RESUMO
The contribution of neuroglial interactions to the regulation of energy balance has gained increasing acceptance in recent years. In this context, endozepines, endogenous analogs of benzodiazepine derived from diazepam-binding inhibitor, are now emerging as major players. Produced by glial cells (astrocytes and tanycytes), endozepines have been known for two decades to exert potent anorexigenic effects by acting at the hypothalamic level. However, it is only recently that their modes of action, including the mechanisms by which they modulate energy metabolism, have begun to be elucidated. The data available today are abundant, significant, and sometimes contradictory, revealing a much more complex regulation than initially expected. Several mechanisms of action of endozepines seem to coexist at the central level, particularly in the hypothalamus. The brainstem has also recently emerged as a potential site of action for endozepines. In addition to their central anorexigenic effects, endozepines may also display peripheral effects promoting orexigenic actions, adding to their complexity and raising yet more questions. In this review, we attempt to provide an overview of our current knowledge in this rapidly evolving field and to pinpoint questions that remain unanswered.
Assuntos
Inibidor da Ligação a Diazepam , Neuroglia , Inibidor da Ligação a Diazepam/metabolismo , Metabolismo Energético , Hipotálamo/metabolismo , Neuroglia/metabolismo , PeptídeosRESUMO
The metabolic syndrome, which comprises obesity and diabetes, is a major public health problem and the awareness of energy homeostasis control remains an important worldwide issue. The energy balance is finely regulated by the central nervous system (CNS), notably through neuronal networks, located in the hypothalamus and the dorsal vagal complex (DVC), which integrate nutritional, humoral and nervous information from the periphery. The glial cells' contribution to these processes emerged few year ago. However, its underlying mechanism remains unclear. Glial connexin 43 hemichannels (Cx43 HCs) enable direct exchange with the extracellular space and can regulate neuronal network activity. In the present study, we sought to determine the possible involvement of glial Cx43 HCs in energy balance regulation. We here show that Cx43 is strongly expressed in the hypothalamus and DVC and is associated with glial cells. Remarkably, we observed a close apposition of Cx43 with synaptic elements in both the hypothalamus and DVC. Moreover, the expression of hypothalamic Cx43 mRNA and protein is modulated in response to fasting and diet-induced obesity. Functionally, we found that Cx43 HCs are largely open in the arcuate nucleus (ARC) from acute mice hypothalamic slices under basal condition, and significantly inhibited by TAT-GAP19, a mimetic peptide that specifically blocks Cx43 HCs activity. Moreover, intracerebroventricular (i.c.v.) TAT-GAP19 injection strongly decreased food intake, without further alteration of glycaemia, energy expenditures or locomotor activity. Using the immediate early gene c-Fos expression, we found that i.c.v. TAT-GAP19 injection induced neuronal activation in hypothalamic and brainstem nuclei dedicated to food intake regulation. Altogether, these results suggest a tonic delivery of orexigenic molecules associated with glial Cx43 HCs activity and a possible modulation of this tonus during fasting and obesity.
Assuntos
Conexina 43/metabolismo , Conexina 43/fisiologia , Ingestão de Alimentos , Síndrome Metabólica/metabolismo , Neuroglia/fisiologia , Fragmentos de Peptídeos/fisiologia , Animais , Astrócitos/metabolismo , Conexina 43/síntese química , Conexina 43/genética , Metabolismo Energético , Células Ependimogliais/metabolismo , Regulação da Expressão Gênica , Homeostase/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Síndrome Metabólica/genética , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Fragmentos de Peptídeos/síntese química , Proteínas Proto-Oncogênicas c-fos/metabolismo , Núcleo Solitário/metabolismoRESUMO
Research on energy homeostasis has focused on neuronal signaling; however, the role of glial cells has remained little explored. Glial endozepines exert anorexigenic actions by mechanisms which remain poorly understood. In this context, the present study was designed to decipher the mechanisms underlying the anorexigenic action of endozepines and to investigate their potential curative effect on high-fat diet-induced obesity. We carried out a combination of physiological, pharmacological, and molecular analyses together to dissect the underlying mechanisms of endozepine-induced hypophagia. To evaluate the potential anti-obesity effect of endozepines, different model of obesity were used, i.e., ob/ob and diet-induced obese mice. We show that the intracerebral administration of endozepines enhances satiety by targeting anorexigenic brain circuitry and induces STAT3 phosphorylation, a hallmark of leptin signaling. Strikingly, endozepines are entirely ineffective at reducing food intake in the presence of a circulating leptin antagonist and in leptin-deficient mice (ob/ob) but potentiate the reduced food intake and weight loss induced by exogenous leptin administration in these animals. Endozepines reversed high fat diet-induced obesity by reducing food intake and restored leptin-induced STAT3 phosphorylation in the hypothalamus. Interestingly, we observed that glucose and insulin synergistically enhance tanycytic endozepine expression and release. Finally, endozepines, which induce ERK activation necessary for leptin transport into the brain in cultured tanycytes, require tanycytic leptin receptor expression to promote STAT3 phosphorylation in the hypothalamus. Our data identify endozepines as potential anti-obesity compounds in part through the modulation of the LepR-ERK-dependent tanycytic leptin shuttle.
Assuntos
Inibidor da Ligação a Diazepam/metabolismo , Dieta Hiperlipídica , Hipotálamo/metabolismo , Leptina/metabolismo , Neuroglia/metabolismo , Obesidade/metabolismo , Animais , Ingestão de Alimentos/fisiologia , Metabolismo Energético/fisiologia , Homeostase/fisiologia , Leptina/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos ObesosRESUMO
Brain-derived neurotrophic factor (BDNF) has recently been implicated as an anorexigenic factor in the central control of food intake. Previous studies focused on the hypothalamus as a probable site of action for this neurotrophin. It was demonstrated that BDNF is an important downstream effector of melanocortin signaling in the ventromedial hypothalamus. In this study, we addressed whether BDNF can modulate food intake in the hindbrain autonomic integrator of food intake regulation, i.e. the dorsal vagal complex (DVC). To this end, we used two complementary methodological approaches in adult rats. First, we measured the effects of intraparenchymal infusions of exogenous BDNF within the DVC on food intake and body weight. Second, we measured the endogenous BDNF protein content in the DVC and hypothalamus after food deprivation, refeeding, or peripheral treatments by the anorexigenic hormones leptin and cholecystokinin (CCK). BDNF infusion within the DVC induced anorexia and weight loss. In the DVC, BDNF protein content decreased after 48 h food deprivation and increased after refeeding. Acute and repetitive peripheral leptin injections induced an increase of the BDNF protein content within the DVC. Moreover, peripheral CCK treatment induced a transient increase of BDNF protein content first in the DVC (30 min after CCK) and later on in the hypothalamus (2 h after CCK). Taken together, these results strongly support the view that BDNF plays a role as an anorexigenic factor in the DVC. Our data also suggest that BDNF may constitute a common downstream effector of leptin and CCK, possibly involved in their synergistic action.