Dysfonction métabolique et stress chronique: un nouveau regard sur la pandémie de "diabésité" [Metabolic dysfunction and chronic stress: a new sight at "diabesity" pandemic]

Chronic stress in Western society can activate the autonomus, neuroendocrine and inflammatory/immunlogic systems. Chronic exposure to stressors can indeed stimulate the hypothalamic-pituitary-adrenal axis and induce a disbalance between anabolic and catabolic hormones, responsible of an increased in visceral fat and of insulin resistance. These metabolic consequences can lead to pre-diabetes. Exposure to chronic stress results in allostatic load and its pathophysiologic consequences. The knowledge of this mecanisms and the cardiovascular and metabolic risk related, should influence our way of thinking about patient care. To decrease allostatic load, practitioners can rely on therapeutic relation. Therapeutic education is one of the skill that can be use to create therapeutic relation.

Astressin B, a nonselective corticotropin-releasing hormone receptor antagonist, prevents the inhibitory effect of ghrelin on luteinizing hormone pulse frequency in the ovariectomized rhesus monkey.

Administration of ghrelin, a key peptide in the regulation of energy homeostasis, has been shown to decrease LH pulse frequency while concomitantly elevating cortisol levels. Because increased endogenous CRH release in stress is associated with an inhibition of reproductive function, we have tested here whether the pulsatile LH decrease after ghrelin may reflect an activated hypothalamic-pituitary-adrenal axis and be prevented by a CRH antagonist. After a 3-h baseline LH pulse frequency monitoring, five adult ovariectomized rhesus monkeys received a 5-h saline (protocol 1) or ghrelin (100-microg bolus followed by 100 microg/h, protocol 2) infusion. In protocols 3 and 4, animals were given astressin B, a nonspecific CRH receptor antagonist (0.45 mg/kg im) 90 min before ghrelin or saline infusion. Blood samples were taken every 15 min for LH measurements, whereas cortisol and GH were measured every 45 min. Mean LH pulse frequency during the 5-h ghrelin infusion was significantly lower than in all other treatments (P < 0.05) and when compared with the baseline period (P < 0.05). Pretreatment with astressin B prevented the decrease. Ghrelin stimulated cortisol and GH secretion, whereas astressin B pretreatment prevented the cortisol, but not the GH, release. Our data indicate that CRH release mediates the inhibitory effect of ghrelin on LH pulse frequency and suggest that the inhibitory impact of an insufficient energy balance on reproductive function may in part be mediated by the hypothalamic-pituitary-adrenal axis.

Cortisol salival como indicador de estrés fisiológico en niños y adultos; revisión sistemática.

Salivary cortisol is a steroid hormone that is produced in the hypothalamic-pituitary-adrenal axis and secreted into saliva when persons are under stress. High levels of cortisol in saliva can be produced by many different factors, including obesity and certain psychological disorders. The articles selected for inclusion in this review were identified using Google Scholar and Medline, and this search obtained a total of 57 items. The validity of these studies was established according to the degree of evidence presented, by citations and by their applicability to the healthcare context in Spain. Specifically, this review takes into consideration studies of salivary cortisol and stress in children and adults, and those examining the relation between high levels of salivary cortisol and other disorders such as anxiety, attention-deficit/hyperactivity disorder, social phobia or emotional deprivation. These studies show that salivary cortisol is a clear indicator of stress in both children and adults. High levels of this hormone in saliva are associated with the following main consequences: reduced immune function, affecting healing and thus prolonging recovery time; delayed growth in children; increased blood pressure and heart rate in both children and adults.

A role for the endocrine and pro-inflammatory mediator MIF in the control of insulin secretion during stress.

The systemic response to injury or infection is often accompanied by significant alterations in host metabolism and glucose homeostasis. Within the liver, these changes include a decrease in glycogenesis and an increase in gluconeogenesis, and in peripheral tissues, the development of insulin resistance and the increased utilization of glucose by non-insulin-dependent pathways. Depending on the severity and the duration of the response, both hyper- and hypoglycemia can ensue and each can become a clinically important manifestation of the systemic inflammatory response. The protein known as macrophage migration inhibitory factor (MIF) has been identified recently to play a central role in host immunity and to regulate glucocorticoid effects on the immune and inflammatory systems. MIF is released in vivo from activated immune cells as well as by the anterior pituitary gland upon stimulation of the hypothalamic-pituitary-adrenal axis. MIF also has been found to be secreted together with insulin from the pancreatic beta-cells and to act as an autocrine factor to stimulate insulin release. Since circulating MIF levels are elevated during stress or systemic inflammatory processes, this protein may play a central role in the control of insulin secretion during various disease states.

Evénements traumatiques et réponses de stress: le rôle de l'ocytocine et de l'attachement [Traumatic events and stress responses: the role of oxytocin and attachement].

Being repeatedly confronted to very difficult situations since childhood influences the way indivuals will later respond to even mildly stressful events. The hypothalamic-pituitary-adrenal axis (HPA) is a complex system implicated in regulating neuroendocrine responses to stress. Its activation produces among others the <stress hormonea, cortisol. However, the regulation of the physiological response to stress depends on psychological factors linked with the representations that individuals develop regarding their close relationships i.e. attachment. Furthermore, attachment representations seem to be associated with oxytocin, a hormone involved both in cortisol reduction and in positive social behaviours.

Adiposity in children born small for gestational age.

Epidemiological studies indicate that children born small for gestational age (SGA) have an increased risk of metabolic and cardiovascular disorders as adults. This suggests that foetal undernutrition leads to permanent metabolic alterations, which predispose to metabolic abnormalities upon exposure to environmental factors such as low physical activity and/or high-energy intake in later life (thrifty phenotype hypothesis). However, this relationship is not restricted to foetal undernutrition or intrauterine growth retardation, but is also found for children born premature, or for high birth weight children. Furthermore, early post-natal nutrition, and more specifically catch-up growth, appear to modulate cardiovascular risk as well. Intrauterine growth retardation can be induced in animal models by energy/protein restriction, or ligation of uterine arteries. In such models, altered glucose homeostasis, including low beta-cell mass, low insulin secretion and insulin resistance is observed after a few weeks of age. In humans, several studies have confirmed that children born SGA have insulin resistance as adolescents and young adults. Alterations of glucose homeostasis and increased lipid oxidation can indeed be observed already in non-diabetic children born SGA at early pubertal stages. These children also have alterations of stature and changes in body composition (increased fat mass), which may contribute to the pathogenesis of insulin resistance. Permanent metabolic changes induced by foetal/early neonatal nutrition (metabolic inprinting) may involve modulation of gene expression through DNA methylation, or alterations of organ structure. It is also possible that events occurring during foetal/neonatal development lead to long-lasting alterations of the hypothalamo-pituitary-adrenal axis or the hypothalamo-pituitary-insulin-like growth factor-1 axis.

Neurobiology of suicide: do biomarkers exist?

Clinical risk factors have a low predictive value on suicide. This may explain the increasing interest in potential neurobiological correlates and specific heritable markers of suicide vulnerability. This review aims to present the current neurobiological findings that have been shown to be implicated in suicide completers and to discuss how postmortem studies may be useful in characterizing these individuals. Data on the role of the main neurobiological systems in suicidality, such as the neurotransmitter families, hypothalamic-pituitary-adrenal axis, neurotrophic factors, and polyamines, are exposed at the different biochemical, genetic, and epigenetic levels. Some neuroanatomic and neuropathological aspects as well as their in vivo morphological and functional neuroimaging correlates are also described. Except for the serotoninergic system, particularly with respect to the polymorphism of the gene coding for the serotonin transporter (5-HTTLPR) and brain-derived neurotrophic factor, data did not converge to produce a univocal consensus. The possible limitations of currently published studies are discussed, as well as the scope for long-term prospective studies.

Sociodemographic, behavioral and genetic determinants of allostatic load in a Swiss population-based study.

Allostatic load (AL) is a marker of physiological dysregulation which reflects exposure to chronic stress. High AL has been related to poorer health outcomes including mortality. We examine here the association of socioeconomic and lifestyle factors with AL. Additionally, we investigate the extent to which AL is genetically determined. We included 803 participants (52% women, mean age 48±16years) from a population and family-based Swiss study. We computed an AL index aggregating 14 markers from cardiovascular, metabolic, lipidic, oxidative, hypothalamus-pituitary-adrenal and inflammatory homeostatic axes. Education and occupational position were used as indicators of socioeconomic status. Marital status, stress, alcohol intake, smoking, dietary patterns and physical activity were considered as lifestyle factors. Heritability of AL was estimated by maximum likelihood. Women with a low occupational position had higher AL (low vs. high OR=3.99, 95%CI [1.22;13.05]), while the opposite was observed for men (middle vs. high OR=0.48, 95%CI [0.23;0.99]). Education tended to be inversely associated with AL in both sexes(low vs. high OR=3.54, 95%CI [1.69;7.4]/OR=1.59, 95%CI [0.88;2.90] in women/men). Heavy drinking men as well as women abstaining from alcohol had higher AL than moderate drinkers. Physical activity was protective against AL while high salt intake was related to increased AL risk. The heritability of AL was estimated to be 29.5% ±7.9%. Our results suggest that generalized physiological dysregulation, as measured by AL, is determined by both environmental and genetic factors. The genetic contribution to AL remains modest when compared to the environmental component, which explains approximately 70% of the phenotypic variance.

Atrial natriuretic peptide and feeding activity patterns in rats

This review presents historical data about atrial natriuretic peptide (ANP) from its discovery as an atrial natriuretic factor (ANF) to its role as an atrial natriuretic hormone (ANH). As a hormone, ANP can interact with the hypothalamic-pituitary-adrenal axis (HPA-A) and is related to feeding activity patterns in the rat. Food restriction proved to be an interesting model to investigate this relationship. The role of ANP must be understood within a context of peripheral and central interactions involving different peptides and pathways

Cortisol and 17-a-hydroxy-progesterone levels in infants with refractory hypotension born at 30 weeks of gestation or less

Refractory hypotension is frequent in very low-birth weight infants, whose hypothalamic-pituitary-adrenal axis has been suggested to be immature. The objective of the present study was to evaluate basal cortisol and 17-a-OH-progesterone in the first 36 h of life in preterm infants with and without refractory hypotension (mean arterial blood pressure below the lower limit for gestational age throughout the study despite aggressive volume expansion and use of vasopressors). Thirty-five infants with £30 weeks of gestation and a birth weight £1250 g, with no postnatal use of corticosteroid or death in the first 48 h were studied. Mean arterial pressure was measured every 4 h during the first 48 h. Cortisol and 17-a-OH-progesterone were determined at 12 and 36 h and patients were divided into refractory hypotensive (N = 15) and control (N = 20) groups. The groups were not different regarding type of delivery, use of prenatal corticosteroid, requirement of mechanical ventilation, use of vasopressor drugs, morphine, fentanyl, prophylactic indomethacin, and mean sample timing. Although refractory hypotensive newborns were more immature, were smaller, suffered more deaths after 48 h of life and had a higher SNAPPE-2 score, their cortisol and 17-a-OH-progesterone levels were not different from controls at 12 h and at 36 h. The increase of cortisol in newborns with refractory hypotension 36 h after birth was significantly higher than in controls. Despite the fact that refractory hypotensive very low-birth weight neonates were submitted to a very stressful condition, their cortisol and 17-a-OH-progesterone levels were similar to controls.

Maternal undernutrition and the offspring kidney: from fetal to adult life

Maternal dietary protein restriction during pregnancy is associated with low fetal birth weight and leads to renal morphological and physiological changes. Different mechanisms can contribute to this phenotype: exposure to fetal glucocorticoid, alterations in the components of the renin-angiotensin system, apoptosis, and DNA methylation. A low-protein diet during gestation decreases the activity of placental 11ß-hydroxysteroid dehydrogenase, exposing the fetus to glucocorticoids and resetting the hypothalamic-pituitary-adrenal axis in the offspring. The abnormal function/expression of type 1 (AT1R) or type 2 (AT2R) AngII receptors during any period of life may be the consequence or cause of renal adaptation. AT1R is up-regulated, compared with control, on the first day after birth of offspring born to low-protein diet mothers, but this protein appears to be down-regulated by 12 days of age and thereafter. In these offspring, AT2R expression differs from control at 1 day of age, but is also down-regulated thereafter, with low nephron numbers at all ages: from the fetal period, at the end of nephron formation, and during adulthood. However, during adulthood, the glomerular filtration rate is not altered, due to glomerulus and podocyte hypertrophy. Kidney tubule transporters are regulated by physiological mechanisms; Na+/K+-ATPase is inhibited by AngII and, in this model, the down-regulated AngII receptors fail to inhibit Na+/K+-ATPase, leading to increased Na+ reabsorption, contributing to the hypertensive status. We also considered the modulation of pro-apoptotic and anti-apoptotic factors during nephrogenesis, since organogenesis depends upon a tight balance between proliferation, differentiation and cell death.

Les effets d’un traitement au corticostérone sur la transmission dopaminergique mésocorticale du rat en période de stress

L’axe hypothalamo-hypophyso-surrénalien joue un rôle essentiel dans l’adaptation et la réponse au stress. Toutefois, l’hyperactivation de cet axe ou des niveaux chroniquement élevés de glucocorticoïdes (GC) entraînent des conséquences pathologiques. Le système dopaminergique mésocortical, qui se projette dans le cortex préfrontal médian (CPFm), joue un rôle adaptatif en protégeant contre le stress. Jusqu’à présent, les interactions fonctionnelles entre les GC (ex : corticostérone) et le système dopaminergique mésocortical ne sont pas élucidées. Dans ce mémoire, nous avons évalué les effets des GC sur les fonctions dopaminergiques préfrontales en élevant chroniquement, à l’aide de minipompes osmotiques, les niveaux de corticostérone aux concentrations physiologiques maximales (1 mg/kg/h pendant 7 jours). Ce traitement n’a pas modifié significativement, chez les rats stressés ou non, les niveaux post mortem de dopamine et de son métabolite dans le tissu du CPFm. Toutefois, l’évaluation par voltamétrie in vivo des changements de dopamine extracellulaire dans le CPFmv a permis d’observer que la corticostérone augmente significativement la libération de dopamine en réponse à l’exposition à l’odeur de renard et au pincement de la queue. Nos études nous permettent de conclure que la corticostérone potentialise la fonction dopaminergique mésocorticale qui, à son tour, facilite la régulation négative en période de stress.

La détermination d’un sous-groupe de contrevenants de la conduite avec capacités affaiblies à risque élevé de récidive : l’utilité de l’axe hypothalamo-hypophyso-surrénalien

Les contrevenants de la conduite avec capacités affaiblies (CCA) n’entrent pas tous dans les registres de la sécurité routière avec le même risque de récidive. Pour pallier cette hétérogénéité, cette thèse propose de modéliser les interrelations entre les traits de personnalité et les comportements à risque associés à la récidive et de détecter un sous-groupe de contrevenants au risque de récidive élevé à l’aide de l’axe hypothalamo-hypophyso-surrénalien (HHS). Plus particulièrement, les trois articles de cette thèse s’intéressent au cortisol, l’hormone du stress. Le premier article élabore un modèle théorique réconciliant les connaissances sur l’axe HHS issues du domaine de la CCA et de domaines connexes. Lors de précédentes études, le nombre de condamnations antérieures pour CCA a été associé négativement à la réactivité du cortisol à la suite d’une situation stressante. Chez les récidivistes, cette faible réactivité s’explique partiellement par la recherche d’expériences, une dimension de la recherche de sensations. Au-delà ce trait de personnalité désinhibiteur, une faible activité de l’axe HHS a été associée à d’autres traits (c.-à-d. impulsivité et tendances antisociales) et d’autres comportements à risque (c.-à-d. infractions routières, arrestations criminelles et consommation problématique de substances psychoactives). Ce modèle intégrant la réactivité du cortisol permet une conceptualisation approfondie des diverses caractéristiques des contrevenants de la CCA et explique hypothétiquement la répétition des comportements à risque. Les deux articles suivants se penchent sur l’intérêt empirique d’utiliser l’axe HHS pour déterminer un sous-groupe de contrevenants à risque élevé de récidive. Plus précisément, le deuxième article émet l’hypothèse que les récidivistes (n = 30) ayant une faible activité de leur cortisol (c.-à-d. médiane de la surface sous la courbe relative au niveau de base et relative à la réactivité) ont davantage de traits de personnalité désinhibiteurs et de comportements à risque que les récidivistes ayant une forte activité. L’hypothèse n’a pas été confirmée. Au contraire, les récidivistes présentant une faible réactivité commettent moins d’infractions routières et d’arrestations criminelles que ceux ayant une forte réactivité. Quant à lui, le troisième article investigue une hypothèse similaire auprès des contrevenants primaires (n = 139). Les contrevenants manifestant une faible réactivité du cortisol (c.-à-d. différence entre prélèvements post-stress et pré-stress) ont davantage d’impulsivité attentionnelle, de non-planification, d’arrestations criminelles et de cigarettes fumées par jour que les contrevenants ayant une forte réactivité. Lors d’analyses exploratoires, la présence d’une variété de traits de personnalité désinhibiteurs et de comportements à risque chez les contrevenants primaires présentant une faible réactivité lorsque comparé au groupe contrôle (n = 31) suggère encore une fois leur risque élevé de récidive. L’intérêt d’ajouter un mécanisme neurobiologique pour modéliser les interrelations entre les traits de personnalité désinhibiteurs et les comportements à risque des contrevenants de la CCA a été exploré dans cette thèse. La détermination d’un sous-groupe de contrevenants présentant un risque élevé de récidive, à l’aide de l’axe HHS, semble davantage profitable auprès de l’hétérogène population des contrevenants primaires. En contrepartie, l’axe HHS ne permet pas de déterminer un sous-groupe ayant une problématique sévère auprès des récidivistes à l’extrême du continuum du risque.

Contribution de modèle demande-contrôle-soutien à la variation des concentrations de cortisol salivaire

L’objectif principal de ce mémoire est d’approfondir les connaissances à propos de l’impact des stresseurs organisationnels sur la concentration du cortisol salivaire. Plus précisément, nous étudierons la contribution des modèles demande-contrôle de Karasek (1979) et demande-contrôle-soutien de Karasek et Theorell (1990) à la variation du cortisol salivaire chez les individus. Les associations entre les composantes principales de chacun des modèles (demandes psychologiques, latitude décisionnelle et soutien social), mais également les effets d’interaction inclus dans ces modèles, c’est-à-dire de l’effet modérateur de la latitude décisionnelle et du soutien social, seront étudiés. L’axe HPS a été associé aux symptômes de la santé mentale (Abelson et al., 2007; Havermans et al., 2011; Vreeburg et al., 2009b, 2010, 2013; Staufenbiel, 2013) ainsi qu’aux stresseurs en milieu de travail (Chida et Steptoe, 2009). À l’heure actuelle, le cortisol salivaire serait un indicateur de l’axe hypothalamo-pituito-surrénalien (HPS) le plus prometteur pour mesurer la réponse physiologique face à un événement stressant ou à un stress chronique (Maïna et al., 2009). Les données proviennent de l’étude SALVEO, menée par l’Équipe de recherche sur le travail et la santé mentale de l’Université de Montréal. Les résultats des analyses multiniveaux ne soutiennent pas l’implication du modèle demande-contrôle-soutien sur la concentration de cortisol. En effet, elles ne permettent pas de conclure que les effets, autant principaux que d’interaction, du modèle demande-contrôle-soutien expliquent la variation dans les concentrations de cortisol. La consommation de tabac est significativement reliée à la concentration de cortisol salivaire et doit être prise en considération dans les études futures. Par conséquent, ces résultats suggèrent que d’autres recherches sont nécessaires pour comprendre comment les stresseurs du travail s’incorporent à l’individu au niveau physiologique. Des connaissances approfondies de ces associations permettraient de mieux comprendre les associations entre le stress à long terme et les effets sur la santé, c’est-à-dire, comment les tensions au travail affectent la santé mentale à long terme (Karhula et al., 2015).

Corticoides : 60 años después, una asignatura pendiente

El objetivo de este artículo es hacer una breve recopilación de la fisiología del eje hipotálamo-hipofisiario-suprarrenal, para comprender el papel de los corticoides exógenos como herramientas terapéuticas en innumerables patologías, que, utilizados de manera inapropiada, pueden causar efectos deletéreos importantes. La historia de los corticoides empezó hace 164 años, en 1843, cuando Thomas Addison describió los síntomas de la insuficiencia suprarrenal. Casi 100 años después, el 21 de septiembre de 1948, marcó un hito en la historia de la medicina, cuando, en la Clínica Mayo, el Dr. Hench inyectó 100 g de cortisona por primera vez en un paciente con artritis reumatoidea. En 1950, Hench, Kendall y Reichstein recibieron el Premio Nobel de Medicina y Fisiología. En la corteza de las glándulas suprarrenales se sintetizan, a partir del colesterol, tres hormonas diferentes con diversos efectos sobre la homeostasis. Los glucocorticoides sintéticos se clasifican por su potencia antiinflamatoria, vida media y efecto mineralocorticoide; operan en casi todas las células por medio de mecanismos de acción genómicos y no genómicos, lo que genera diferentes respuestas, de ahí su amplio efecto terapéutico en esclerosis múltiple, rechazo de trasplantes, enfermedades respiratorias, como asma y Epoc, entre otras.