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The adipokine sFRP4 induces insulin resistance and lipogenesis in the liver

Tina Hörbelt1, Birgit Knebel2, Pia Fahlbusch1

  • 1Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at the Heinrich-Heine-University Duesseldorf, Leibniz Center for Diabetes Research, Auf'm Hennekamp 65, 40225 Duesseldorf, Germany; German Center of Diabetes Research Partner, Duesseldorf, Germany; Medical Faculty, Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Heinrich Heine University, Düsseldorf, Germany.

Biochimica Et Biophysica Acta. Molecular Basis of Disease
|July 24, 2019
PubMed

Insights

Secreted frizzled-related protein 4 (sFRP4) in visceral fat is linked to non-alcoholic fatty liver disease (NAFLD) and insulin resistance. sFRP4 disrupts insulin action in liver cells, promoting fat synthesis and worsening metabolic dysfunction.

Area of Science:

  • Metabolic disease research
  • Endocrinology
  • Molecular biology

Background:

  • Secreted frizzled-related protein 4 (sFRP4) is an adipokine with elevated expression in obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD).
  • The precise role of sFRP4 in the development of these metabolic pathologies remains unclear.

Purpose of the Study:

  • To investigate the association between visceral fat sFRP4 expression and NAFLD in obese men.
  • To determine if sFRP4 directly impacts insulin action, lipid, and glucose metabolism in primary human hepatocytes and myotubes.

Main Methods:

  • Association study of sFRP4 gene expression in visceral fat with clinical parameters (insulin sensitivity, triglycerides, NAFLD) in obese men.
  • In vitro studies using primary human skeletal muscle cells (hSkMC) and primary hepatocytes from metabolic healthy and insulin-resistant mice (aP2-SREBP-1c).
  • Analysis of insulin signaling pathways, glycogen synthesis, gluconeogenesis, and de novo lipogenesis (DNL) in response to sFRP4 treatment.

Main Results:

  • Visceral fat sFRP4 expression correlated with insulin sensitivity, triglyceride levels, and the presence of NAFLD in obese men.
  • In hepatocytes, sFRP4 impaired insulin signaling by reducing IRS1 and FoxO1, inhibiting insulin-mediated Akt activation and glycogen synthesis, and reducing gluconeogenesis suppression.
  • sFRP4 promoted insulin-stimulated hepatic de novo lipogenesis (DNL) and induced glycolysis in myotubes, exacerbating insulin resistance in hepatocytes from insulin-resistant mice.

Conclusions:

  • sFRP4 in visceral fat is associated with NAFLD and insulin resistance.
  • sFRP4 directly interferes with hepatocyte insulin action, promoting hepatic DNL and glycolysis in myotubes.
  • These actions of sFRP4 may contribute to a cycle of hepatic lipid accumulation and worsening insulin resistance.
Keywords:
AdipokinesFoxO1Hepatic insulin resistanceInsulin actionInsulin resistanceNAFLDsFRP4

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