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Glucagon-like peptide-1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as anti-obesity strategies. Surprisingly whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the CNS. Serotonin depletion impaired the ability of exendin-4, a clinically utilized GLP-1 analogue, to reduce body weight in rats, suggesting serotonin is a critical mediator of the energy balance impact of GLP-1R activation. Serotonin turnover and expression of 5HT2A and 5HT2C serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that 5HT2A, but surprisingly not 5HT2C, receptor is critical for weight-loss, anorexia and fat mass reduction induced by central GLP-1R activation. Importantly, central 5HT2A receptors are also required for peripherally injected liraglutide to reduce feeding and weight. Dorsal raphe (DR) harbors cell bodies of serotonin producing neurons that supply serotonin to the hypothalamic nuclei. We show that GLP-1R stimulation in DR is sufficient to induce hypophagia and increase electrical activity of the DR serotonin neurons. Finally our results disassociate brain metabolic and emotionality pathways impacted by GLP-1R activation. This study identifies serotonin as new critical neural substrate for GLP-1 impact on energy homeostasis, and expands the current map of brain areas impacted by GLP-1R activation.

Neonatal infection can sensitize the adult substantia nigra (SN) to secondary insults, causing a decrease in antioxidant capacity which may lead to Parkinson's disease in adults. We studied the prolonged effect of systemic infection by (i.p.) administration of lipopolysaccharide (LPS) on interleukin (IL)-1β, the antioxidant regulator nuclear factor-erythroid 2-related factor 2 (Nrf2), and the peroxisome proliferator-activated receptor γ coactivator (PGC)-1α in rat SN.Five-day-old rat pups were treated with LPS (i.p. 2 mg/kg). After 65 days, the mRNA level of IL-1β was significantly increased, in parallel with a decrease in that of the rate-limiting enzyme in glutathione synthesis, the γ-glutamylcysteine ligase catalytic subunit (γGCLc), Nrf2, and brain-derived neurotrophic factor (BDNF). Protein levels of γGCLc and Nrf2 were decreased while IL-1β protein was significantly increased. These LPS-induced long-term changes correlated with a decrease in phosphorylated (active) AKT (pAKT) and phosphorylated (inactive) GSK-3β (pGSK-3β). In another set of experiments, a 0.1% Spirulina-containing diet was given to lactating mothers 24 h before the LPS treatment of the pups. The Spirulina-supplemented diet decreased IL-1β protein expression in SN and elevated the mRNA level of γGCLc, Nrf2 protein, PGC-1α protein, and pAKT.Early-life infection can negatively affect Nrf2, pAKT, and pGSK-3β for a long time in SN. A diet enriched with antioxidant and anti-inflammatory phytochemicals can partly restore some, but not all, of the effects on the antioxidant defense, possibly via normalizing effects on pAKT.

Background: The transcription factor Nrf2, encoded by the gene, is an important regulator of the cellular protection against oxidative stress. Parkinson's disease is a neurodegenerative disease highly associated with oxidative stress. In a previously published study, we reported associations of haplotypes with risk and age at onset of idiopathic Parkinson's disease in a Swedish discovery material and a Polish replication material. Here, we have extended the replication study and performed meta-analyses including the Polish material and four new independent European patient-control materials. Furthermore, all SNPs included in the haplotype windows were investigated individually for associations with Parkinson's disease in meta-analyses including all six materials. Methods: Totally 1038 patients and 1600 control subjects were studied. Based on previous haplotype associations with Parkinson's disease, five tag SNPs were genotyped by allelic discrimination and three functional promoter SNPs were genotyped by sequencing. The impact of individual SNPs and haplotypes on risk and age at onset of Parkinson's disease were investigated in each material individually and in meta-analyses of the obtained results. Results: Meta-analyses of haplotypes showed association of haplotype GAAAA, including the fully functional promoter haplotype AGC, with decreased risk (OR=0.8 per allele, p=0.012) and delayed onset (+1.1 years per allele, p=0.048) of Parkinson's disease. These results support the previously observed protective effect of this haplotype in the first study. Further, meta-analyses of the SNPs included in the haplotypes revealed four SNPs associated with age at onset of Parkinson's disease (rs7557529 G>A, -1.0 years per allele, p=0.042; rs35652124 A>G, -1.1 years per allele, p=0.045; rs2886161 A>G, -1.2 years per allele, p=0.021; rs1806649 G>A, +1.2 years per allele, p=0.029). One of these (rs35652124) is a functional SNP located in the promoter. No individual SNP was associated with risk of Parkinson's disease. Conclusion: Our results support the hypothesis that variation in the gene, encoding a central protein in the cellular protection against oxidative stress, may contribute to the pathogenesis of Parkinson's disease. Functional studies are now needed to explore these results further., peer-reviewed