Impaired insulin signaling upon loss of ovarian function is associated with a reduction of tristetraprolin and an increased stabilization of chemokine in adipose tissue. (5th February 2018)

• Record Type: Journal Article
• Authors: Choi, Eun-Kyung; Rajasekaran, Monisha; Sul, Ok-Joo; Joe, Yeonsoo; Chung, Hyun-Taeg; Yu, Rina; Choi, Hye-Seon
• Is Part Of: Molecular and cellular endocrinology. Volume 461(2018)
• Page Start: 122
• Page End: 131
• Publication Date: 2018-02-05
• Subjects: Impaired insulin signaling -- TTP -- Loss of ovarian function -- Chemokines -- Adipose tissue; ARE adenylate uridylate-rich element -- AT adipose tissue -- ATM adipose tissue macrophage -- BMM bone marrow-derived macrophage -- DIO diet-induced obesity -- GRO-α growth-related oncogene -- H&E hematoxylin-eosin -- HFD high-fat diet -- IR insulin resistance -- KC keratinocyte-derived chemokine -- KO knockout -- MIP-1α macrophage inflammatory protein 1α -- miR microRNA -- MCP-1 monocyte chemoattractant protein-1 -- OVX ovariectomy -- PI3K phosphoinositol 3-kinase -- qPCR real-time quantitative PCR -- ROS reactive oxygen species -- RPS ribosomal protein of the small subunit -- TTP tristetraprolin/zinc finger protein 36 -- WT wild type; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2017.09.002
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: Loss of ovarian function can activate inflammation and lead to insulin resistance (IR). IR is also a core feature of obesity and obesity-associated metabolic dysfunction. Tristetraprolin/zinc finger protein 36 (TTP) interferes with TNF-α production by destabilizing TNF-α mRNA, and mice deficient in TTP develop a complex syndrome of inflammatory disease (Carballo et al., 1998; Taylor et al., 1999). We hypothesized that ovariectomy (OVX) might also prime inflammation by reducing tristetraprolin/zinc finger protein 36 (TTP) levels. We used a mouse OVX model to study impaired insulin signaling due to loss of ovarian function by evaluating Akt activity upon insulin stimulus. Impaired insulin signaling was initially detected in adipose tissue (AT) at 4 weeks after OVX, and then spread to liver and muscle, finally resulting in systemic IR at 12 weeks after OVX. OVX decreased TTP protein levels and increased adipocyte size, oxidative stress, chemokine expression and fat mass in AT by 4 weeks after surgery. TTP deficiency due to TTP gene deletion induced aberrant insulin signaling and increased chemokine expression and macrophage numbers in AT but did not increase adipocyte size, oxidative stress, or fat mass, suggesting that it promotes insulin signaling by decreasing AT inflammation independent of oxidative stress and adiposity. OVX, like TTP deficiency, increased the stability of chemokine transcripts as assessed from their half-lives. Our data indicate that the impaired insulin signaling resulting from OVX is due to an OVX-induced reduction of TTP and the resulting stabilization of inflammatory chemokines. Graphical abstract: Image 1 Highlights: A reduction in TTP upon OVX is responsible partly for the impaired insulin signaling induced by OVX in adipose tissue.