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Updated: Sep 15, 2025

Measuring the Rate of Lipolysis in Ex Vivo Murine Adipose Tissue and Primary Preadipocytes Differentiated In Vitro
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p21-activated kinases (PAKs) regulate FGF1/PDE4D antilipolytic pathway and insulin resistance in adipocytes

Judith Seigner1, Johannes Krier1, David Spähn2

  • 1Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich, Tübingen, Germany; Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, University Hospital of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany.

Molecular Metabolism
|July 14, 2025
PubMed

Insights

p21-activated kinases (PAKs) regulate the Fibroblast growth factor 1/Phosphodiesterase 4D pathway, impacting fat breakdown and glucose levels. This discovery offers new therapeutic targets for type 2 diabetes (T2D) and insulin resistance (IR).

Area of Science:

  • Metabolism
  • Endocrinology
  • Cell Biology

Background:

  • Adipose tissue dysfunction, lipotoxicity, and insulin resistance (IR) are central to type 2 diabetes (T2D).
  • The Fibroblast growth factor 1 (FGF1)/Phosphodiesterase 4D (PDE4D) pathway regulates glucose and lipid metabolism by suppressing lipolysis.
  • Upstream regulators of PDE4D phosphorylation, crucial for its activity, were previously unknown.

Purpose of the Study:

  • To identify upstream signaling mechanisms regulating PDE4D phosphorylation and the FGF1/PDE4D pathway.
  • To investigate the role of p21-activated kinases (PAKs) in adipocyte function, differentiation, and their link to T2D.

Main Methods:

  • In vitro studies using murine adipocytes to examine the effects of FGF1 and PAK inhibition on PDE4D phosphorylation, cAMP levels, and lipolysis.
  • Chronic inhibition of PAKs in mouse and human adipocyte cultures to assess lipid accumulation, adipogenic marker expression, and IR.

Main Results:

  • PAKs were identified as key regulators of PDE4D phosphorylation and FGF1-mediated suppression of lipolysis.
  • Inhibition of PAKs disrupted FGF1's antilipolytic function and altered cAMP regulation by PDE4D.
  • Chronic PAK inhibition reduced adiposity, decreased adipogenic markers, and induced IR in adipocytes.

Conclusions:

  • PAKs are critical regulators of the FGF1/PDE4D antilipolytic pathway in adipocytes.
  • PAKs play a significant role in adipogenesis and the development of insulin resistance.
  • PAKs represent a potential therapeutic target for managing T2D and related metabolic disorders.
Keywords:
AdipogenesisFGF1/PDE4DInsulin resistanceLipolysisType 2 diabetesp21-activated kinases

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