Physiological and pathophysiological roles of hypothalamic astrocytes in metabolism.

The role of glial cells, including astrocytes, in metabolic control has received increasing attention in recent years. Although the original interest in these macroglial cells was a result of astrogliosis being observed in the hypothalamus of diet-induced obese subjects, studies have also focused on how they participate in the physiological control of appetite and energy expenditure. Astrocytes express receptors for numerous hormones, growth factors and neuropeptides. Some functions of astrocytes include transport of nutrients and hormones from the circulation to the brain, storage of glycogen, participation in glucose sensing, synaptic plasticity, uptake and metabolism of neurotransmitters, release of substances to modify neurotransmission, and cytokine production, amongst others. In the hypothalamus, these physiological glial functions impact on neuronal circuits that control systemic metabolism to modify their outputs. The initial response of astrocytes to poor dietary habits and obesity involves activation of neuroprotective mechanisms but, with chronic exposure to these situations, hypothalamic astrocytes participate in the development of some of the damaging secondary effects. The present review discusses not only some of the physiological functions of hypothalamic astrocytes in metabolism, but also their role in the secondary complications of obesity, such as insulin resistance and cardiovascular affectations.

Fetal undernutrition is associated with perinatal sex-dependent alterations in oxidative status.

Intrauterine growth retardation predisposes to hypertension development, known as fetal programming. Females are less susceptible, which has been mainly attributed to estrogen influence. We hypothesize that perinatal differences in oxidative status might also contribute. We studied 21-day-old (prepuberal) and 6-month-old male and female offspring from rats fed ad libitum during gestation (Control) or with 50% of Control daily intake from day 10 to delivery (maternal undernutrition, MUN). We assessed in vivo blood pressure and the following plasma biomarkers of oxidative status: protein carbonyls, thiols, reduced glutathione (GSH), total antioxidant capacity, superoxide anion scavenging activity (SOSA) and catalase activities; we calculated a global score (oxy-score) from them. Estradiol and melatonin concentration was measured in young rats. Prepuberal MUN males were normotensive but already exhibited increased carbonyls and lower thiols, GSH, SOSA and melatonin; oxy-score was significantly lower compared to Control males. Prepuberal MUN females only exhibited reduced SOSA compared to Control females. Adult rats from all experimental groups showed a significant increase in carbonyls and a decrease in antioxidants compared to prepuberal rats; oxy-score was negative in adult rats suggesting the development of a prooxidative status as rat age. Adult MUN males were hypertensive and exhibited the highest increase in carbonyls despite similar or even higher antioxidant levels compared to Controls. Adult MUN females remained normotensive and did not exhibit differences in any of the biomarkers compared to Controls. The better global antioxidant status developed by MUN females during perinatal life could contribute to their protection against hypertension programming.

Prolonged leptin treatment increases transient outward K⁺ current via upregulation of Kv4.2 and Kv4.3 channel subunits in adult rat ventricular myocytes.

Circulating leptin levels are elevated in obesity and hyperleptinaemia has been postulated to be an independent risk factor for the development of cardiovascular diseases. Although many studies have been published on the mechanisms involved in the effects of leptin on cardiac function and pathological remodeling, scarce information is currently available analyzing the influence of prolonged leptin treatment on ionic cardiac channels remodeling in adult ventricular myocytes. Enzymatically isolated adult rat ventricular myocytes were treated with leptin or vehicle for 48h. Real-Time RT-PCR were used to analyze mRNA expression of Kir2.1, Cav1.2, Cav 3.1, Kv4.2 and Kv4.3 α-subunits and KChIP2 auxiliary subunit. The fast transient outward potassium channels (Itof) α-subunits Kv4.2, Kv4.3 and KChIP2 were analyzed by Western-blot. The fast transient outward potassium current and the action potentials were recorded in isolated myocytes by the whole-cell patch-clamp technique. Leptin treatment induced an up-regulation of Kv4.2, Kv4.3 and KChIP2 subunits mRNA expression. However, transcriptional levels of Kir2.1, Cav1.2, or Cav3.1 α-subunit channels were unmodified by leptin. Protein expression levels of Kv4.2, Kv4.3 and KChIP2 subunits were also increased by leptin. The electrophysiological study showed that leptin increases the fast transient outward potassium current amplitudes and densities shortening action potential duration. In addition, leptin activated Akt signaling in cardiomyocytes and this mechanism was involved in the effect of leptin on Itof channels. In conclusión, leptin increases both the expression and function of Itof channels in adult ventricular myocytes and this mechanism involves Akt signaling. Altogether these data suggest that leptin could exert beneficial or detrimental effects depending on the initial ventricular myocyte repolarizing reserve.

El sistema endocannabinoide como diana para reducir el riesgo cardiometabólico y la obesidad / The endocannabinoid system as a target for decreasing cardiometabolic risk and obesity

El sobrepeso y la obesidad han adquirido una dimensión pandémica y se considera que el exceso de peso incluye la asociación de otros factores de riesgo cardiometabólico, como dislipemia aterogénica, hipertensión arterial, resistencia a la insulina y disglucemia, así como un estado proinflamatorio y protrombótico. El objetivo de esta revisión es dar a conocer el descubrimiento reciente de un novedoso sistema endógeno denominado sistema endocannabinoide involucrado en la obesidad y el riesgo cardiometabólico. Recientemente, el tejido adiposo se ha reconocido como un órgano humoral que expresa y segrega varias adipocinas, como leptina, adiponectina, resistina y numerosas citocinas que incluyen el factor de necrosis tumoral alfa y la interleucina 6. Como consecuencia de este agrupamiento de factores de riesgo cardiovascular y metabólico, la expectativa de vida de los pacientes con sobrepeso y obesos se reduce al compararla con individuos de peso normal. Se presentan los resultados de algunos estudios preclínicos y clínicos que han mostrado los efectos dependientes de su bloqueo en el control de la homeostasis de energía y de parámetros metabólicos. Se enfatiza la necesidad de un nuevo enfoque de control del sobrepeso y de los factores de riesgo asociados, basados en su patogenia, que incluya el bloqueo del sistema endocannabinoide, el cual desempeña un papel fundamental en la regulación de la ingestión de alimentos y en la emergencia del conjunto de factores proaterogénicos (AU)

Overweight and obesity have reached pandemic dimensions, and are associated with other cardiometabolic risk factors,such as; atherogenic dyslipemia, high blood pressure, insulin resistance, and dysglycemia, as well as a pro-inflammatory and thrombotic states. The aim of this review is to show the recent discovery of a novel endogenic system, called endocannabinoid system, involved in obesity and cardiometabolic risk. Recently, fat tissue has been recognized as a humoral organ expressing and secreting some adipokines, such as: leptin, adiponectin, resistin, and many cytokines including alfa-tumoral necrosis factor, and interleukin 6. As consequence of this grouping of cardiovascular and metabolic risk factors, the life-expectancy of overweight and obese patients is decreased compared to individuals of normal weight. The authors present the findings of some preclinical and clinical studies showing effects dependent of its blockade on control of energy-homeostasis and metabolic parameters. The need of a new approach to controlling overweight and its related risk factors is emphasised, based in its pathogenesis, including blocking of the endocannabinoid system, which plays a critical role in regulation of food ingestion, and in the emergence of pro-atherogenic factors (AU)

Anxiolytic-like effect of a serotonergic ligand with high affinity for 5-HT1A, 5-HT2A and 5-HT3 receptors.

S-(-)-2-[[4-(napht-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-alpha]-pyrazine (CSP-2503) is a serotonin (5-HT) receptor ligand with selectivity and high affinity for 5-HT1A, 5-HT2A and 5-HT3 receptors. CSP-2503 reduced rectal temperature and 5-HT neuronal hypothalamic activity in mice, decreased electrical activity of raphe nuclei cells in rats and blocked the enhancement of adenylate cyclase activity induced by forskolin in HeLa cells transfected with the human 5-HT1A receptor. This compound also blocked head-twitches induced by the 5-HT(2A/2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Contractions of guinea pig ileum induced by the 5-HT3 receptor agonist 2-methyl-5-HT were prevented by CSP-2503. Moreover, it reduced the bradycardia reflex induced by 2-methyl-5-HT in anaesthetized rats. In the light/dark box and social interaction tests, CSP-2503 presented anxiolytic activity, an action shared by 5-HT1 agonists and 5-HT3 antagonists. Taken together, these results suggest that CSP-2503 is a new 5-HT1 receptor agonist with 5-HT2A and 5-HT3)receptor antagonist activities that might be useful in a number of conditions associated with anxiety.