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βAR-mTOR-lipin1 pathway mediates PKA-RIIβ deficiency-induced adipose browning.
- Source :
-
Theranostics [Theranostics] 2024 Aug 26; Vol. 14 (13), pp. 5316-5335. Date of Electronic Publication: 2024 Aug 26 (Print Publication: 2024). - Publication Year :
- 2024
-
Abstract
- Background: Enhancing white adipose tissue (WAT) browning combats obesity. The RIIβ subunit of cAMP-dependent protein kinase (PKA) is primarily expressed in the brain and adipose tissue. Deletion of the hypothalamic RIIβ gene centrally induces WAT browning, yet the peripheral mechanisms mediating this process remain unexplored. Methods: This study investigates the mechanisms underlying WAT browning in RIIβ-KO mice. Genetic approaches such as β3-adrenergic receptors (β3ARs) deletion and sympathetic denervation of WAT were utilized. Genome-wide transcriptomic sequencing and bioinformatic analysis were employed to identify potential mediators of WAT browning. siRNA assays were employed to knock down mTOR and lipin1 in vitro , while AAV-shRNAs were used for the same purpose in vivo . Results: We found that WAT browning substantially contributes to the lean and obesity-resistant phenotypes of RIIβ-KO mice. The WAT browning can be dampened by β <subscript>3</subscript> ARs deletion or WAT sympathetic denervation. We identified that adipocytic mTOR and lipin1 may act as mediators of the WAT browning. Inhibition of mTOR or lipin1 abrogates WAT browning and hinders the lean phenotype of RIIβ-KO mice. In human subcutaneous white adipocytes and mouse white adipocytes, β <subscript>3</subscript> AR stimulation can activate mTOR and causes lipin1 nuclear translocation; knockdown of mTOR and Lipin1 mitigates WAT browning-associated gene expression, impedes mitochondrial activity. Moreover, mTOR knockdown reduces lipin1 level and nuclear translocation, indicating that lipin1 may act downstream of mTOR. Additionally, in vivo knockdown of mTOR and Lipin1 diminished WAT browning and increased adiposity. Conclusions: The β <subscript>3</subscript> AR-activated mTOR-lipin1 axis mediates WAT browning, offering new insights into the molecular basis of PKA-regulated WAT browning. These findings provide potential adipose target candidates for the development of drugs to treat obesity.<br />Competing Interests: Competing Interests: The authors have declared that no competing interest exists.<br /> (© The author(s).)
- Subjects :
- Animals
Mice
Obesity metabolism
Obesity genetics
Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit metabolism
Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit genetics
Receptors, Adrenergic, beta-3 metabolism
Receptors, Adrenergic, beta-3 genetics
Signal Transduction
Male
Mice, Inbred C57BL
Humans
Cyclic AMP-Dependent Protein Kinases metabolism
TOR Serine-Threonine Kinases metabolism
Mice, Knockout
Adipose Tissue, Brown metabolism
Adipose Tissue, White metabolism
Phosphatidate Phosphatase metabolism
Phosphatidate Phosphatase genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1838-7640
- Volume :
- 14
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Theranostics
- Publication Type :
- Academic Journal
- Accession number :
- 39267778
- Full Text :
- https://doi.org/10.7150/thno.97046