STEM and EDXS characterisation of physico-chemical reactions at the periphery of sol-gel derived Zn-substituted hydroxyapatites during interactions with biological fluids

With its good properties of biocompatibility and bioactivity hydroxyapatite (HA) is highly used as bone substitutes and as coatings on metallic prostheses. In order to improve bioactive properties of HA we have elaborated Zn2+ doped hydroxyapatite. Zn2+ ions substitute for Ca2+ cations in the HA structure and four Zn concentrations (Zn/Zn+Ca) were prepared 0.5, 1, 2, 5 % at. To study physico-chemical reactions at the materials periphery, we immersed the bioceramics into biological fluids for delays from 1 day to 20 days. The surface changes were studied at the nanometer scale by scanning transmission electron microscopy associated to energy dispersive X-ray spectroscopy. After 20 days of immersion we observed the formation of a calcium-phosphate layer at the periphery of the HA doped with 5% of zinc. This layer contains magnesium and its thickness was around 200 nm. Formation of this Ca-P-Mg layer represents bioactivity properties of the 5% Zn-substituted hydroxyapatite. This biologically active layer improves properties of HA and will permit a chemical bond between the ceramic and bone

Microgliosis: a double-edged sword in the control of food intake

Maintaining energy balance is essential for survival and health. This physiological function is controlled by the brain, which adapts food intake to energy needs. Indeed, the brain constantly receives a multitude of biological signals that are derived from digested foods or that originate from the gastrointestinal tract, energy stores (liver and adipose tissues) and other metabolically active organs (muscles). These signals, which include circulating nutrients, hormones and neuronal inputs from the periphery, collectively provide information on the overall energy status of the body. In the brain, several neuronal populations can specifically detect these signals. Nutrient-sensing neurons are found in discrete brain areas and are highly enriched in the hypothalamus. In turn, specialized brain circuits coordinate homeostatic responses acting mainly on appetite, peripheral metabolism, activity and arousal. Accumulating evidence shows that hypothalamic microglial cells located at the vicinity of these circuits can influence the brain control of energy balance. However, microglial cells could have opposite effects on energy balance, that is homeostatic or detrimental, and the conditions for this shift are not totally understood yet. One hypothesis relies on the extent of microglial activation, and nutritional lipids can considerably change it

Postprandial hyperglycemia stimulates neuroglial plasticity in hypothalamic POMC neurons after a balanced meal

Mechanistic studies in rodents evidenced synaptic remodeling in neuronal circuits that control food intake. However, the physiological relevance of this process is not well defined. Here, we show that the firing activity of anorexigenic POMC neurons located in the hypothalamus is increased after a standard meal. Postprandial hyperactivity of POMC neurons relies on synaptic plasticity that engages pre-synaptic mechanisms, which does not involve structural remodeling of synapses but retraction of glial coverage. These functional and morphological neuroglial changes are triggered by postprandial hyperglycemia. Chemogenetically induced glial retraction on POMC neurons is sufficient to increase POMC activity and modify meal patterns. These findings indicate that synaptic plasticity within the melanocortin system happens at the timescale of meals and likely contributes to short-term control of food intake. Interestingly, these effects are lost with a high-fat meal, suggesting that neuroglial plasticity of POMC neurons is involved in the satietogenic properties of foods.Contrôle nerveux de la prise alimentaire et du métabolisme par une molécule neurale d'adhésion cellulaireISITE " BFCRéseau d'Innovation sur les Voies de Signalisation en Sciences de la Vi

Contribution des voies de la cyclooxygénase et de la NO synthase aux propriétés pharmacologiques des anti-inflammatoires non stéroïdiens

NANCY1-SCD Pharmacie-Odontologie (543952101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Plasticity of the melanocortin system: Determinants and possible consequences on food intake

The melanocortin system is one of the most important neuronal pathways involved in the regulation of food intake and is probably the best characterized. Agouti-related peptide (AgRP) and proopiomelanocortin (POMC) expressing neurons located in the arcuate nucleus of the hypothalamus are the key elements of this system. These two neuronal populations are sensitive to circulating molecules and receive many excitatory and inhibitory inputs from various brain areas. According to sensory and metabolic information they integrate, these neurons control different aspects of feeding behavior and orchestrate autonomic responses aimed at maintaining energy homeostasis. Interestingly, composition and abundance of pre-synaptic inputs onto arcuate AgRP and POMC neurons vary in the adult hypothalamus in response to changes in the metabolic state, a phenomenon that can be recapitulated by treatment with hormones, such as leptin or ghrelin. As described in other neuroendrocrine systems, glia might be determinant to shift the synaptic configuration of AgRP and POMC neurons. Here, we discuss the physiological outcome of the synaptic plasticity of the melanocortin system, and more particularly its contribution to the control of energy balance. The discovery of this attribute has changed how we view obesity and related disorders, and opens new perspectives for their management

Inactivation of Socs3 in the hypothalamus enhances the hindbrain response to endogenous satiety signals via oxytocin signaling

Leptin is an adipocyte-derived hormone that controls energy balance by acting primarily in the CNS, but its action is lost in common forms of obesity due to central leptin resistance. One potential mechanism for such leptin resistance is an increased hypothalamic expression of Suppressor of cytokine signaling 3 (Socs3), a feedback inhibitor of the Jak-Stat pathway that prevents Stat3 activation. Ample studies have confirmed the important role of Socs3 in leptin resistance and obesity. However, the degree to which Socs3 participates in the regulation of energy homeostasis in nonobese conditions remains largely undetermined. In this study, using adult mice maintained under standard diet, we demonstrate that Socs3 deficiency in the mediobasal hypothalamus (MBH) reduces food intake, protects against body weight gain, and limits adiposity, suggesting that Socs3 is necessary for normal body weight maintenance. Mechanistically, MBH Socs3-deficient mice display increased hindbrain sensitivity to endogenous, meal-related satiety signals, mediated by oxytocin signaling. Thus, oxytocin signaling likely mediates the effect of hypothalamic leptin on satiety circuits of the caudal brainstem. This provides an anatomical substrate for the effect of leptin on meal size, and more generally, a mechanism for how the brain controls short-term food intake as a function of the energetic stores available in the organism to maintain energy homeostasis. Any dysfunction in this pathway could potentially lead to overeating and obesity

Crosstalk between hypothalamic neurons and olfactory system: a tracing and anatomo-fuctional investigation in mouse

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Evaluation of the 26RFa/GPR103 peptidergic system in a mouse model of insulinopenia

International audienc

The histone acetyltransferase MOF activates hypothalamic polysialylation to prevent diet-induced obesity in mice

Overfeeding causes rapid synaptic remodeling in hypothalamus feeding circuits. Polysialylation of cell surface molecules is a key step in this neuronal rewiring and allows normalization of food intake. Here we examined the role of hypothalamic polysialylation in the long-term maintenance of body weight, and deciphered the molecular sequence underlying its nutritional regulation. We found that upon high fat diet (HFD), reduced hypothalamic polysialylation exacerbated the diet-induced obese phenotype in mice. Upon HFD, the histone acetyltransferase MOF was rapidly recruited on the St8sia4 polysialyltransferase-encoding gene. Mof silencing in the mediobasal hypothalamus of adult mice prevented activation of the St8sia4 gene transcription, reduced polysialylation, altered the acute homeostatic feeding response to HFD and increased the body weight gain. These findings indicate that impaired hypothalamic polysialylation contribute to the development of obesity, and establish a role for MOF in the brain control of energy balance

Interactions between the regulatory peptide 26RFa (QRFP) and insulin in the regulation of glucose homeostasis in two complementary models: The high fat 26RFa-deficient mice and the streptozotocin insulin-deficient mice

International audienceThe regulatory peptide 26RFa (QRFP) is involved in the control of glucose homeostasis at the periphery by acting as an incretin, and in the brain by mediating the central antihyperglycemic effect of insulin, indicating the occurrence of a close relationship between 26RFa and insulin in the regulation of glucose metabolism. Here, we investigated the physiological interactions between 26RFa and insulin in two complementary models i.e. a model of obese/hyperglycemic mice deficient for 26RFa and a model of diabetic mice deficient for insulin. For this, transgenic 26RFa-deficient mice were made obese and chronically hyperglycemic by a 3-month high fat diet (HFD) and second group of mice was made diabetic by destruction of the β cells of the pancreatic islets using a single injection of streptozotocin. Our data reveal that 26RFa deficiency does not impact significantly the “glycemic” phenotype of the HFD mice. The pancreatic islets, liver, white adipose tissue masses are not altered by the lack of 26RFa production but the brown adipose tissue (BAT) weight is significantly increased in these animals. In diabetic insulin-deficient mice, the injection of 26RFa does not exhibit any beneficial effect on the impaired glucose homeostasis characterizing this model. Finally, we show that streptozotocin diabetic mice display lowered plasma 26RFa levels as compared to untreated mice, whereas the expression of the peptide in the duodenum is not affected. Taken together, the present results indicate that dysregulation of glucose homeostasis in obese/hyperglycemic mice is not aggravated by the absence of 26RFa that may be compensated by the increase of BAT mass. In diabetic insulin-deficient mice, the antihypergycemic effect of 26RFa is totally blunted probably as a result of the impaired insulin production characterizing this model, avoiding therefore the action of the peptide