👤 Jorge Manzanares

The glucagon-like peptide-1 receptor (GLP-1R) has emerged as a promising therapeutic option for alcohol use disorder (AUD), yet the underlying mechanisms and neurocircuitry involved remain unclear. This study aimed to analyze GLP-1R gene expression changes in brain regions associated with alcohol's effects, including the prefrontal cortex (PFC), nucleus accumbens (NAc), and hippocampus (HIP), in mice following 42 days of voluntary ethanol consumption (VEC; 10% v/v) and postmortem samples from 18 patients with AUD. Additionally, we examined the expression of OPRM1 (mu-opioid receptor) and BDNF (brain-derived neurotrophic factor), key targets related to alcohol intake and reward, in the NAc and HIP, respectively. GLP-1R gene expression was significantly reduced in all brain regions of ethanol-exposed mice and AUD patients. These reductions paralleled decreased OPRM1 and BDNF expression in the NAc and HIP, respectively. Pearson and Spearman correlation analyses revealed no significant associations between gene expression and age, RIN, pH, postmortem interval (PMI), body mass index (BMI), smoking status, age of onset of alcohol use, or years of drinking. In summary, chronic alcohol consumption in humans or mice was associated with decreased GLP-1R gene expression in brain regions involved in the reinforcing effects of ethanol. These findings open new avenues for further research into how this emerging receptor could serve as a potential biomarker and therapeutic target in AUD. Show less

Recent studies have associated alterations of neuronal plasticity in specific brain areas with suicidal behavior. The Notch signaling pathway plays a relevant role in the control of stem cell maintenance, cell migration, and neuronal plasticity. In the present study, the gene expression of the four Notch receptors (NOTCH1-4), the five canonical ligands (DLL1, DLL3, DLL4, JAGGED1, and JAGGED2), the two non-canonical ligands (DLK1 and DLK2), and the transcription factors (HES1, HEY1, and HEY2) were measured in the dorsolateral prefrontal cortex (DLPFC) and amygdala (AMY) of suicide victims (S; n = 13 males, with no clinical psychiatric history and non-treated with anxiolytic or antidepressant drugs) and their corresponding controls (C; n = 13 males) by real-time PCR. The results revealed a reduction of NOTCH2 and NOTCH1, NOTCH3, and NOTCH4 gene expression in the DLPFC and AMY of S compared with C, respectively. DLL1 levels were increased in the DLPFC and decreased in the AMY, whereas DLL4, JAGGED1, and JAGGED2 were significantly decreased in the regions analyzed. DLK1 was reduced in the AMY, whereas no changes were observed in the DLPFC and in DLK2 expression levels in any of the regions analyzed. HES1 was significantly reduced in both brain regions from S, whereas there were no significant changes in HEY1 and HEY2. This study provides evidence suggesting that the Notch signaling pathway could be a potential key target in the treatment of suicidal behaviors. Show less

Type 2 diabetic patients have an increased prevalence of hypertriglyceridemia. RBP4 has been associated with insulin resistance and hypertriglyceridemia in obesity, the metabolic syndrome and type 2 diabetes. APOA5 is proposed to be a genetic modulator of triglycerides. The aim of this study was to evaluate the relationship between RBP4 plasma levels and lipid disturbances and to determine the impact of the APOA5-1131 T>C variant on this relationship in type 2 diabetic patients. A total of 165 type 2 diabetic patients were included in the study. RBP4 plasma levels and the APOA5-1131 T>C variant were determined and the complete lipid profile was assessed by sequential ultracentrifugation. RBP4 was positively correlated with triglyceride levels in plasma and with all the components of triglyceride-rich lipoproteins. Despite the fact that a statistically significant relationship between the APOA5 genetic variant and RBP4 plasma levels was not found, the hypertriglyceridemic effect of high RBP4 levels was enhanced by the presence of the APOA5-1131 T>C genetic variant. Correlation coefficients were 2-fold higher for TC carriers compared to TT carriers with regard to RBP4 plasma levels and all the components of triglyceride-rich lipoproteins. Those type 2 diabetic patients with high RBP4 plasma concentrations and who were TC carriers showed an increased incidence of hypertriglyceridemia (OR=7.46, P=0.010). RBP4 is associated with hypertriglyceridemia in type 2 diabetic patients. The RBP4 effect is conditioned by the presence of the APOA5-1131 T>C genetic variant. Show less

Variations of the apolipoprotein A5 (APOA5) gene are strongly associated with hypertriglyceridemia. Vitamin E is transported in triglyceride (TG)-rich lipoproteins and therefore could also be modulated by apoAV. Patients with type 2 diabetes have a tendency towards high TG values and increased oxidative stress. We examined the impact of genetic APOA5 variation (-1131T-->C) on vitamin E and oxidative status in 169 non-smoker type 2 diabetic patients. Plasma samples were analyzed for lipids, lipoproteins, vitamin E, oxidized low-density lipoprotein (oxLDL), lipoperoxides, autoantibodies against oxLDL and diene formation of LDL. Vitamin E concentrations were higher in TC carriers compared with TT carriers (45.48+/-8.20 micromol/L vs. 40.32+/-10.47 micromol/L; p=0.02). The prevalence of the TC genotype was 2.6-fold higher among individuals with high vitamin E concentrations (p=0.02). The APOA5 polymorphism did not determine any differences in oxidative status. Fasting TG concentration was a significant 21% higher in carriers of the TC genotype (p=0.04) due to higher TG concentrations in very-low-density lipoprotein (VLDL) and high-density lipoprotein. The APOA5-1131T-->C polymorphism is associated with both higher vitamin E concentrations and higher VLDL-TGs in diabetic patients. Show less