AI Article Synopsis

  • Adipose tissue lipolysis, the breakdown of fat, is controlled by a signaling pathway involving cAMP and protein kinase A (PKA), which targets a protein called PAK4 for degradation.
  • Mice with higher levels of PAK4 in their fat tissue show reduced fat breakdown and increased obesity, while mice lacking PAK4 or treated with a PAK4 inhibitor lose weight and improve insulin sensitivity.
  • PAK4 interferes with lipolysis by phosphorylating and inhibiting the action of key proteins (FABP4 and HSL) involved in fat metabolism, with elevated PAK4 levels linked to obesity in humans, suggesting that targeting PAK4 could be a potential obesity treatment.

Article Abstract

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.

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Source
http://dx.doi.org/10.1038/s42255-023-00957-xDOI Listing

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