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The adipokine sFRP4 induces insulin resistance and lipogenesis in the liver

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Abstract
Secreted frizzled-related protein (sFRP) 4 is an adipokine with increased expression in white adipose tissue from obese subjects with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Yet, it is unknown whether sFRP4 action contributes to the development of these pathologies. Here, we determined whether sFRP4 expression in visceral fat associates with NAFLD and whether it directly interferes with insulin action and lipid and glucose metabolism in primary hepatocytes and myotubes. The association of sFRP4 with clinical measures was investigated in obese men with or without type 2 diabetes and with or without biopsy-proven NAFLD. To determine the impact of sFRP4 on metabolic parameters, primary human myotubes (hSkMC), or primary hepatocytes from metabolic healthy C57B16 and from systemic insulin-resistant mice, i.e. aP2-SREBP-1c, were used. Gene expression of sFRP4 in visceral fat from obese men associated with insulin sensitivity, triglycerides and NAFLD. In C57B16 hepatocytes, sFRP4 disturbed insulin action. Specifically, sFRP4 decreased the abundance of IRS1 and FoxO1 together with impaired insulin-mediated activation of Akt-signalling and glycogen synthesis and a reduced suppression of gluconeogenesis by insulin. Moreover, sFRP4 enhanced insulin-stimulated hepatic de novo lipogenesis (DNL). In hSkMC, sFRP4 induced glycolysis rather than inhibiting insulin signalling. Finally, in hepatocytes from aP2-SREBP-1c mice, sFRP4 potentiates existing insulin resistance. Collectively, we show that sFRP4 interferes with hepatocyte insulin action. Physiologically, sFRP4 promotes DNL in hepatocytes and glycolysis in myotubes. These sFRP4-mediated responses may result in a vicious cycle, in which enhanced rates of DNL and glycolysis aggravate hepatic lipid accumulation and insulin resistance.
Keywords
Insulin action, Adipokines, NAFLD, Insulin resistance, Hepatic insulin resistance, sFRP4, FoxO1, PROTEIN 4 SFRP4, ADIPOSE-TISSUE, NUCLEAR SREBP-1C, SCORING SYSTEM, FATTY, DISEASE, FOXO1, DIFFERENTIATION, INDIVIDUALS, SUPPRESSION

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MLA
Hörbelt, Tina, et al. “The Adipokine SFRP4 Induces Insulin Resistance and Lipogenesis in the Liver.” BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, vol. 1865, no. 10, 2019, pp. 2671–84.
APA
Hörbelt, T., Knebel, B., Fahlbusch, P., Barbosa, D., Herzfeld de Wiza, D., Van de Velde, F., … Kotzka, J. (2019). The adipokine sFRP4 induces insulin resistance and lipogenesis in the liver. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, 1865(10), 2671–2684.
Chicago author-date
Hörbelt, Tina, Birgit Knebel, Pia Fahlbusch, David Barbosa, Daniella Herzfeld de Wiza, Frederique Van de Velde, Yves Van Nieuwenhove, et al. 2019. “The Adipokine SFRP4 Induces Insulin Resistance and Lipogenesis in the Liver.” BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE 1865 (10): 2671–84.
Chicago author-date (all authors)
Hörbelt, Tina, Birgit Knebel, Pia Fahlbusch, David Barbosa, Daniella Herzfeld de Wiza, Frederique Van de Velde, Yves Van Nieuwenhove, Bruno Lapauw, G Hege Thoresen, Hadi Al-Hasani, Dirk Müller-Wieland, Margriet Ouwens, and Jorg Kotzka. 2019. “The Adipokine SFRP4 Induces Insulin Resistance and Lipogenesis in the Liver.” BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE 1865 (10): 2671–2684.
Vancouver
1.
Hörbelt T, Knebel B, Fahlbusch P, Barbosa D, Herzfeld de Wiza D, Van de Velde F, et al. The adipokine sFRP4 induces insulin resistance and lipogenesis in the liver. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE. 2019;1865(10):2671–84.
IEEE
[1]
T. Hörbelt et al., “The adipokine sFRP4 induces insulin resistance and lipogenesis in the liver,” BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, vol. 1865, no. 10, pp. 2671–2684, 2019.
@article{8644040,
  abstract     = {Secreted frizzled-related protein (sFRP) 4 is an adipokine with increased expression in white adipose tissue from obese subjects with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Yet, it is unknown whether sFRP4 action contributes to the development of these pathologies. Here, we determined whether sFRP4 expression in visceral fat associates with NAFLD and whether it directly interferes with insulin action and lipid and glucose metabolism in primary hepatocytes and myotubes. The association of sFRP4 with clinical measures was investigated in obese men with or without type 2 diabetes and with or without biopsy-proven NAFLD. To determine the impact of sFRP4 on metabolic parameters, primary human myotubes (hSkMC), or primary hepatocytes from metabolic healthy C57B16 and from systemic insulin-resistant mice, i.e. aP2-SREBP-1c, were used. Gene expression of sFRP4 in visceral fat from obese men associated with insulin sensitivity, triglycerides and NAFLD. In C57B16 hepatocytes, sFRP4 disturbed insulin action. Specifically, sFRP4 decreased the abundance of IRS1 and FoxO1 together with impaired insulin-mediated activation of Akt-signalling and glycogen synthesis and a reduced suppression of gluconeogenesis by insulin. Moreover, sFRP4 enhanced insulin-stimulated hepatic de novo lipogenesis (DNL). In hSkMC, sFRP4 induced glycolysis rather than inhibiting insulin signalling. Finally, in hepatocytes from aP2-SREBP-1c mice, sFRP4 potentiates existing insulin resistance. Collectively, we show that sFRP4 interferes with hepatocyte insulin action. Physiologically, sFRP4 promotes DNL in hepatocytes and glycolysis in myotubes. These sFRP4-mediated responses may result in a vicious cycle, in which enhanced rates of DNL and glycolysis aggravate hepatic lipid accumulation and insulin resistance.},
  author       = {Hörbelt, Tina and Knebel, Birgit and Fahlbusch, Pia and Barbosa, David and  Herzfeld de Wiza, Daniella and Van de Velde, Frederique and Van Nieuwenhove, Yves and Lapauw, Bruno and Thoresen, G Hege and Al-Hasani, Hadi and Müller-Wieland, Dirk and Ouwens, Margriet and Kotzka, Jorg},
  issn         = {0925-4439},
  journal      = {BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE},
  keywords     = {Insulin action,Adipokines,NAFLD,Insulin resistance,Hepatic insulin resistance,sFRP4,FoxO1,PROTEIN 4 SFRP4,ADIPOSE-TISSUE,NUCLEAR SREBP-1C,SCORING SYSTEM,FATTY,DISEASE,FOXO1,DIFFERENTIATION,INDIVIDUALS,SUPPRESSION},
  language     = {eng},
  number       = {10},
  pages        = {2671--2684},
  title        = {The adipokine sFRP4 induces insulin resistance and lipogenesis in the liver},
  url          = {http://dx.doi.org/10.1016/j.bbadis.2019.07.008},
  volume       = {1865},
  year         = {2019},
}

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