Abstract P234: Arterial Hypertension, Insulin Resistance And Depressive-like Behavior In Crtc1 -deficient Mice

Abstract

Background: Epidemiological evidence has demonstrated a link between cardiovascular disease, metabolic syndrome and depression. Whether this association is causal and what mechanisms may be involved is still unknown. Studies in humans and mice suggest that alterations of the CREB-BDNF pathway can contribute to the development of both, eating disorders and major depressive disorders. Mice deficient in the CREB-regulated transcriptional coactivator 1 (Crtc1) have been shown to become overweight and display depressive-like behavior. Here, we investigated whether Crtc1 -deficient mice concomitantly exhibit a hypertensive, insulin resistant and depression-like phenotype. Methods: Mean arterial blood pressure and heart rate were measured by radiotelemetry in unrestrained Crtc1 -deficient mice (KO) and wildtype littermates (WT). Renal renin expression was quantified by qPCR. Insulin resistance was determined by the i.p. glucose tolerance test, and depressive-like behavior was assessed by the soiled bedding preference test. Results: Crtc1 -deficient mice had higher arterial blood pressures (dark: KO 117±2 mm Hg, WT 107±2 mm Hg, p<0.05; light: KO 102±2 mm Hg, WT 94±2 mm Hg, p<0.05, 1-way ANOVA, n=8-11) and heart rates (dark: KO 593±11 bpm, WT 596±7 bpm; light: KO 529±12 bpm, WT 494±8 bpm, p<0.05, 1-way ANOVA, n=8-11). Relative renin mRNA expression was not different between genotypes (KO 0.86±0.07, WT 1.00±0.10, n=10). Glucose tolerance was significantly impaired in Crtc1 -deficient mice (maximum plasma glucose concentrations KO 423±27 mg/dl, WT 295±27 mg/dl, p<0.0001, 2-way ANOVA, n=9). In the soiled bedding preference test, male Crtc1 -deficient mice exhibited a lack of preference for female-soiled bedding over clean bedding (female vs. clean KO 75.3±11.2 s vs 79.0±11.0 s, WT 119.5±13.5 s vs. 51.5±10.5 s, n=2-3). Conclusions: Crtc1 might be a molecular component of a pathway that connects arterial hypertension, metabolic syndrome and depression.