p21-activated kinase 4 counteracts PKA-dependent lipolysis by phosphorylating FABP4 and HSL.

Autor: Yu HC; Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju, Korea., Jeon YG; School of Biological Sciences, Seoul National University, Seoul, Korea., Na AY; School of Pharmacy, Sungkyunkwan University, Suwon, Korea., Han CY; School of Pharmacy, Jeonbuk National University, Jeonju, Korea., Lee MR; Department of Surgery, Jeonbuk National University Hospital, Jeonju, Korea., Yang JD; Department of Surgery, Jeonbuk National University Hospital, Jeonju, Korea., Yu HC; Department of Surgery, Jeonbuk National University Hospital, Jeonju, Korea., Son JB; Voronoi, Incheon, Korea., Kim ND; Voronoi, Incheon, Korea., Kim JB; School of Biological Sciences, Seoul National University, Seoul, Korea., Lee S; School of Pharmacy, Sungkyunkwan University, Suwon, Korea. sangkyu@skku.edu., Bae EJ; School of Pharmacy, Jeonbuk National University, Jeonju, Korea. ejbae7@jbnu.ac.kr., Park BH; Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju, Korea. bhpark@jbnu.ac.kr.
Jazyk: angličtina
Zdroj: Nature metabolism [Nat Metab] 2024 Jan; Vol. 6 (1), pp. 94-112. Date of Electronic Publication: 2024 Jan 12.
DOI: 10.1038/s42255-023-00957-x
Abstrakt: Adipose tissue lipolysis is mediated by cAMP-protein kinase A (PKA)-dependent intracellular signalling. Here, we show that PKA targets p21-activated kinase 4 (PAK4), leading to its protein degradation. Adipose tissue-specific overexpression of PAK4 in mice attenuates lipolysis and exacerbates diet-induced obesity. Conversely, adipose tissue-specific knockout of Pak4 or the administration of a PAK4 inhibitor in mice ameliorates diet-induced obesity and insulin resistance while enhancing lipolysis. Pak4 knockout also increases energy expenditure and adipose tissue browning activity. Mechanistically, PAK4 directly phosphorylates fatty acid-binding protein 4 (FABP4) at T126 and hormone-sensitive lipase (HSL) at S565, impairing their interaction and thereby inhibiting lipolysis. Levels of PAK4 and the phosphorylation of FABP4-T126 and HSL-S565 are enhanced in the visceral fat of individuals with obesity compared to their lean counterparts. In summary, we have uncovered an important role for FABP4 phosphorylation in regulating adipose tissue lipolysis, and PAK4 inhibition may offer a therapeutic strategy for the treatment of obesity.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
Externí odkaz: