👤 Sophie Dreux

Hypothalamic inflammation plays a key pathophysiological mechanism linking chronic consumption of a high fat diet (HFD) to the development of obesity and associated metabolic complications. Pilot studies report that oral glutamine (Gln) supplementation might reduce waist circumference and improve metabolic and inflammatory status in obesity patients. Although Gln metabolism plays a key role in intercellular communication in the central nervous system, its potential beneficial effects remain unexplored in these contexts. Here, we aimed to evaluate how stress and glutamine supplementation can modulate the hypothalamic response to HFD in mice using a chronic-restraint stress (CRS) model, which mimics IBS symptoms. From week 12 to week 14, mice received or not Gln diluted in drinking water (2 g/kg/day) and were placed in restraint tubes (2 h/day) for the last four consecutive days of protocol. Male and female obese mice showed a difference in vulnerability to CRS-induced effects. Moreover, mice responded to Gln supplementation in a sex-dependent manner, especially in stress conditions. Hypothalamic pathways regulating energy homeostasis were more impacted in male mice, whereas factors involved in neuroinflammation were more affected in female mice. Gln supplementation led to an increase in Mc4r and Bdnf mRNA levels and GFAP expression in male mice, while upregulated Iba1 and Il6 mRNA levels as well as signs of microgliosis were observed in stressed females. In conclusion, mice with obesity showed sex-specific hypothalamic response to glutamine supplementation and stress. Further investigations should be done to decipher underlying mechanisms. Show less

Despite numerous studies on fetal therapy for myelomeningoceles (MMC), the pathophysiology of this malformation remains poorly understood. This study aimed to analyze the biochemical profile and proteome of amniotic fluid (AF) supernatants from MMC fetuses to explore the prenatal pathophysiology. Biochemical analysis of 61 AF samples from MMC fetuses was compared with 45 healthy fetuses' samples. Proteome analysis was conducted in 18 MMC and 18 healthy singleton fetuses, and in 5 dichorionic pregnancies with MMC fetuses and their healthy co-twins. ELISA tests were used to validate proteome results. Biochemical analysis revealed anal incontinence in 37 % of MMC cases, absent in controls (p < 0.0001). Proteomics identified 2453 quantified proteins with 39 significantly up-regulated and 10 down-regulated in the MMC group. Up-regulated proteins included ectodomains of CHL1, APLP1, SEZ6, SEZ6L, known targets of the protease BACE1. We explored the overlap of neonatal cerebrospinal fluid (CSF) and AF proteome and highlighted 411 proteins in common, mostly upregulated in MMC AF compared to controls. Our study thoroughly characterizes the AF proteome and reveals numerous proteins to be changed as a consequence of MMC. Many of these proteins are typical constituents of CSF. No difference in AF inflammation markers were observed between MMC and healthy fetuses. SIGNIFICANCE: This study provides good evidence that neuroepithelial destruction in MMC is independent of inflammation or presumed meconium toxicity. Show less