Effects of Cardiotrophin on Adipocytes

Abstract

Cardiotrophin (CT-1) is a naturally occurring protein member of the interleukin (IL)-6 cytokine family and signals through the gp130/leukemia inhibitory factor receptor (LIFR) heterodimer. The formation of gp130/ LIFR complex triggers the auto/trans-phosphorylation of associated Janus kinases, leading to the activation of Janus kinase/STAT and MAPK (ERK1 and -2) signaling pathways. Since adipocytes express both gp130 and LIFR proteins and are responsive to other IL-6 family cytokines, we examined the effects of CT-1 on 3T3-L1 adipocytes. Our studies have shown that CT-1 administration results in a dose-and time-dependent activation and nuclear translocation of STAT1, -3, -5A, and -5B as well as ERK1 and -2. We also confirmed the ability of CT-1 to induce signaling in fat cells in vivo. Our studies revealed that neither CT-1 nor ciliary neurotrophic factor treatment affected adipocyte differentiation. However, acute CT-1 treatment caused an increase in SOCS-3 mRNA in adipocytes and a transient decrease in peroxisome proliferator-activated receptor ␥ (PPAR␥) mRNA that was regulated by the binding of STAT1 to the PPAR␥2 promoter. The effects of CT-1 on SOCS-3 and PPAR␥ mRNA were independent of MAPK activation. Chronic administration of CT-1 to 3T3-L1 adipocytes resulted in a decrease of both fatty acid synthase and insulin receptor substrate-1 protein expression yet did not effect the expression of a variety of other adipocyte proteins. Moreover, chronic CT-1 treatment resulted in the development of insulin resistance as judged by a decrease in insulin-stimulated glucose uptake. In summary, CT-1 is a potent regulator of signaling in adipocytes in vitro and in vivo, and our current efforts are focused on determining the role of this cardioprotective cytokine on adipocyte physiology.

Cardiotrophin 1 protects beta cells from apoptosis and prevents streptozotocin-induced diabetes in a mouse model

“…CT-1 levels in plasma [35] and adipose tissue [36] have recently been correlated with the pathology of the metabolic syndrome, suggesting that CT-1 may be involved in a protective mechanism against the metabolic changes that occur during the initial stages of the disease [37]. Moreover, the presence of CT1 polymorphisms have also been associated with the development of hypertension [38] and cardiomyopathies [39].…”

Adipogenesis

“…Numerous findings in the last decade have highlighted the differential effects of gp130 cytokines on important adipocyte functions. These studies have shown that adipocytes in vitro and adipose tissue in vivo are responsive to gp130 cytokines (Balhoff and Stephens 1998;Stephens et al 1998;Lagathu et al 2003;Rotter et al 2003;Zvonic et al 2003Zvonic et al , 2004Tenney et al 2005;White et al 2008) and exert differential effects on adipogenesis. To date, no gp130 cytokines have been shown to promote adipogenesis, but as shown in Table 1, several cytokines in this family have been shown to inhibit adipocyte development (Keller et al 1993;Meng et al 2001;Zvonic et al 2003Zvonic et al , 2004Sopasakis et al 2004;Hogan and Stephens 2005;Miyaoka et al 2006;Song et al 2007;White et al 2008).…”

Cardiotrophin-1 Review

“…Moreover, chronic CT-1 treatment resulted in the development of insulin resistance as judged by a decrease in insulin-stimulated glucose uptake. In summary, CT-1 is a potent regulator of signaling in adipocytes in vitro and in vivo 88 .…”