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Subchronic gestational stress leads to permanent modifications in the hippocampus-hypothalamus-pituitary-adrenal axis of offspring probably due to the increase in circulating glucocorticoids known to affect prenatal programming. The aim of this study was to investigate whether cell turnover is affected in the hippocampus-hypothalamus-pituitary axis by subchronic prenatal stress and the intracellular mechanisms involved. Restraint stress was performed in pregnant rats during the last week of gestation (45 minutes; 3 times/day). Only male offspring were used for this study and were sacrificed at 6 months of age. In prenatally stressed adults a decrease in markers of cell death and proliferation was observed in the hippocampus, hypothalamus and pituitary. This was associated with an increase in insulin-like growth factor-I mRNA levels, phosphorylation of CREB and calpastatin levels and inhibition of calpain -2 and caspase -8 activation. Levels of the anti-apoptotic protein Bcl-2 were increased and levels of the pro-apoptotic factor p53 were reduced. In conclusion, prenatal restraint stress induces a long-term decrease in cell turnover in the hippocampus-hypothalamus-pituitary axis that might be at least partly mediated by an autocrine-paracrine IGF-I effect. These changes could condition the response of this axis to future physiological and pathophysiological situations., Depto. de Medicina Legal, Psiquiatría y Patología, Fac. de Medicina, TRUE, pub

The propensity to develop neurodegenerative diseases is influenced by diverse factors including genetic background, sex, lifestyle, including dietary habits and being overweight, and age. Indeed, with aging, there is an increased incidence of obesity and neurodegenerative processes, both of which are associated with inflammatory responses, in a sex-specific manner. High fat diet (HFD) commonly leads to obesity and markedly affects metabolism, both peripherally and centrally. Here we analyzed the metabolic and inflammatory responses of middle-aged (11-12 months old) transgenic amyloid precursor protein (TgAPP) mice of both sexes to HFD for 18 weeks (starting at 7-8 months of age). We found clear sex differences with females gaining significantly more weight and fat mass than males, with a larger increase in circulating leptin levels and expression of inflammatory markers in visceral adipose tissue. Glycemia and insulin levels increased in HFD fed mice of both sexes, with TgAPP mice being more affected than wild type (WT) mice. In the hypothalamus, murine amyloid ß (Aß) levels were increased by HFD intake exclusively in males, reaching statistical significance in TgAPP males. On a low fat diet (LFD), TgAPP males had significantly lower mRNA levels of the anorexigenic neuropeptide proopiomelanocortin (POMC) than WT males, with HFD intake decreasing the expression of the orexigenic neuropeptides Agouti-related peptide (AgRP) and neuropeptide Y (NPY), especially in TgAPP mice. In females, HFD increased POMC mRNA levels but had no effect on AgRP or NPY mRNA levels, and with no effect on genotype. There was no effect of diet or genotype on the hypothalamic inflammatory markers analyzed or the astrogliosis marker glial acidic protein (GFAP); however, levels of the microglial marker Iba-1 increased selectively in male TgAPP mice. In summary, the response to HFD intake was significantly affected by sex, with fewer effects due to genotype. Hypothalamic inflammatory cytokine ex

Ministerio de Economía y Competitividad (MINECO), Universidad Complutense de Madrid, Depto. de Farmacología, Farmacognosia y Botánica, Fac. de Farmacia, TRUE, pub

Insulin receptor substrate (IRS) 2 is a key mediator of insulin signaling and IRS-2 knockout (IRS2−/−) mice are a preclinical model to study the development of diabetes, as they develop peripheral insulin resistance and beta-cell failure. The differential inflammatory profile and insulin signaling in the hypothalamus of non-diabetic (ND) and diabetic (D) IRS2−/− mice might be implicated in the onset of diabetes. Because the lipid profile is related to changes in inflammation and insulin sensitivity, we analyzed whether ND IRS2−/− mice presented a different hypothalamic fatty acid metabolism and lipid pattern than D IRS2−/− mice and the relationship with inflammation and markers of insulin sensitivity. ND IRS2−/− mice showed elevated hypothalamic anti-inflammatory cytokines, while D IRS2−/− mice displayed a proinflammatory profile. The increased activity of enzymes related to the pentose-phosphate route and lipid anabolism and elevated polyunsaturated fatty acid levels were found in the hypothalamus of ND IRS2−/− mice. Conversely, D IRS2−/− mice have no changes in fatty acid composition, but hypothalamic energy balance and markers related to anti-inflammatory and insulin-sensitizing properties were reduced. The data suggest that the concurrence of an anti-inflammatory profile, increased insulin sensitivity and polyunsaturated fatty acids content in the hypothalamus may slow down or delay the onset of diabetes.

Insulin receptor substrate (IRS) 2 is a key mediator of insulin signaling and IRS-2 knockout (IRS2(-/-)) mice are a preclinical model to study the development of diabetes, as they develop peripheral insulin resistance and beta-cell failure. The differential inflammatory profile and insulin signaling in the hypothalamus of non-diabetic (ND) and diabetic (D) IRS2(-/-) mice might be implicated in the onset of diabetes. Because the lipid profile is related to changes in inflammation and insulin sensitivity, we analyzed whether ND IRS2(-/-) mice presented a different hypothalamic fatty acid metabolism and lipid pattern than D IRS2(-/-) mice and the relationship with inflammation and markers of insulin sensitivity. ND IRS2(-/-) mice showed elevated hypothalamic anti-inflammatory cytokines, while D IRS2(-/-) mice displayed a proinflammatory profile. The increased activity of enzymes related to the pentose-phosphate route and lipid anabolism and elevated polyunsaturated fatty acid levels were found in the hypothalamus of ND IRS2(-/-) mice. Conversely, D IRS2(-/-) mice have no changes in fatty acid composition, but hypothalamic energy balance and markers related to anti-inflammatory and insulin-sensitizing properties were reduced. The data suggest that the concurrence of an anti-inflammatory profile, increased insulin sensitivity and polyunsaturated fatty acids content in the hypothalamus may slow down or delay the onset of diabetes.