334651
|
| 2024 |
A protein-coding mutation in the transmembrane (TM) domain of Adcy3 in rats (Adcy3mut/mut) increases adiposity and alters emotional behaviors in a sex-dependent manner. Male Adcy3mut/mut rats showed increased passive coping and decreased memory, while females showed increased anxiety-like behavior. Adcy3mut/mut males had decreased hypothalamic CREB signaling, with decreased p-AMPK signaling in both sexes, linking the TM domain of ADCY3 to cAMP/CREB and AMPK signaling. |
CRISPR-SpCas9 TM-domain mutation in WKY rats, high-fat diet feeding, behavioral tests, Western blotting for CREB and p-AMPK |
Obesity (Silver Spring, Md.) |
Medium |
39632398
|
| 2023 |
The Akkermansia muciniphila membrane protein Amuc_1100 promotes lipolysis and browning in 3T3-L1 preadipocytes by upregulating the AC3/PKA/HSL pathway, increasing lipolysis-related genes (AC3, PKA, HSL) and phosphorylating HSL at Ser660, placing ADCY3 upstream of PKA and HSL in adipocyte lipolysis signaling. |
Transcriptomics in 3T3-L1 preadipocytes, qPCR, Western blotting, in vivo and in vitro fat accumulation assays |
Microbiology spectrum |
Low |
36847500
|
| 2019 |
Liraglutide upregulates hepatic AC3 expression and cAMP/PKA activity in obese mice, leading to increased phosphorylated HSL (p-HSL Ser660) and promoting lipolysis via the AC3/PKA/HSL pathway. |
In vivo liraglutide treatment of obese mice, Western blotting, RT-qPCR, cAMP and PKA activity assays in liver tissue |
Diabetes, metabolic syndrome and obesity : targets and therapy |
Low |
31564937
|
| 2024 |
In vivo experiments in a rat epilepsy model show that H2S targets and downregulates AC3 expression, thereby modulating the AC3/cAMP/PKA signaling pathway to regulate TRPV2 expression. The AC3 activator forskolin reversed the downregulatory effects of H2S on this pathway, establishing AC3 as a functional node upstream of cAMP/PKA/TRPV2 in seizure regulation. |
Proteomics in LiCl/Pilocarpine-induced seizure rat model, Western blotting, immunofluorescence, pharmacological rescue with AC3 activator forskolin, EEG and behavioral tests |
Neurochemistry international |
Low |
38290616
|
| 2024 |
A novel homozygous nonsense variant in ADCY3 (p.Thr840X) causes severe early-onset obesity. In vitro and in silico functional analyses showed downregulation and impaired activation of the ADCY3 protein, confirming loss of enzymatic activity as the pathogenic mechanism. |
Gene panel sequencing, in vitro functional assay of ADCY3 activity, in silico protein modeling |
International journal of molecular sciences |
Medium |
39519366
|
| 2025 |
ADCY3 catalyzes the production of cAMP in adipose tissue and is rhythmically expressed there with BMAL1 binding near the Ser107/Pro107 site. A transmembrane domain mutation in Adcy3 causes partial loss of enzymatic function, decreasing cAMP production in response to β-3 adrenergic receptor agonist stimulation in adipose tissue ex vivo, reducing serum free fatty acids and adipose triglyceride lipase expression, and contributing to increased adiposity via decreased lipolytic responsiveness. |
CRISPR rat model, ex vivo adipose tissue cAMP production assay with β-3 adrenergic receptor agonist, serum FFA measurement, gene expression analysis, cold exposure body temperature measurement |
Research square (preprint)preprint |
Medium |
41542040
|
| 2025 |
In mouse olfactory bulb astrocytes, AC3 (along with AC1) acts downstream of α1 adrenergic receptors as a Ca2+/calmodulin-dependent adenylyl cyclase to produce cAMP in response to norepinephrine/phenylephrine, linking Ca2+ signaling to cAMP production through ADCY3. |
Live imaging with cAMP and Ca2+ reporters in mouse olfactory bulb astrocytes, pharmacological receptor subtype dissection, Ca2+ depletion experiments |
bioRxivpreprint |
Medium |
bio_10.1101_2025.11.10.687535
|
| 2024 |
In a mouse carotid body model of chronic intermittent hypoxia (CIH), Adcy3-dependent cAMP production is downstream of Olfr78 activation by H2S. CIH increases cAMP in the carotid body, absent in Adcy3, Cth, and Olfr78 null mice. CIH-induced cAMP via ADCY3 mediates enhanced Ca2+ influx through cyclic nucleotide-gated channels (CNGA2). Adcy3 null mice do not exhibit carotid body activation or autonomic dysfunction in response to CIH. |
Adcy3 null mouse model, cAMP measurement in carotid body, Ca2+ imaging in glomus cells, comparison across Adcy3, Olfr78, Cth, and Cnga2 mutant mice |
bioRxivpreprint |
Medium |
bio_10.1101_2024.09.24.614747
|
| 2026 |
The obesity risk SNP rs713586-C allele reduces ADCY3 promoter activity via impaired ZFP42 transcription factor binding, leading to decreased TET1 recruitment and increased DNA methylation at the ADCY3 enhancer and promoter regions, suppressing ADCY3 expression. Dnajc27 knockout mice did not develop obesity, excluding DNAJC27 as the functional target of rs713586, while ADCY3 downregulation was confirmed as the relevant mechanism. |
Dual-luciferase reporter assay, CRISPR/Cas9 genome editing in cell lines, Dnajc27 knockout mice, bisulfite sequencing for DNA methylation, ZFP42-TET1 interaction analysis |
EBioMedicine |
High |
41494241
|
| 2025 |
A transmembrane domain mutation in Adcy3 decreases hypothalamic cAMP production in rats without altering ADCY3 membrane content, demonstrating that the TM domain is required for enzymatic (cAMP-generating) function. Adcy3mut/mut rats showed sex-specific depression- and anxiety-like behaviors and food seeking, with increased leptin levels in males. |
CRISPR rat model, hypothalamic cAMP measurement, membrane fractionation and Western blotting, comprehensive behavioral testing |
bioRxivpreprint |
Medium |
bio_10.1101_2025.03.28.645767
|
| 2025 |
ADCY3 overexpression in adipocytes impairs adipogenesis by downregulating the adipogenic transcription factors CEBPα and PPARγ, reduces lipid droplet number and size by suppressing triglyceride synthesis and fatty acid metabolism genes (DGAT1, DGAT2, ACC, SCD, FASN, ACSL1), and suppresses oxidative phosphorylation genes through PPARγ signaling. |
ADCY3 overexpression in adipocytes, transcriptomic profiling, gene expression and protein analysis (qPCR, Western blotting), lipid droplet quantification |
Functional & integrative genomics |
Low |
41350952
|