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FoxO1 suppresses Fgf21 during hepatic insulin resistance to impair peripheral glucose utilization and acute cold

Oliver Stöhr1, Rongya Tao1, Ji Miao1

  • 1Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.

Cell Reports
|March 24, 2021
PubMed

Insights

Reduced fibroblast growth factor 21 (Fgf21) due to hepatic FoxO1 contributes to metabolic dysfunction in insulin-resistant mice. Restoring Fgf21 or FoxO1 improved glucose utilization and cold tolerance.

Area of Science:

  • Metabolic regulation
  • Endocrinology
  • Molecular biology

Background:

  • Fibroblast growth factor 21 (Fgf21) is a key regulator of glucose homeostasis and energy balance.
  • Elevated Fgf21 levels in insulin-resistant states suggest potential Fgf21 resistance.
  • Understanding Fgf21's role in hepatic insulin resistance is crucial for metabolic health.

Purpose of the Study:

  • To investigate the role of hepatic FoxO1 in regulating Fgf21 production and its contribution to metabolic dysfunction in insulin resistance.
  • To explore therapeutic strategies targeting the Fgf21-FoxO1 axis in hepatic insulin resistance.

Main Methods:

  • Utilized a mouse model of severe hepatic insulin resistance (LDKO mice) with genetic deletion of hepatic Irs1 and Irs2.
  • Investigated the impact of hepatic FoxO1 knockout and Fgf21 restoration (via adenoviral infection) on metabolic parameters.
  • Assessed glucose utilization in brown adipose tissue (BAT) and skeletal muscle, thermogenic gene expression, and cold tolerance.

Main Results:

  • Modestly reduced Fgf21 levels, caused by hepatic FoxO1 suppression, contribute to metabolic dysregulation in LDKO mice.
  • Knockout of hepatic FoxO1 or direct Fgf21 restoration normalized glucose utilization and BAT thermogenic gene expression.
  • Restoration of Fgf21 function corrected cold intolerance in LDKO mice, highlighting BAT's importance.

Conclusions:

  • Hepatic FoxO1-mediated suppression of Fgf21 is a significant factor in metabolic dysfunction during hepatic insulin resistance.
  • Targeting the Fgf21-FoxO1 pathway offers a potential therapeutic avenue for improving metabolic health.
  • Fgf21-dependent plasticity of BAT is vital for maintaining metabolic health under conditions of hepatic insulin resistance.
Keywords:
FGF21FoxO1brown adipose tissuecold intoleranceglucose disposalhepatic insulin resistancehepatokineinsulin receptor substrateperipheral insulin resistance

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