The adipokine sFRP4 induces insulin resistance and lipogenesis in the liver

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1865; no. 10; pp. 2671 - 2684
• Main Authors: Hörbelt, Tina, Knebel, Birgit, Fahlbusch, Pia, Barbosa, David, de Wiza, Daniella Herzfeld, Van de Velde, Frederique, Van Nieuwenhove, Yves, Lapauw, Bruno, Thoresen, G. Hege, Al-Hasani, Hadi, Müller-Wieland, Dirk, Ouwens, D. Margriet, Kotzka, Jorg
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2019
• Subjects: Adipokines; Adipokines - metabolism; Adipose Tissue, White; Adult; Animals; Diabetes Mellitus, Type 2 - metabolism; Disease Models, Animal; Fatty Acids - metabolism; Female; Forkhead Box Protein O1 - metabolism; FoxO1; Gene Expression Regulation; Gluconeogenesis; Hepatic insulin resistance; Hepatocytes - metabolism; Humans; Insulin - metabolism; Insulin action; Insulin Receptor Substrate Proteins - metabolism; Insulin resistance; Insulin Resistance - physiology; Lipogenesis - physiology; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Middle Aged; Muscle Fibers, Skeletal - metabolism; NAFLD; Non-alcoholic Fatty Liver Disease - metabolism; Obesity - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; sFRP4; Signal Transduction; Sterol Regulatory Element Binding Protein 1; Triglycerides - metabolism; HOMA2-%B; NAFLD; DNL; SAT; VAT; ALT; Adipokines; SREBP-1c; Insulin action; HOMA-IR; GGT; sFRP4; BZ; Insulin resistance; Hepatic insulin resistance; BMI; FoxO1
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2019.07.008

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 C57Bl6 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 C57Bl6 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. [Display omitted] •Visceral adipose tissue sFRP4 mRNA expression correlates with insulin sensitivity and NAFLD in humans.•sFRP4 increases glycolysis in myotubes.•sFRP4 selectively inhibits glucose metabolism and enhances de novo lipogenesis in hepatocytes.•sFRP4 aggravates insulin resistance in hepatocytes from a mouse model with severe fatty liver.