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Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway

Mary D L Chau1, Jiaping Gao, Qing Yang

  • 1Cardiovascular and Metabolism Disease Area, Novartis Institute for Biomedical Research, Inc., Cambridge, MA 02139, USA.

Proceedings of the National Academy of Sciences of the United States of America
|July 10, 2010
PubMed

Insights

Fibroblast growth factor 21 (FGF21) enhances energy homeostasis by activating AMPK and SIRT1 in fat cells. This boosts mitochondrial function, improving glucose and lipid metabolism.

Area of Science:

  • Metabolic Regulation
  • Cellular Metabolism
  • Obesity and Diabetes Research

Background:

  • Fibroblast growth factor 21 (FGF21) is a key metabolic regulator with demonstrated benefits in obesity and diabetes models.
  • The precise molecular mechanisms underlying FGF21's metabolic regulatory functions are not fully understood.

Purpose of the Study:

  • To elucidate the mechanisms by which FGF21 regulates energy homeostasis in adipocytes.
  • To investigate the role of AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) in FGF21's metabolic actions.

Main Methods:

  • Investigated FGF21 effects on adipocytes and white adipose tissue from ob/ob mice.
  • Measured AMPK phosphorylation, cellular NAD(+) levels, and SIRT1 activity.
  • Assessed mitochondrial oxidative function via oxygen consumption and citrate synthase activity.
  • Examined the involvement of serine/threonine kinase 11 (STK11/LKB1) and downstream targets like PGC-1alpha.

Main Results:

  • FGF21 treatment increased AMPK phosphorylation and NAD(+) levels in adipocytes.
  • FGF21 activated SIRT1, leading to deacetylation of PGC-1alpha and histone 3.
  • Enhanced mitochondrial oxidative capacity was observed, evidenced by increased oxygen consumption and citrate synthase activity.
  • FGF21's effects were dependent on STK11/LKB1, AMPK, SIRT1, and PGC-1alpha.

Conclusions:

  • FGF21 regulates energy homeostasis in adipocytes through an AMPK-SIRT1-PGC1alpha signaling pathway.
  • This pathway enhances mitochondrial oxidative capacity, contributing to FGF21's metabolic benefits.
  • Understanding this mechanism provides insight into potential therapeutic strategies for metabolic disorders.

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