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2.
Nat Neurosci ; 24(12): 1660-1672, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34795451

RESUMO

Neurons that produce gonadotropin-releasing hormone (GnRH), which control fertility, complete their nose-to-brain migration by birth. However, their function depends on integration within a complex neuroglial network during postnatal development. Here, we show that rodent GnRH neurons use a prostaglandin D2 receptor DP1 signaling mechanism during infancy to recruit newborn astrocytes that 'escort' them into adulthood, and that the impairment of postnatal hypothalamic gliogenesis markedly alters sexual maturation by preventing this recruitment, a process mimicked by the endocrine disruptor bisphenol A. Inhibition of DP1 signaling in the infantile preoptic region, where GnRH cell bodies reside, disrupts the correct wiring and firing of GnRH neurons, alters minipuberty or the first activation of the hypothalamic-pituitary-gonadal axis during infancy, and delays the timely acquisition of reproductive capacity. These findings uncover a previously unknown neuron-to-neural-progenitor communication pathway and demonstrate that postnatal astrogenesis is a basic component of a complex set of mechanisms used by the neuroendocrine brain to control sexual maturation.


Assuntos
Hormônio Liberador de Gonadotropina , Maturidade Sexual , Astrócitos/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Hipotálamo/fisiologia , Neurônios/fisiologia , Maturidade Sexual/fisiologia
3.
EMBO Rep ; 21(9): e49807, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32657019

RESUMO

This study investigated the role of CDK4 in the oxidative metabolism of brown adipose tissue (BAT). BAT from Cdk4-/- mice exhibited fewer lipids and increased mitochondrial volume and expression of canonical thermogenic genes, rendering these mice more resistant to cold exposure. Interestingly, these effects were not BAT cell-autonomous but rather driven by increased sympathetic innervation. In particular, the ventromedial hypothalamus (VMH) is known to modulate BAT activation via the sympathetic nervous system. We thus examined the effects of VMH neuron-specific Cdk4 deletion. These mice display increased sympathetic innervation and enhanced cold tolerance, similar to Cdk4-/- mice, in addition to browning of scWAT. Overall, we provide evidence showing that CDK4 modulates thermogenesis by regulating sympathetic innervation of adipose tissue depots through hypothalamic nuclei, including the VMH. This demonstrates that CDK4 not only negatively regulates oxidative pathways, but also modulates the central regulation of metabolism through its action in the brain.


Assuntos
Tecido Adiposo Branco , Termogênese , Adipócitos Marrons , Tecido Adiposo Marrom , Animais , Hipotálamo , Camundongos , Termogênese/genética
4.
Cell Metab ; 30(4): 833-844.e7, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31474567

RESUMO

The hypothalamus plays a key role in the detection of energy substrates to regulate energy homeostasis. Tanycytes, the hypothalamic ependymo-glia, are located at a privileged position to integrate multiple peripheral inputs. We observed that tanycytes produce and secrete Fgf21 and are located close to Fgf21-sensitive neurons. Fasting, likely via the increase in circulating fatty acids, regulates this central Fgf21 production. Tanycytes store palmitate in lipid droplets and oxidize it, leading to the activation of a reactive oxygen species (ROS)/p38-MAPK signaling pathway, which is essential for tanycytic Fgf21 expression upon palmitate exposure. Tanycytic Fgf21 deletion triggers an increase in lipolysis, likely due to impaired inhibition of key neurons during fasting. Mice deleted for tanycytic Fgf21 exhibit increased energy expenditure and a reduction in fat mass gain, reminiscent of a browning phenotype. Our results suggest that tanycytes sense free fatty acids to maintain body lipid homeostasis through Fgf21 signaling within the hypothalamus.


Assuntos
Células Ependimogliais/metabolismo , Jejum/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Hipotálamo/metabolismo , Palmitatos/metabolismo , Células 3T3-L1 , Animais , Células Ependimogliais/citologia , Hipotálamo/citologia , Gotículas Lipídicas/metabolismo , Lipólise , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
5.
Sci Rep ; 6: 34909, 2016 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-27708432

RESUMO

Ketone bodies have been shown to transiently stimulate food intake and modify energy homeostasis regulatory systems following cerebral infusion for a moderate period of time (<6 hours). As ketone bodies are usually enhanced during episodes of fasting, this effect might correspond to a physiological regulation. In contrast, ketone bodies levels remain elevated for prolonged periods during obesity, and thus could play an important role in the development of this pathology. In order to understand this transition, ketone bodies were infused through a catheter inserted in the carotid to directly stimulate the brain for a period of 24 hours. Food ingested and blood circulating parameters involved in metabolic control as well as glucose homeostasis were determined. Results show that ketone bodies infusion for 24 hours increased food intake associated with a stimulation of hypothalamic orexigenic neuropeptides. Moreover, insulinemia was increased and caused a decrease in glucose production despite an increased resistance to insulin. The present study confirms that ketone bodies reaching the brain stimulates food intake. Moreover, we provide evidence that a prolonged hyperketonemia leads to a dysregulation of energy homeostasis control mechanisms. Finally, this study shows that brain exposure to ketone bodies alters insulin signaling and consequently glucose homeostasis.


Assuntos
Ingestão de Alimentos/fisiologia , Hipotálamo/metabolismo , Corpos Cetônicos/metabolismo , Ácido 3-Hidroxibutírico/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Artérias Carótidas , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/genética , Regulação da Expressão Gênica , Homeostase , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiopatologia , Infusões Intra-Arteriais , Resistência à Insulina , Corpos Cetônicos/genética , Corpos Cetônicos/farmacologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Camundongos Endogâmicos C57BL , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Pró-Opiomelanocortina/metabolismo , Simportadores/metabolismo
6.
Am J Physiol Endocrinol Metab ; 310(2): E103-15, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26530151

RESUMO

Monocarboxylates have been implicated in the control of energy homeostasis. Among them, the putative role of ketone bodies produced notably during high-fat diet (HFD) has not been thoroughly explored. In this study, we aimed to determine the impact of a specific rise in cerebral ketone bodies on food intake and energy homeostasis regulation. A carotid infusion of ketone bodies was performed on mice to stimulate sensitive brain areas for 6 or 12 h. At each time point, food intake and different markers of energy homeostasis were analyzed to reveal the consequences of cerebral increase in ketone body level detection. First, an increase in food intake appeared over a 12-h period of brain ketone body perfusion. This stimulated food intake was associated with an increased expression of the hypothalamic neuropeptides NPY and AgRP as well as phosphorylated AMPK and is due to ketone bodies sensed by the brain, as blood ketone body levels did not change at that time. In parallel, gluconeogenesis and insulin sensitivity were transiently altered. Indeed, a dysregulation of glucose production and insulin secretion was observed after 6 h of ketone body perfusion, which reversed to normal at 12 h of perfusion. Altogether, these results suggest that an increase in brain ketone body concentration leads to hyperphagia and a transient perturbation of peripheral metabolic homeostasis.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Corpos Cetônicos/farmacologia , Adenilato Quinase/metabolismo , Proteína Relacionada com Agouti/metabolismo , Animais , Glicemia , Dieta Hiperlipídica , Ingestão de Alimentos/fisiologia , Metabolismo Energético/fisiologia , Gluconeogênese/efeitos dos fármacos , Gluconeogênese/fisiologia , Homeostase , Hipotálamo/metabolismo , Resistência à Insulina/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuropeptídeo Y/metabolismo , Fosforilação/efeitos dos fármacos
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