Apelin receptors: From signaling to antidiabetic strategy.

The G protein-coupled receptor APJ and its cognate ligand, apelin, are widely expressed throughout human body. They are implicated in different key physiological processes such as angiogenesis, cardiovascular functions, fluid homeostasis and energy metabolism regulation. On the other hand, this couple ligand-receptor is also involved in the development and progression of different pathologies including diabetes, obesity, cardiovascular disease and cancer. Recently, a new endogenous peptidic ligand of APJ, named Elabela/Toddler, has been identified and shown to play a crucial role in embryonic development. Whereas nothing is yet known regarding Elabela/Toddler functions in adulthood, apelin has been extensively described as a beneficial adipokine regarding to glucose and lipid metabolism and is endowed with anti-diabetic and anti-obesity properties. Indeed, there is a growing body of evidence supporting apelin signaling as a novel promising therapeutic target for metabolic disorders (obesity, type 2 diabetes). In this review, we provide an overview of the pharmacological properties of APJ and its endogenous ligands. We also report the activity of peptidic and non-peptidic agonists and antagonists targeting APJ described in the literature. Finally, we highlight the important role of this signaling pathway in the control of energy metabolism at the peripheral level and in the central nervous system in both physiological conditions and during obesity or diabetes.

Gut microbiota controls adipose tissue expansion, gut barrier and glucose metabolism: novel insights into molecular targets and interventions using prebiotics.

Crosstalk between organs is crucial for controlling numerous homeostatic systems (e.g. energy balance, glucose metabolism and immunity). Several pathological conditions, such as obesity and type 2 diabetes, are characterised by a loss of or excessive inter-organ communication that contributes to the development of disease. Recently, we and others have identified several mechanisms linking the gut microbiota with the development of obesity and associated disorders (e.g. insulin resistance, type 2 diabetes, hepatic steatosis). Among these, we described the concept of metabolic endotoxaemia (increase in plasma lipopolysaccharide levels) as one of the triggering factors leading to the development of metabolic inflammation and insulin resistance. Growing evidence suggests that gut microbes contribute to the onset of low-grade inflammation characterising these metabolic disorders via mechanisms associated with gut barrier dysfunctions. We have demonstrated that enteroendocrine cells (producing glucagon-like peptide-1, peptide YY and glucagon-like peptide-2) and the endocannabinoid system control gut permeability and metabolic endotoxaemia. Recently, we hypothesised that specific metabolic dysregulations occurring at the level of numerous organs (e.g. gut, adipose tissue, muscles, liver and brain) rely from gut microbiota modifications. In this review, we discuss the mechanisms linking gut permeability, adipose tissue metabolism, and glucose homeostasis, and recent findings that show interactions between the gut microbiota, the endocannabinoid system and the apelinergic system. These specific systems are discussed in the context of the gut-to-peripheral organ axis (intestine, adipose tissue and brain) and impacts on metabolic regulation. In the present review, we also briefly describe the impact of a variety of non-digestible nutrients (i.e. inulin-type fructans, arabinoxylans, chitin glucans and polyphenols). Their effects on the composition of the gut microbiota and activity are discussed in the context of obesity and type 2 diabetes.

Involvement of NPY Y2 receptor subtype in the control of the spontaneous NO/GnRH release at the rat median eminence.

The role of nitric oxide (NO) from vascular endothelium in the control of GnRH release at the median eminence (ME) level is well established. Interactions between NPY receptor/endothelium/nitric oxide are clearly demonstrated. While several studies implicate NPY Y1 receptor in the control of GnRH/LH at the time of the preovulatory LH surge, our results also demonstrate the importance of NPY Y2 receptor in the control of GnRH release via endothelial NO. We conclude that NPY may be one of the elements implicated in the generation of the spontaneous NO/GnRH via Y2 receptor located on endothelium.

Variation of endothelial nitric oxide synthase synthesis in the median eminence during the rat estrous cycle: an additional argument for the implication of vascular blood vessel in the control of GnRH release.

Recent studies from our laboratory suggested that the vascular endothelium of the median eminence was involved via nitric oxide secretion in the modulation of GnRH release during the estrous cycle. To further investigate that issue, we studied the variations of endothelial nitric oxide synthase protein and mRNA in the median eminence of female rats killed at different time points of the day and/or of the estrous cycle. Endothelial nitric oxide synthase protein levels were measured by Western blot, and endothelial nitric oxide synthase mRNA analysis was performed with semiquantitative RT-PCR (for each time point, n = 4). The results revealed that endothelial nitric oxide synthase synthesis varied markedly across the estrous cycle. Indeed, endothelial nitric oxide synthase protein (n = 20) and mRNA (n = 16) levels increase significantly on 0800 h and 1600 h proestrus compared with 1400 h diestrus II. In a second step, quantification analysis were made in median eminence obtained from ovariectomized and ovariectomized, E2 benzoate primed rat. The results show a significant increase in expression of endothelial nitric oxide synthase protein as well as endothelial nitric oxide synthase mRNA in ovx-E2 primed rat median eminence. Concurrently, the levels of the cav-1 protein, a specific endogenous inhibitor of endothelial nitric oxide synthase, were measured in median eminence during estrous cycle and in ME from ovx and ovx-E2 primed rats. A significant decrease of median eminence cav-1 was noted on 1600 h proestrus and in ovx-E2 primed rats when compared with 1400 h diestrus II and ovx, respectively. Altogether, these results strongly suggest that high NO release from median eminence observed on proestrus may be due to an increase of endothelial nitric oxide synthase expression and a decrease of the cav-1 protein levels. These findings demonstrate that E2 is able to modulate endothelial nitric oxide synthase and cav-1 expression both during the estrous cycle and in experimental conditions and consequently reinforce the idea that nitric oxide acting on GnRH release, is essentially endothelial in origin. These results may also imply that variations of endothelial nitric oxide synthase expression are essential for the pulsatile/cyclic nitric oxide median eminence release observed in a previous study.

Evidence for a spontaneous nitric oxide release from the rat median eminence: influence on gonadotropin-releasing hormone release.

The involvement of nitric oxide (NO) as a gaseous neurotransmitter in the hypothalamic control of pituitary LH secretion has been demonstrated. NO, as a diffusible signaling gas, has the ability to control and synchronize the activity of the neighboring cells. NO is secreted at the median eminence (ME), the common termination field for the antehypophysiotropic neurons, under the stimulation of other signaling substances. At the ME, NO stimulates GnRH release from neuroendocrine terminals. The present studies were undertaken to determine whether NO is secreted spontaneously from ME fragments ex vivo and whether its secretion is correlated to GnRH release. To accomplish this, female rats were killed at different time points of the day and/or of the estrous cycle. The spontaneous NO release was monitored in real time, with an amperometric probe, during 4 periods of 30 min, from individual ME fragments (for each time point, n = 4). GnRH levels were measured in parallel for each incubation-period by RIA. The results revealed that NO was released in a pulsatile manner from female ME fragments and, unambiguously, that the amplitude of NO secretion varied markedly across the estrous cycle. Indeed, though the NO pulse period (32 +/- 1 min, n = 36) and duration (21 +/- 2 min, n = 36) did not vary significantly across the estrous cycle, the amplitude of this secretion pulse was significantly higher on proestrus (Pro; 39 +/- 3 nM, n = 20), compared with diestrus (16 +/- 1 nM, n = 8) or estrus (23 +/- 3 nM, n = 8, P < 0.05). The GnRH levels in the incubation medium were positively correlated to NO secretion across the estrous cycle (r = 0.86, P < 0.003, n = 9), confirming that NO and GnRH release are coupled. Furthermore, 5 x 10(-7) M L-N(5)-(1-iminoethyl)ornithine (L-NIO), a NO synthase inhibitor, succeeded in inhibiting the strong NO-GnRH secretory coupling and GnRH release on PRO: Because at this concentration, L-NIO selectively inhibits endothelial NO synthase, the results further demonstrate that the major source of NO involved in GnRH release at the ME is endothelial in origin. Additionally, the induction of a massive NO/GnRH release in 15-day ovariectomized rat treated with estradiol benzoate strongly suggested that estradiol is participating in the stimulation of NO release activity between diestrus II and PRO: The present study is the first demonstrating that ME can spontaneously release NO and that NO's rhythm of secretion varies markedly across the estrous cycle. This pulsatile/cyclic ME NO release may constitute the synchronizing link to anatomically scattered GnRH neurons.