Cardiotrophin‐1 Regulates Adipokine Production in 3T3‐L1 Adipocytes and Adipose Tissue From Obese Mice

Abstract

Cardiotrophin-1 (CT-1) belongs to the IL-6 family of cytokines. Previous studies of our group revealed that CT-1 is a key regulator of glucose and lipid metabolism. The aim of the present study was to analyze the in vitro and in vivo effects of CT-1 on the production of several adipokines involved in body weight regulation, nutrient metabolism, and inflammation. For this purpose, 3T3-L1 adipocytes were incubated with recombinant protein CT-1 (rCT-1) (1-40 ng/ml) for 1 and 18 h. Moreover, the acute effects of rCT-1 administration (0.2 mg/kg, i.v.) for 30 min and 3 h on adipokines levels were also evaluated in high-fat fed obese mice. In 3T3-L1 adipocytes, rCT-1 treatment downregulated the expression and secretion of leptin, resistin, and visfatin. However, rCT-1 significantly stimulated apelin mRNA and secretion. rCT-1 (18 h) also promoted the activation by phosphorylation of AKT, ERK 1/2, and STAT3. Interestingly, pre-treatment with the PI3K inhibitor LY294002 reversed the stimulatory effects of rCT-1 on apelin expression, suggesting that this pathway could be mediating the effects of rCT-1 on apelin production. In contrast, acute administration of rCT-1 (30 min and 3 h) to diet-induced obese mice downregulated leptin and resistin, without significantly modifying apelin or visfatin mRNA in adipose tissue. Furthermore, CT-1 null mice exhibited altered expression of adipokines in adipose tissue. The present study demonstrates that rCT-1 modulates the production of adipokines in vitro and in vivo, suggesting that the regulation of the secretory function of adipocytes could be involved in the metabolic actions of this cytokine. J. Cell. Physiol. 232: 2469-2477, 2017. © 2016 Wiley Periodicals, Inc.

Role of Omentin, Vaspin, Cardiotrophin-1, TWEAK and NOV/CCN3 in Obesity and Diabetes Development

“…Lower levels of CT-1 expression are also seen in testis and brain [ 75 ]. Interestingly, adipose tissue has been also identified as a source of CT-1, acting as an adipokine [ 80 , 81 ]. Therefore, CT-1 could act not only in a paracrinic manner, but also as an endocrine factor involved in the regulation of several physiological/pathophysiological functions [ 82 ].…”

“…Indeed, studies performed in mice have shown that gene expression levels of CT-1 were down-regulated in white adipose tissue from diet-induced obese mice [ 88 , 89 ]. Moreover, plasma levels of this cytokine are elevated in patients with obesity and metabolic syndrome, suggesting that CT-1 could be considered as a marker and a link between adipose tissue, insulin resistance and cardiovascular diseases [ 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ]. Contrariwise, another study stated that overweight and obese subjects had significantly lower CT-1 levels than those with normal weight [ 92 ].…”

“…In addition, CT-1 also modulates the adipokine secretory pattern of adipocytes. Thus, CT-1 treatment increases apelin gene expression and secretion, while downregulates the production of leptin, resistin and visfatin in 3T3-L1 adipocytes [ 81 ]. Furthermore, acute administration of CT-1 to diet-induced obese mice downregulated leptin and resistin gene expression, without significantly modifying apelin mRNA levels in adipose tissue [ 81 ].…”

“…Thus, CT-1 treatment increases apelin gene expression and secretion, while downregulates the production of leptin, resistin and visfatin in 3T3-L1 adipocytes [ 81 ]. Furthermore, acute administration of CT-1 to diet-induced obese mice downregulated leptin and resistin gene expression, without significantly modifying apelin mRNA levels in adipose tissue [ 81 ]. It is important to highlight that during the last decade, white adipose tissue has been established as an important endocrine organ with a key relevance in the regulation of food intake, energy expenditure and glucose and lipid homeostasis [ 99 ].…”

“…In this context, it has been demonstrated that AKT is a major mediator in the stimulatory effect of rCT-1 in glucose uptake by cultured myocytes and adipocytes [ 86 ]. Moreover, the PI3K/AKT pathway seems to be also mediating the stimulatory effects of rCT-1 on apelin gene expression and secretion in cultured 3T3-L1 adipocytes, since pre-treatment with the PI3K inhibitor LY294002 partially reversed this effect [ 81 ]. AMPK activation is also involved in the metabolic effects of CT-1 in liver and skeletal muscle, where it increases fatty acid oxidation, [ 86 , 87 ].…”