RESUMEN
OBJECTIVE: Oligodendrocyte progenitor cell differentiation is regulated by nutritional signals in the adult median eminence (ME), but the consequences on local myelination are unknown. The aim of this study was to characterize myelin plasticity in the ME of adult mice in health or in response to chronic nutritional challenge and determine its relevance to the regulation of energy balance. METHODS: We assessed new oligodendrocyte (OL) and myelin generation and stability in the ME of healthy adult male mice using bromodeoxyuridine labelling and genetic fate mapping tools. We evaluated the contribution of microglia to ME myelin plasticity in PLX5622-treated C57BL/6J mice and in Pdgfra-Cre/ERT2;R26R-eYFP;Myrffl/fl mice, where adult oligodendrogenesis is blunted. Next, we investigated how high-fat feeding or caloric restriction impact ME OL lineage progression and myelination. Finally, we characterized the functional relevance of adult oligodendrogenesis on energy balance regulation. RESULTS: We show that myelinating OLs are continuously and rapidly generated in the adult ME. Paradoxically, OL number and myelin amounts remain remarkably stable in the adult ME. In fact, the high rate of new OL and myelin generation in the ME is offset by continuous turnover of both. We show that microglia are required for continuous OL and myelin production, and that ME myelin plasticity regulates the recruitment of local immune cells. Finally, we provide evidence that ME myelination is regulated by the body's energetic status and demonstrate that ME OL and myelin plasticity are required for the regulation of energy balance and hypothalamic leptin sensitivity. CONCLUSIONS: This study identifies a new mechanism modulating leptin sensitivity and the central control of energy balance and uncovers a previously unappreciated form of structural plasticity in the ME.
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Leptina , Vaina de Mielina , Ratones , Masculino , Animales , Vaina de Mielina/fisiología , Ratones Transgénicos , Eminencia Media , Ratones Endogámicos C57BLRESUMEN
The hypothalamus plays a key role in coordinating fundamental body functions. Despite recent progress in single-cell technologies, a unified catalog and molecular characterization of the heterogeneous cell types and, specifically, neuronal subtypes in this brain region are still lacking. Here, we present an integrated reference atlas, 'HypoMap,' of the murine hypothalamus, consisting of 384,925 cells, with the ability to incorporate new additional experiments. We validate HypoMap by comparing data collected from Smart-Seq+Fluidigm C1 and bulk RNA sequencing of selected neuronal cell types with different degrees of cellular heterogeneity. Finally, via HypoMap, we identify classes of neurons expressing glucagon-like peptide-1 receptor (Glp1r) and prepronociceptin (Pnoc), and validate them using single-molecule in situ hybridization. Collectively, HypoMap provides a unified framework for the systematic functional annotation of murine hypothalamic cell types, and it can serve as an important platform to unravel the functional organization of hypothalamic neurocircuits and to identify druggable targets for treating metabolic disorders.
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Receptor del Péptido 1 Similar al Glucagón , Hipotálamo , Ratones , Animales , Receptor del Péptido 1 Similar al Glucagón/genética , Hipotálamo/metabolismo , Neuronas/metabolismo , Análisis de Secuencia de ARN , Expresión GénicaRESUMEN
The mediobasal hypothalamus (MBH; arcuate nucleus of the hypothalamus [ARH] and median eminence [ME]) is a key nutrient sensing site for the production of the complex homeostatic feedback responses required for the maintenance of energy balance. Here, we show that refeeding after an overnight fast rapidly triggers proliferation and differentiation of oligodendrocyte progenitors, leading to the production of new oligodendrocytes in the ME specifically. During this nutritional paradigm, ME perineuronal nets (PNNs), emerging regulators of ARH metabolic functions, are rapidly remodeled, and this process requires myelin regulatory factor (Myrf) in oligodendrocyte progenitors. In genetically obese ob/ob mice, nutritional regulations of ME oligodendrocyte differentiation and PNN remodeling are blunted, and enzymatic digestion of local PNN increases food intake and weight gain. We conclude that MBH PNNs are required for the maintenance of energy balance in lean mice and are remodeled in the adult ME by the nutritional control of oligodendrocyte differentiation.
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Diferenciación Celular , Eminencia Media/citología , Red Nerviosa/fisiología , Fenómenos Fisiológicos de la Nutrición , Oligodendroglía/citología , Adulto , Animales , Linaje de la Célula , Proliferación Celular , Humanos , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones Endogámicos C57BL , Oligodendroglía/ultraestructura , Análisis de la Célula Individual , Transcriptoma/genéticaRESUMEN
An acute increase in the circulating concentration of glucocorticoid hormones is essential for the survival of severe somatic stresses. Circulating concentrations of GDF15, a hormone that acts in the brain to reduce food intake, are frequently elevated in stressful states. We now report that GDF15 potently activates the hypothalamic-pituitary-adrenal (HPA) axis in mice and rats. A blocking antibody to the GDNF-family receptor α-like receptor completely prevented the corticosterone response to GDF15 administration. In wild-type mice exposed to a range of stressful stimuli, circulating levels of both corticosterone and GDF15 rose acutely. In the case of Escherichia coli or lipopolysaccharide injections, the vigorous proinflammatory cytokine response elicited was sufficient to produce a near-maximal HPA response, regardless of the presence or absence of GDF15. In contrast, the activation of the HPA axis seen in wild-type mice in response to the administration of genotoxic or endoplasmic reticulum toxins, which do not provoke a marked rise in cytokines, was absent in Gdf15-/- mice. In conclusion, consistent with its proposed role as a sentinel hormone, endogenous GDF15 is required for the activation of the protective HPA response to toxins that do not induce a substantial cytokine response. In the context of efforts to develop GDF15 as an antiobesity therapeutic, these findings identify a biomarker of target engagement and a previously unrecognized pharmacodynamic effect, which will require monitoring in human studies.
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Factor 15 de Diferenciación de Crecimiento/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Animales , Cisplatino/administración & dosificación , Cisplatino/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Glucocorticoides/metabolismo , Factor 15 de Diferenciación de Crecimiento/administración & dosificación , Humanos , Lipopolisacáridos , Ratones , Ratas , Tunicamicina/farmacologíaRESUMEN
Wernicke's encephalopathy is caused by thiamine deficiency and has a range of presenting features, including gait disturbance, altered cognitive state, nystagmus and other eye movement disorders. In the past, Wernicke's encephalopathy was described almost exclusively in the alcohol-dependent population. However, in current times, Wernicke's encephalopathy is also well recognized in many other patient groups, including patients following bariatric surgery, gastrointestinal surgery, cancer and pancreatitis. Early recognition of Wernicke's encephalopathy is vital, as prompt treatment can restore cognitive or ocular function and can prevent permanent disability. Unfortunately, Wernicke's encephalopathy is often undiagnosed - presumably because it is relatively uncommon and has a variable clinical presentation. Clinical biochemists have a unique role in advising clinicians about potential nutritional or metabolic causes of unexplained neurological symptoms and to prompt consideration of thiamine deficiency as a potential cause in high-risk patient groups. The aim of this review is to summarize the clinical features, diagnosis and treatment of Wernicke's encephalopathy and to highlight some non-traditional causes, such as after bariatric surgery.
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Cirugía Bariátrica/efectos adversos , Complicaciones Posoperatorias , Encefalopatía de Wernicke , Humanos , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/terapia , Encefalopatía de Wernicke/diagnóstico , Encefalopatía de Wernicke/etiología , Encefalopatía de Wernicke/terapiaRESUMEN
OBJECTIVE: Arcuate proopiomelanocortin (POMC) neurons are critical nodes in the control of body weight. Often characterized simply as direct targets for leptin, recent data suggest a more complex architecture. METHODS: Using single cell RNA sequencing, we have generated an atlas of gene expression in murine POMC neurons. RESULTS: Of 163 neurons, 118 expressed high levels of Pomc with little/no Agrp expression and were considered "canonical" POMC neurons (P+). The other 45/163 expressed low levels of Pomc and high levels of Agrp (A+P+). Unbiased clustering analysis of P+ neurons revealed four different classes, each with distinct cell surface receptor gene expression profiles. Further, only 12% (14/118) of P+ neurons expressed the leptin receptor (Lepr) compared with 58% (26/45) of A+P+ neurons. In contrast, the insulin receptor (Insr) was expressed at similar frequency on P+ and A+P+ neurons (64% and 55%, respectively). CONCLUSION: These data reveal arcuate POMC neurons to be a highly heterogeneous population. Accession Numbers: GSE92707.