Animal survival relies on a constant balance between energy supply and energy expenditure, which is controlled by several neuroendocrine functions that integrate metabolic information and adapt the ...response of the organism to physiological demands. Polarized ependymoglial cells lining the floor of the third ventricle and sending a single process within metabolic hypothalamic parenchyma, tanycytes are henceforth described as key components of the hypothalamic neural network controlling energy balance. Their strategic position and peculiar properties convey them diverse physiological functions ranging from blood/brain traffic controllers, metabolic modulators, and neural stem/progenitor cells. At the molecular level, these functions rely on an accurate regulation of gene expression. Indeed, tanycytes are characterized by their own molecular signature which is mostly associated to their diverse physiological functions, and the detection of variations in nutrient/hormone levels leads to an adequate modulation of genetic profile in order to ensure energy homeostasis. The aim of this review is to summarize recent knowledge on the nutritional control of tanycyte gene expression.
Insulin resistance is a hallmark of diabetes and an unmet clinical need. Insulin inhibits hepatic glucose production and promotes lipogenesis by suppressing FOXO1-dependent activation of G6pase and ...inhibition of glucokinase, respectively. The tight coupling of these events poses a dual conundrum: mechanistically, as the FOXO1 corepressor of glucokinase is unknown, and clinically, as inhibition of glucose production is predicted to increase lipogenesis. Here, we report that SIN3A is the insulin-sensitive FOXO1 corepressor of glucokinase. Genetic ablation of SIN3A abolishes nutrient regulation of glucokinase without affecting other FOXO1 target genes and lowers glycemia without concurrent steatosis. To extend this work, we executed a small-molecule screen and discovered selective inhibitors of FOXO-dependent glucose production devoid of lipogenic activity in hepatocytes. In addition to identifying a novel mode of insulin action, these data raise the possibility of developing selective modulators of unliganded transcription factors to dial out adverse effects of insulin sensitizers.
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•Discovery of SIN3a as the FOXO corepressor of hepatic glucokinase•SIN3a regulates hepatic insulin sensitivity•Corepressor clearance as a novel mechanism of gene induction by insulin•Selective targeting of the activator and repressor functions of FOXO1
The transcriptional output of FOXO1 can be selectively modulated in a way that might reduce adverse effects of insulin sensitizers.
The development of insulin resistance (IR) in the liver is a key pathophysiologic event in the development of type 2 diabetes. Although insulin loses its ability to suppress glucose production, it ...largely retains its capacity to drive lipogenesis. This selective IR results in the characteristic hyperglycemia and dyslipidemia of type 2 diabetes. The delineation of two branched pathways of insulin receptor (InsR) signaling to glucose versus triglyceride production, one through FoxO and the other through SREBP-1c, provides a mechanism to account for this pathophysiological abnormality. We tested the complementary hypothesis that selective IR arises due to different intrinsic sensitivities of glucose production versus de novo lipogenesis to insulin as a result of cell-autonomous down-regulation of InsR number in response to chronic hyperinsulinemia. We demonstrate in mouse primary hepatocytes that chronic hyperinsulinemia abrogates insulin's inhibition of glucose production, but not its stimulation of de novo lipogenesis. Using a competitive inhibitor of InsR, we show that there is a 4-fold difference between levels of InsR inhibition required to cause resistance of glucose production versus lipogenesis to the actions of insulin. Our data support a parsimonious model in which differential InsR activation underlies the selective IR of glucose production relative to lipogenesis, but both processes require signaling through Akt1/2.
Background: The liver produces both excessive glucose and lipids in type 2 diabetes.
Results: Glucose production is more vulnerable to insulin receptor (InsR) impairment ex vivo than is lipogenesis.
Conclusion: Selective insulin resistance arises due to inherent, cell-autonomous differences in the insulin responsiveness of glucose versus lipid metabolism.
Significance: InsR itself may represent a locus of treatment of diabetes.
The delivery of blood-borne molecules conveying metabolic information to neural networks that regulate energy homeostasis is restricted by brain barriers. The fenestrated endothelium of median ...eminence microvessels and tight junctions between tanycytes together compose one of these. Here, we show that the decrease in blood glucose levels during fasting alters the structural organization of this blood-hypothalamus barrier, resulting in the improved access of metabolic substrates to the arcuate nucleus. These changes are mimicked by 2-deoxyglucose-induced glucoprivation and reversed by raising blood glucose levels after fasting. Furthermore, we show that VEGF-A expression in tanycytes modulates these barrier properties. The neutralization of VEGF signaling blocks fasting-induced barrier remodeling and significantly impairs the physiological response to refeeding. These results implicate glucose in the control of blood-hypothalamus exchanges through a VEGF-dependent mechanism and demonstrate a hitherto unappreciated role for tanycytes and the permeable microvessels associated with them in the adaptive metabolic response to fasting.
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► Fasting induces the plasticity of brain barriers in hypothalamic feeding regions ► Central neuroglucopenia triggers blood-hypothalamus barrier plasticity ► Fasting-induced brain barrier plasticity requires VEGF-A expression in tanycytes ► The tanycytic barrier modulates blood-borne signals access to CNS feeding circuits
To maintain homeostasis, hypothalamic neurons in the arcuate nucleus must dynamically sense and integrate a multitude of peripheral signals. Blood-borne molecules must therefore be able to circumvent ...the tightly sealed vasculature of the blood–brain barrier to rapidly access their target neurons. However, how information encoded by circulating appetite-modifying hormones is conveyed to central hypothalamic neurons remains largely unexplored. Using in vivo multiphoton microscopy together with fluorescently labeled ligands, we demonstrate that circulating ghrelin, a versatile regulator of energy expenditure and feeding behavior, rapidly binds neurons in the vicinity of fenestrated capillaries, and that the number of labeled cell bodies varies with feeding status. Thus, by virtue of its vascular connections, the hypothalamus is able to directly sense peripheral signals, modifying energy status accordingly.
Glucagon-like peptide 1 (GLP-1), produced in the intestine and the brain, can stimulate insulin secretion from the pancreas and alleviate type 2 diabetes. The cytokine interleukin-6 (IL-6) may ...enhance insulin secretion from β-cells by stimulating peripheral GLP-1 production. GLP-1 and its analogs also reduce food intake and body weight, clinically beneficial actions that are likely exerted at the level of the CNS, but otherwise are poorly understood. The cytokines IL-6 and interleukin 1β (IL-1β) may exert an anti-obesity effect in the CNS during health. Here we found that central injection of a clinically used GLP-1 receptor agonist, exendin-4, potently increased the expression of IL-6 in the hypothalamus (11-fold) and the hindbrain (4-fold) and of IL-1β in the hypothalamus, without changing the expression of other inflammation-associated genes. Furthermore, hypothalamic and hindbrain interleukin-associated intracellular signals phosphorylated signal transducer and activator of transcription-3 (pSTAT3) and suppressor of cytokine signaling-1 (SOCS1) were also elevated by exendin-4. Pharmacologic disruption of CNS IL-1 receptor or IL-6 biological activity attenuated anorexia and body weight loss induced by central exendin-4 administration in a rat. Simultaneous blockade of IL-1 and IL-6 activity led to a more potent attenuation of exendin-4 effects on food intake. Mice with global IL-1 receptor gene knockout or central IL-6 receptor knockdown showed attenuated decrease in food intake and body weight in response to peripheral exendin-4 treatment. GLP-1 receptor activation in the mouse neuronal Neuro2A cell line also resulted in increased IL-6 expression. These data outline a previously unidentified role of the central IL-1 and IL-6 in mediating the anorexic and body weight loss effects of GLP-1 receptor activation.
Reproductive competence in mammals depends on the projection of gonadotropin-releasing hormone (GnRH) neurons to the hypothalamic median eminence (ME) and the timely release of GnRH into the ...hypothalamic-pituitary-gonadal axis. In adult rodents, GnRH neurons and the specialized glial cells named tanycytes periodically undergo cytoskeletal plasticity. However, the mechanisms that regulate this plasticity are still largely unknown. We demonstrate that Semaphorin7A, expressed by tanycytes, plays a dual role, inducing the retraction of GnRH terminals and promoting their ensheathment by tanycytic end feet via the receptors PlexinC1 and Itgb1, respectively. Moreover, Semaphorin7A expression is regulated during the oestrous cycle by the fluctuating levels of gonadal steroids. Genetic invalidation of Semaphorin7A receptors in mice induces neuronal and glial rearrangements in the ME and abolishes normal oestrous cyclicity and fertility. These results show a role for Semaphorin7A signalling in mediating periodic neuroglial remodelling in the adult ME during the ovarian cycle.
Abstract Objective Excess nutrient supply and rapid weight gain during early life are risk factors for the development of obesity during adulthood. This metabolic malprogramming may be mediated by ...endocrine disturbances during critical periods of development. Ghrelin is a metabolic hormone secreted from the stomach that acts centrally to promote feeding behavior by binding to growth hormone secretagogue receptors in the arcuate nucleus of the hypothalamus. Here, we examined whether neonatal overnutrition causes changes in the ghrelin system. Methods We used a well-described mouse model of divergent litter sizes to study the effects of postnatal overfeeding on the central and peripheral ghrelin systems during postnatal development. Results Mice raised in small litters became overweight during lactation and remained overweight with increased adiposity as adults. Neonatally overnourished mice showed attenuated levels of total and acyl ghrelin in serum and decreased levels of Ghrelin mRNA expression in the stomach during the third week of postnatal life. Normalization of hypoghrelinemia in overnourished pups was relatively ineffective at ameliorating metabolic outcomes, suggesting that small litter pups may present ghrelin resistance. Consistent with this idea, neonatally overnourished pups displayed an impaired central response to peripheral ghrelin. The mechanisms underlying this ghrelin resistance appear to include diminished ghrelin transport into the hypothalamus. Conclusions Early postnatal overnutrition results in central resistance to peripheral ghrelin during important periods of hypothalamic development. Because ghrelin signaling has recently been implicated in the neonatal programming of metabolism, these alterations in the ghrelin system may contribute to the metabolic defects observed in postnatally overnourished mice.
During hypothalamic development, the germinative neuroepithelium gives birth to diverse neural cells that regulate numerous physiological functions in adulthood.
Here, we studied the ontogeny of ...ependymal cells in the mouse mediobasal hypothalamus using the BrdU approach and publicly available single-cell RNAseq datasets.
We observed that while typical ependymal cells are mainly produced at E13, tanycyte birth depends on time and subtypes and lasts up to P8. Typical ependymocytes and β tanycytes are the first to arise at the top and bottom of the dorsoventral axis around E13, whereas α tanycytes emerge later in development, generating an outside-in dorsoventral gradient along the third ventricle. Additionally, α tanycyte generation displayed a rostral-to-caudal pattern. Finally, tanycytes mature progressively until they reach transcriptional maturity between P4 and P14.
Altogether, this data shows that ependyma generation differs in time and distribution, highlighting the heterogeneity of the third ventricle.
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