Biology subjects

Prevost, G.

Publications and source records attributed to Prevost, G..

5 recordsLinked to original sources

bioRxiv2026

Functional characterization of the 26RFa/orexin neurons of the lateral hypothalamic area reveals their key role in the control of glucose homeostasis

Defining the nature and molecular mechanisms of the neurocircuitry controlling glucose homeostasis is crucial in understanding how alterations in these pathways promote the development of obesity and type 2 diabetes. Here, we functionally characterize a population of lateral hypothalamic neurons co-expressing the anti-hyperglycemic neuropeptides 26RFa and orexin. Using complementary chemogenetic, pharmacological and genetic approaches, including mice deficient for 26RFa, orexin or both neuropeptides, we investigated the respective contribution of each signaling system to glucose homeostasis. We found that lateral hypothalamic 26RFa neurons extensively co-express orexin, defining a distinct peptidergic population with convergent anti-hyperglycemic properties. Unexpectedly, chemogenetic activation of these neurons potentiated glucose-induced hyperglycemia despite the anti-hyperglycemic properties of both neuropeptides. To understand this paradox, we examined the transcriptional responses of the 26RFa and orexin peptidergic systems and found that neuronal activation was associated with coordinated, glycemic state-dependent downregulation of both signaling systems. Furthermore, genetic loss-of-function approaches revealed distinct contributions of the two neuropeptidergic systems, with orexin signaling mediating most of the metabolic consequences of neuronal activation, whereas 26RFa signaling is required for the dynamic regulation of orexin expression. Finally, our findings provide new insights into the functional organization of lateral hypothalamic 26RFa/orexin neurons and advance our understanding of how coordinated neuropeptidergic signaling contributes to systemic glucose homeostasis.

neuroscience↗

bioRxiv2025

Characterization of Staphylococcus lugdunensis biofilm reveals key differences according to clonal lineage and iron availability

To understand the mechanisms involved in the evolutionary success of Staphyloccocus lugdunensis clones, we compared the biofilm-forming ability of representative strains of the seven clonal complexes (CCs) in rich and iron-restricted conditions, and characterized the extracellular matrix (ECM) of two highly biofilm-forming strains under each condition. Over 90% of the 49 S. lugdunensis strains produced biofilm in both conditions, with a level of production depending on the iron availability and clonal lineage. Two behaviors were observed: a significantly higher production in rich medium than in iron-restricted medium for CC1, CC2, and some CC3 strains, and the opposite phenomenon for CC6 ones. Analysis of the ECM of two representative strains using confocal microscopy showed that biofilm of the CC3 strain in rich medium contained similar amounts of proteins, eDNA and polysaccharides while that of CC6 strain was predominantly proteinaceous. Under iron-restricted conditions, biofilm structure and composition of both strains completely differed from those obtained in rich conditions. The proteomic analysis of their biofilm ECM by liquid chromatography coupled to tandem mass spectrometry identified 321 proteins common to both strains, mainly intracellular and in particular ribosomal. Of note, 202 proteins differed between the strains in terms of abundance, with a higher proportion of membrane proteins in the CC3 strain. This study performed on a large cohort of strains shows that S. lugdunensis biofilm-forming capacity is strongly associated with CC and iron availability. This analysis of biofilm-associated proteins in S. lugdunensis opens the way to propose new molecular targets for anti-biofilm strategies. IMPORTANCEThe ability of S. lugdunensis to produce biofilm is considered as a critical virulence factor. As biofilm is strongly associated with persistence and difficult-to-treat infections, characterizing biofilm production and composition, particularly in iron-deficient environments encountered during infection, can provide a better understanding of therapeutic failures. Our work is the first to be carried out on such a large collection of S. lugdunensis clinical strains. It shows that this species is a strong biofilm producer, even in an iron-deficient environment, and that the composition of its matrix varies according to both genetic background of the strain and environmental conditions. Moreover, investigating the biofilms protein matrix of two S. lugdunensis strains provides insights into identification of potential targets for biofilm eradication.

microbiology↗

bioRxiv2023

Changes in social behaviour with alterations of MAPK3 and KCTD13/CUL3 pathways in two new outbred rat models for the 16p11.2 syndromes with autism spectrum disorders.

Copy number variations (CNVs) of the human 16p11.2 locus are associated with several developmental/neurocognitive syndromes. Particularly, deletion and duplication of this genetic interval are found in patients with autism spectrum disorders, intellectual disability and other psychiatric traits. The high gene density associated with the region and the strong phenotypic variability of incomplete penetrance, make the study of the 16p11.2 syndromes extremely complex. To systematically study the effect of 16p11.2 CNVs and identify candidate genes and molecular mechanisms involved in the pathophysiology, mouse models were generated previously and showed learning and memory, and to some extent social deficits. To go further in understanding the social deficits caused by 16p11.2 syndromes, we engineered deletion and duplication of the homologous region to the human 16p11.2 genetic interval in two rat outbred strains, Sprague Dawley (SD) and Long Evans (LE). The 16p11.2 rat models displayed convergent defects in social behaviour and only a few cognitive defects. Interestingly major pathways affecting MAPK3 and CUL3 were found altered in the rat 16p11.2 models with additional changes in males compared to females. Altogether, the consequences of the 16p11.2 genetic region dosage on social behaviour are now found in three different species: humans, mice and rats. In addition, the rat models pointed to sexual dimorphism, with lower severity of phenotypes in rat females compared to male mutants. This phenomenon is also observed in humans. We are convinced that the two rat models will be key to further investigating social behaviour and understanding the brain mechanisms and specific brain regions that are key to controlling social behaviour.

animal behavior and cognition↗

bioRxiv2021

Identification of a discrete neuronal circuit that relays insulin signaling into the brain to regulate glucose homeostasis

26RFa (QRFP) is a biologically active peptide that regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity at the periphery. 26RFa is also produced by a neuronal population localized in the hypothalamus. In the present study, we have investigated whether the 26RFa neurons may be involved in the hypothalamic regulation of glucose homeostasis. Our data indicate that 26RFa, i.c.v. injected, induces a robust antihyperglycemic effect associated with an increase of insulin production by the pancreatic islets. In addition, we found that insulin strongly stimulates 26RFa expression and secretion by the hypothalamus. RNAscope experiments revealed that neurons expressing 26RFa in the lateral hypothalamic area and the ventromedial hypothalamic nucleus also express the insulin receptor and that insulin induces the expression of 26RFa in these neurons. Concurrently, we show that the central antihyperglycemic effect of insulin is abolished in presence of a 26RFa receptor (GPR103) antagonist as well as in mice deficient for 26RFa. Finally, our data indicate that the hypothalamic 26RFa neurons are not involved in the central inhibitory effect of insulin on hepatic glucose production, but mediate the central effects of the hormone on its own peripheral production. To conclude, in the present study we have identified a novel actor of the hypothalamic regulation of glucose homeostasis, the 26RFa/GPR103 system and we provide the evidence that this neuronal peptidergic system is a key relay for the central regulation of glucose metabolism by insulin.

physiology↗

bioRxiv2019

Glucose homeostasis is impaired in mice deficient for the neuropeptide 26RFa (QRFP)

Introduction26RFa (QRFP) is a biologically active peptide that has been found to control feeding behaviour by stimulating food intake, and to regulate glucose homeostasis by acting as an incretin. The aim of the present study was thus to investigate the impact of 26RFa gene knockout on the regulation of energy and glucose metabolism. Research design and methods26RFa mutant mice were generated by homologous recombination, in which the entire coding region of prepro-26RFa was replaced by the iCre sequence. Energy and glucose metabolism was evaluated through measurement of complementary parameters. Morphological and physiological alterations of the pancreatic islets were also investigated. ResultsOur data do not reveal significant alteration of energy metabolism in the 26RFa-deficient mice except the occurrence of an increased basal metabolic rate. By contrast, 26RFa mutant mice exhibit an altered glycemic phenotype with an increased hyperglycemia after a glucose challenge associated with an impaired insulin production, and an elevated hepatic glucose production. 2D and 3D immunohistochemical experiments indicate that the insulin content of pancreatic {beta} cells is much lower in the 26RFa-/- mice as compared to the wild-type littermates. ConclusionDisruption of the 26RFa gene induces substantial alteration in the regulation of glucose homeostasis with, in particular, a deficit in insulin production by the pancreatic islets. These findings further support the notion that 26RFa is an important regulator of glucose homeostasis. Significance of this studyO_ST_ABSWhat is already known about this subject?C_ST_ABS26RFa is a biologically active peptide produced in abundance in the gut and the pancreas. 26RFa has been found to regulate glucose homeostasis by acting as an incretin and by increasing insulin sensitivity. What are the new findings?Disruption of the 26RFa gene induces substantial alteration in the regulation of glucose homeostasis with, in particular, a deficit in insulin production by the pancreatic islets, assessing therefore the notion that 26RFa is an important regulator of glucose homeostasis. How might these results change the focus of research or clinical practice?Identification of a novel actor in the regulation of glucose homeostasis is crucial to better understand the general control of glucose metabolism in physiological and pathophysiological conditions, and opens new fields of investigation to develop innovative drugs to treat diabetes mellitus.

physiology↗