Elevated Chemerin Induces Insulin Resistance in Human Granulosa-Lutein Cells from Polycystic Ovary Syndrome Patients

Abstract

Background: The insulin resistance (IR) of the ovarian granulosa cells from polycystic ovary syndrome (PCOS) aggravates the abnormalities in steroidogenesis and anovulation, and chemerin is an adipokine involved in regulating adipogenesis and glucose homeostasis. The underlying mechanism of IR and the role of chemerin in the development of IR remain to be demonstrated. Methods: The granulosa-lutein cells (hGLs) and follicular fluid from PCOS and non-PCOS patients with or without IR were collected to determine the chemerin levels and molecules pertinent to insulin signaling. The effects and molecular mechanism of chemerin on the insulin signaling were investigated in cultured hGLs with immunofluorescence staining, special enzyme-linked immunosorbent assay (ELISA), quantitative real-time PCR (qRT-PCR), western blotting, [18F]-Fluorodeoxyglucose ([18F]-FDG) incorporation and siRNA transfection respectively. Findings: The chemerin levels were elevated in both follicular fluid and hGLs samples obtained from PCOS with IR patients and the hGLs obtained from PCOS with IR patients showed decreased insulin sensitivity and impaired glucose uptake capacity. Moreover, treatment of chemerin attenuated insulin-stimulated glucose uptake by decreasing phosphorylation of Akt and membrane translocation of glucose transporter type 4 (GLUT4) through increasing Ser307 phosphorylation of insulin receptor substrate 1 (IRS1) in cultured hGLs. These effects could be abolished by siRNA-mediated knockdown of chemokine-like receptor 1 (CMKLR1). Furthermore, insulin induced the expression of chemerin in hGLs. Interpretation: Our findings demonstrate a novel role of chemerin in the metabolic dysfunction of PCOS, which suggested that chemerin and its receptor can be further implicated as potential therapeutic targets in the future treatment of PCOS. Funding Statement: This work was supported by the National Natural Science Foundation of China [grant numbers 81771648, 81571499]; the National Key RD the Shanghai Commission of Science and Technology [grant number 17DZ2271100]; the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant [grant number 20161413]; the Program of Shanghai Academic Research Leader in Shanghai Municipal Commission of Health and Family Planning [grant number 2017BR015]; and the Clinical Skills Improvement Project of Major Disorders, Hospital Development Center of Shanghai [grant number 16CR1022A] and Shanghai Technological Innovation Plan [grant number 18140902400]. Declaration of Interests: The authors report no conflicts of interest in this work. Ethics Approval Statement: All samples were collected with written informed consent under a protocol approved by the Ethics Committee of Renji Hospital.