No abstract

Aromatase catalyzes the conversion of testosterone to estradiol and is involved in the physiological effects of sex hormones on brain function. Animal experiments have shown that the aromatase inhibitor, letrozole, can induce anxiety in young ovariectomized females that are used as a model of aging. Whether or not these effects would be similar in intact middle-aged animals is unknown. The aim of our study was to analyze the effects of letrozole on anxiety in middle-aged rats of both sexes. Fifteen month old male and female rats were treated daily with either letrozole or vehicle for 2 weeks. The elevated plus maze was used to test anxiety-like behaviour. Sex differences were found not only in plasma concentrations of testosterone but also in the effects of letrozole treatment on plasma testosterone (P<.05). The interaction between sex and treatment was also proven in locomotor activity (P<.05) and time spent in the open arms of the elevated plus maze (P<.05). Letrozole-treated male rats spent 95% less time in the open arms of the elevated plus maze than the control rats did (P<.05) suggesting an anxiogenic effect of aromatase inhibition. This difference was not found between letrozole-treated and vehicle-treated females. In contrast to previous experiments on young animals, letrozole seems to induce anxiety in male but not in female middle-aged rats. This sex-specific effect might be related to sex differences of oestrogen and androgen signalling in aging brains. These results should be taken into account in clinical applications of letrozole, especially in men.

In non-diabetics, low levels of soluble receptor for advanced glycations end products (sRAGE) associate with an increased risk of development of diabetes, cardiovascular afflictions, or death. The majority of studies in non-diabetics report an inverse relationship between measures of obesity, cardiometabolic risk factors and sRAGE and/or endogenous secretory RAGE (esRAGE) levels. To elucidate whether this inconsistency is related to the metabolically healthy obese phenotype, or a different impact of the risk factors in presence and absence of obesity, we analyzed data from 2206 apparently healthy adolescents (51 % girls) aged 15-to-19 years. The association of sRAGE levels with soluble vascular adhesion protein-1/semicarbazide sensitive amine oxidase (sVAP-1/SSAO) was also investigated. Centrally obese, including metabolically healthy, adolescents present significantly lower sRAGE and esRAGE, but not sVAP-1, levels in comparison with their lean counterparts. An increasing number of cardiometabolic risk factors did not associate with significant changes in sRAGE, esRAGE or sVAP-1 levels either in lean or in obese subjects. In multivariate analyses, WHtR, hsCRP, markers of glucose homeostasis, renal function, adiponectin, and sVAP-1 associated significantly with sRAGE and esRAGE. SVAP-1 correlated significantly with glycemia, adiponectin, hsCRP, and sRAGE. Thus, in adolescents, a decline in sRAGE and esRAGE precedes the development of metabolic syndrome. When combined, standard and non-standard cardiometabolic risk factors explain only minor proportion in a variability of sRAGE and esRAGE (8 %-11 %); or sVAP-1 (12 %-20 %). Elucidation of pathogenetic mechanisms underlying early decline in sRAGE and esRAGE levels in obese adolescents and their clinical impact with regard to future cardiometabolic health requires further studies.

Maternal exposure to a Western type diet during pregnancy might predispose the offspring to manifestation of metabolic and behavioral disturbances in later life. The Western type diet contains large amounts of advanced glycation end products (AGEs). In humans and experimental rodents, the intake of an AGE-rich diet (AGE-RD) negatively affected glucose homeostasis, and initiated the production of reactive oxygen species. Rats consuming the AGE-RD presented changes in behavior. It remains unclear whether maternal intake of the AGE-RD might affect developmental plasticity in offspring. We examined early somatic (weight, incisor eruption, ear unfolding, and eye opening) and neuromotor development, oxidative status, insulin sensitivity (HOMA index) and locomotor activity assessed in PhenoTyper cages in the offspring of mice fed during pregnancy with either the AGE-RD (25% bread crusts/75% control chow) or control chow. Until weaning, the somatic development of offspring did not differ between the two dietary groups. The AGE-RD offspring manifested physiological reflexes (auditory startle, eye lid, ear twitch and righting reflexes) earlier. As young adults, the male offspring of the AGE-RD dams were heavier and less insulin sensitive compared with their control counterparts. The AGE-RD offspring showed higher locomotor activity during the active phase. Our data indicate that the maternal AGE-RD during pregnancy might accelerate the maturation of reflexes in offspring, predispose the male progeny to weight gain and affect their glucose homeostasis. These effects manifest without the direct consumption of the AGE-RD by offspring. Further work is needed to determine the mechanisms by which the maternal AGE-RD affects neurobehavioral pathways in offspring, as well as sex differences in adverse metabolic responses.