Biology subjects

Bouret, S. G.

Publications and source records attributed to Bouret, S. G..

5 recordsLinked to original sources

bioRxiv2025

Vesicle-mediated oxytocin release drives melanocortin circuit maturation during a neonatal critical period

The hypothalamus is crucial for regulating essential bodily functions, including energy balance. It is an exceedingly complex and heterogeneous brain region that contains a variety of neuronal systems that are interconnected with each other. Among these, the melanocortin system, which comprises pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons, displays a remarkable anatomical relationship with oxytocin (OT) neurons in the paraventricular nucleus (PVH). Here, we demonstrate that OT neurons are instrumental in the development of the melanocortin system. Chemogenetic inhibition of OT neurons during the first postnatal week selectively disrupts POMC and AgRP projections to the PVH, without affecting other target nuclei like the dorsomedial nucleus. This developmental role is age-dependent, as silencing OT neurons in juvenile or adult stages has no impact on melanocortin circuits. OT neurons release various neuropeptides and neurotransmitters, and their secretion can be modulated by chemogenetic manipulation. Expressing the botulinum toxin serotype B light chain in OT neurons reveals that their developmental actions rely on SNARE-mediated exocytosis. Moreover, administering an OT receptor antagonist during the first postnatal week leads to similar melanocortin circuit defects and long-term metabolic effects. Furthermore, neonatal chemogenetic activation of OT neurons rescues POMC circuit deficits in a mouse model of Prader-Willi Syndrome. These findings reveal that OT acts as a paracrine neurotrophic factor orchestrating the development of melanocortin circuits during a restricted neonatal critical period.

neuroscience↗

bioRxiv2024

Investigation of a Novel Mouse Model of Prader-Willi Syndrome with Invalidation of Necdin and Magel2

Prader-Willi syndrome (PWS) is a multigenic disorder caused by the loss of seven contiguous paternally expressed genes. Mouse models with inactivation of all PWS genes are lethal. Knockout (KO) mouse models for each candidate gene were generated, but they lack the functional interactions between PWS genes. Here, we revealed an interplay between Necdin and Magel2 "PWS" genes and generated a novel mouse model (named "Madin") with a deletion including both genes. A subset of Madin KO mice showed neonatal lethality. Behaviorally, surviving mutant mice exhibited sensory delays during infancy and alterations in social exploration at adulthood. Madin KO mice had a lower body weight before weaning, persisting after weaning in males only, with reduced fat mass and improved glucose tolerance. Delayed sexual maturation and altered timing of puberty onset were observed in mutant mice. Adult Madin KO mice displayed increased ventilation and a persistent increase in apneas following a hypercapnic challenge. Transcriptomics analyses revealed a dysregulation of key circadian genes and alterations of genes associated with axonal function that were also found in the hypothalamus of patients with PWS. At neuroanatomical levels, we report an impaired maturation of oxytocin neurons and a disrupted development of melanocortin circuits. Together, these data indicate that the Madin KO mouse is a reliable and more genetically relevant model for the study of PWS.

systems biology↗

bioRxiv2020

Defective Autophagy in Sf1 Neurons Perturbs the Metabolic Response to Fasting and Causes Mitochondrial Dysfunction

ObjectiveThe ventromedial nucleus of the hypothalamus (VMH) is a critical component of the forebrain pathways that regulate energy homeostasis. It also plays an important role in the metabolic response to fasting. However, the mechanisms contributing to these physiological processes remain elusive. Autophagy is an evolutionarily conserved mechanism that maintains cellular homeostasis by turning over cellular components and providing nutrients to the cells during starvation. Here we investigated the importance of the autophagy-related gene Atg7 in Sf1-expressing neurons of the VMH in control and fasted conditions. MethodsWe generated Sf1-Cre; Atg7loxP/loxP mice and examined their metabolic and cellular response to fasting. ResultsFasting induces autophagy in the VMH, and mice lacking Atg7 in Sf1-expressing neurons display altered regulation in glucose and leptin homeostasis and impaired energy expenditure regulation in response to fasting. Moreover, loss of Atg7 in Sf1 neurons causes alterations in the central response to fasting. Furthermore, alterations in mitochondria morphology and activity are observed in mutant mice. ConclusionTogether, these data show that autophagy is nutritionally regulated in VMH neurons and that VMH autophagy participates in the control of energy homeostasis during fasting.

neuroscience↗

bioRxiv2019

Maternal Obesity-Induced Endoplasmic Reticulum Stress Causes Metabolic Alterations and Abnormal Hypothalamic Development in the Offspring

The steady increase in the prevalence obesity and associated type II diabetes is a major health concern, particularly among children. Maternal obesity represents a risk factor that contributes to metabolic perturbations in the offspring. Endoplasmic reticulum (ER) stress has emerged as a critical mechanism involved in leptin resistance and type 2 diabetes in adult individuals. Here, we used a mouse model of maternal obesity to investigate the importance of early life ER stress in the nutritional programming of metabolic disease. Offspring of obese dams displayed increased body weight, adiposity, food intake and developed glucose intolerance. Moreover, maternal obesity disrupted the development of melanocortin circuits associated with neonatal hyperleptinemia and leptin resistance. ER stress-related genes were upregulated in the hypothalamus of neonates born to obese mothers and neonatal treatment with the ER stress-relieving drug tauroursodeoxycholic acid improved metabolic and neurodevelopmental deficits and reverses leptin resistance in neonates born to obese dams.

physiology↗

bioRxiv2018

Dicer-miR-103/107 controls developmental switch of POMC progenitors into NPY neurons and impacts glucose homeostasis

Proopiomelanocortin (POMC) neurons are major negative regulators of energy balance. A distinct developmental property of POMC neurons is that they can adopt an orexigenic neuropeptide Y (NPY) phenotype. However, the mechanisms underlying the differentiation of Pomc progenitors remain unknown. Here, we show that the loss of the microRNA (miRNA)- processing enzyme Dicer in POMC neurons causes metabolic defects, an age-dependent decline in the number of Pomc mRNA-expressing cells, and an increased proportion of Pomc progenitors acquiring a NPY phenotype. miRNome microarray screening further identified miR-103/107 as candidates that may be involved in the maturation of Pomc progenitors. In vitro inhibition of miR-103/107 causes a reduction in the number of Pomc-expressing cells and increases the proportion of Pomc progenitors differentiating into NPY neurons. Moreover, in utero silencing of miR-103/107 causes perturbations in glucose homeostasis. Together, these data suggest a role for prenatal miR-103/107 in the maturation of Pomc progenitors and glucose homeostasis.

neuroscience↗