Modern lifestyle has profoundly modified human sleep habits. Sleep duration has shortened over recent decades from 8 to 6.5 hours resulting in chronic sleep deprivation. Additionally, irregular sleep, shift work and travelling across time zones lead to disruption of circadian rhythms and asynchrony between the master hypothalamic clock and pacemakers in peripheral tissues. Furthermore, obstructive sleep apnea syndrome (OSA), which affects 4 - 15% of the population, is not only characterized by impaired sleep architecture but also by repetitive hemoglobin desaturations during sleep. Epidemiological studies have identified impaired sleep as an independent risk factor for all cause of-, as well as for cardiovascular, mortality/morbidity. More recently, sleep abnormalities were causally linked to impairments in glucose homeostasis, metabolic syndrome and Type 2 Diabetes Mellitus (T2DM). This review summarized current knowledge on the metabolic alterations associated with the most prevalent sleep disturbances, i.e. short sleep duration, shift work and OSA. We have focused on various endocrine and molecular mechanisms underlying the associations between inadequate sleep quality, quantity and timing with impaired glucose tolerance, insulin resistance and pancreatic β-cell dysfunction. Of these mechanisms, the role of the hypothalamic-pituitary-adrenal axis, circadian pacemakers in peripheral tissues, adipose tissue metabolism, sympathetic nervous system activation, oxidative stress and whole-body inflammation are discussed. Additionally, the impact of intermittent hypoxia and sleep fragmentation (key components of OSA) on intracellular signaling and metabolism in muscle, liver, fat and pancreas are also examined. In summary, this review provides endocrine and molecular explanations for the associations between common sleep disturbances and the pathogenesis of T2DM.

Commissural axon guidance requires complex modulations of growth cone sensitivity to midline-derived cues, but underlying mechanisms in vertebrates remain largely unknown. By using combinations of ex vivo and in vivo approaches, we uncovered a molecular pathway controlling the gain of response to a midline repellent, Semaphorin3B (Sema3B). First, we provide evidence that Semaphorin3B/Plexin-A1 signaling participates in the guidance of commissural projections at the vertebrate ventral midline. Second, we show that, at the precrossing stage, commissural neurons synthesize the Neuropilin-2 and Plexin-A1 Semaphorin3B receptor subunits, but Plexin-A1 expression is prevented by a calpain1-mediated processing, resulting in silencing commissural responsiveness. Third, we report that, during floor plate (FP) in-growth, calpain1 activity is suppressed by local signals, allowing Plexin-A1 accumulation in the growth cone and sensitization to Sema3B. Finally, we show that the FP cue NrCAM mediates the switch of Plexin-A1 processing underlying growth cone sensitization to Sema3B. This reveals pathway-dependent modulation of guidance receptor processing as a novel mechanism for regulating guidance decisions at intermediate targets.

The chemotropic guidance cue netrin-1 promotes neurite outgrowth through its receptor Deleted in Colorectal Cancer (DCC) via activation of Rac1. The guanine nucleotide exchange factor (GEF) linking netrin-1/DCC to Rac1 activation has not yet been identified. Here, we show that the RhoGEF Trio mediates Rac1 activation in netrin-1 signaling. We found that Trio interacts with the netrin-1 receptor DCC in mouse embryonic brains and that netrin-1-induced Rac1 activation in brain is impaired in the absence of Trio. Trio(-/-) cortical neurons fail to extend neurites in response to netrin-1, while they are able to respond to glutamate. Accordingly, netrin-1-induced commissural axon outgrowth is reduced in Trio(-/-) spinal cord explants, and the guidance of commissural axons toward the floor plate is affected by the absence of Trio. The anterior commissure is absent in Trio-null embryos, and netrin-1/DCC-dependent axonal projections that form the internal capsule and the corpus callosum are defective in the mutants. Taken together, these findings establish Trio as a GEF that mediates netrin-1 signaling in axon outgrowth and guidance through its ability to activate Rac1.

The transcription factor Elk-1 is a nuclear target of mitogen-activated protein kinases and regulates immediate early gene activation by extracellular signals. We show that Elk-1 is also conjugated to SUMO on either lysines 230, 249, or 254. Mutation of all three sites is necessary to fully block SUMOylation in vitro and in vivo. This Elk-1 mutant, Elk-1(3R), shuttles more rapidly to nuclei of Balb/C cells fused to transfected HeLa cells. Coexpression of SUMO-1 or -2 strongly reduces shuttling by Elk-1 without affecting that of Elk-1(3R), indicating that SUMOylation regulates nuclear retention of Elk-1. Accordingly, overexpression of Elk-1(3R) in PC12 cells, where cytoplasmic relocalization of Elk-1 has been linked to differentiation, enhances neurite extension relative to Elk-1. The effect of Elk-1, but not of the 3R mutant, was blocked upon cotransfection with SUMO-1 or -2 and enhanced by coexpression with mutant Ubc-9. Thus, SUMO conjugation is a novel regulator of Elk-1 function through the control of its nuclear-cytoplasmic shuttling.

Obstructive sleep apnea (OSA) is a major risk factor for cardiovascular mortality, and apnea-induced intermittent hypoxia (IH) is known to promote various cardiovascular alterations such as vascular remodeling. However, the mechanisms that underlie IH remain incompletely investigated. We previously demonstrated that the hypoxia-inducible factor-1 (HIF-1) and endothelin-1 (ET-1) are involved in arterial hypertension and myocardial susceptibility to infarction induced by IH. Thus the objective of the present study was to investigate whether both ET-1 and HIF-1 were also involved in the vascular inflammatory remodeling induced by IH. Mice partially deficient for the Hif1α gene (HIF-1α^+/−) and their wild-type equivalents, as well as C57BL/6J mice, treated or not with bosentan, a dual endothelin receptor antagonist, were exposed to IH or normoxia for 2 wk, 8 h/day. Splenocyte proliferative and secretory capacities, aortic nuclear factor-κB (NF-κB) and HIF-1 activities, and expression of cytokines and intima-media thickness (IMT) were measured. IH induced a systemic and aortic inflammation characterized by an increase in splenocyte proliferative and secretory capacities, aortic NF-κB activity, and cytokine expression in the aortic wall. This was accompanied by an increase in IMT. These modifications were prevented in HIF-1α^+/− and bosentan-treated mice. The results of this study suggest that ET-1 is a major contributor to the vascular inflammatory remodeling induced by OSA-related IH, probably through HIF-1-dependent activation of NF-κB.