Resumen de Role of cardiotrophin-1 in adipocyte lipolysis and adipokine production, intestinal sugar uptake and the regulation of circadian clocks
In the last years, several studies have pointed out that CT-1 might play a key role in the regulation of body weight and fat and glucose metabolism, with potential applications for treatment of obesity and insulin resistance.
In the present work, we demonstrated that CT-1 stimulates lipolysis in vitro and in vivo through the activation of the main lipases and lipid droplet associated proteins. CT-1 treatment stimulated basal glycerol and free fatty acid release in a concentration and time-dependent manner in 3T3-L1 adipocytes. This lipolytic action of CT-1 is mainly mediated by activation of HSL through the PKA pathway. In ob/ob mice, acute rCT-1 treatment also promoted PKA-mediated phosphorylation of perilipin and HSL at Ser660 and Ser563, and increased ATGL content in adipose tissue. Our results suggest that the ability of CT-1 to regulate the activity of the main lipases underlies the lipolytic action of this cytokine in vitro and in vivo, and could contribute to CT-1 antiobesity effects.
In addition we observed that CT-1 inhibits the production of adipocyte-secreted hormones implicated in obesity and insulin resistance with pro-inflammatory properties such as leptin, resistin and visfatin in cultured adipocytes, whereas promotes the gene expression and secretion of apelin. Moreover, acute CT-1 administration to obese mice reduced leptin and resistin expression in WAT. Thus, the present study demonstrates the ability of rCT-1 to modulate the production of adipokines in vitro and in vivo, suggesting that the regulation of the secretory function of adipocytes could be also involved in the metabolic actions of this cytokine.
Furthermore, the present investigation has revealed the ability of CT-1 to inhibit intestinal sugar absorption in vitro and in vivo. Mechanistic studies performed in Caco-2 cells showed that the reduction of α-Methyl-D-glucoside uptake induced by CT-1 is accompanied by the downregulation of the expression of the SGLT-1 co-transporter at the apical membrane of the cells. These effects of CT-1 on intestinal sugar absorption could contribute to the hypoglycemic and anti-obesity properties of this cytokine.
Finally, the present study aimed to characterize the potential role of CT-1 in the regulation of metabolic rhythms. Interestingly, the circadian rhythmicity of oxygen consumption rate (VO2) was totally disrupted in old CT-1 deficient (CT-1-/-) obese mice (12 months). Moreover, the lack of CT-1 also induced remarkable alterations in Bmal1 and Cry mRNA levels in young CT-1 null mice, which become also evident for Clock and Per2 in CT-1-/- 12-month-old mice. Moreover, treatment with CT-1 attenuated the drop in adipose Clock mRNA observed in ob/ob mice. Furthermore, in humans the 24-h profile of CT-1 plasma levels showed daytime variations characterized by a pronounced rise during the night period (from 2:00 to 8:00 am), with the acrophase at 8:00 am. Interestingly, the circadian rhythmicity of CT-1 observed in normal weight subjects was lost in overweight/obese individuals. All these observations suggest a potential role of CT-1 as a peripheral regulator of metabolic circadian rhythms.
