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Maria Paz Viveros"Animal models for the study of hypothalamic and extrahypothalamic leptin roles"

Abstract :

In addition to its role in the management of energy balance in adult life, recent data suggest that leptin may have a broader range of physiological actions.
In particular, leptin modulates hypothalamic development and in particular, neuronal circuits involved in metabolic control. There are also leptin receptors in other brain areas such as the hippocampus where this peptide might also play neuroprotective/neurotrophic actions. Moreover, recent data suggest that leptin may have relevant implications in relation to at least certain neuropsychiatric disorders. During the last years we are carrying out a profound psychoneuroimmunoendocrine characterization of a model of early life stress consisting of a single 24-h episode of maternal deprivation (MD) on postnatal day (PND) 9 in Wistar rats. Based on our findings regarding its detrimental impact on developing brain (including neuronal and glial alterations as well as changes in the endocannabinoid system in the hippocampus), we have propose the MD model as a useful tool for testing the neurodevelopmental theory. MD also modified trophic factors and markers of cell turnover and neuronal maturation in the developing hypothalamus. It is worth noting that, in general, numerous sex differences regarding the effects of MD were found. During MD a dramatic decline in leptin levels was observed that was still present 12h after the dam was re-housed with its litter. Moreover, circulating leptin levels of MD rats are markedly decreased at PND 13 and in the adulthood, and MD animals show long term decreased body weights. It has been shown that, in control male rats, plasma leptin increased between PND 4 and 14 and reached a peak level at PND 10, and this interval includes the period in which rats are separated from their mothers in our MD model. So, we propose that leptin deficiency in these animals could play a role in at least certain alterations induced by MD. In order to check this hypothesis we are currently performing a series of experiments in which we analyse the effect of a leptin antagonist administered in 9-day old control non- maternally deprived animals. Notably, the drug induced a marked increase in plasma leptin levels. Regarding the hippocampus, administration of the leptin antagonist induced significant decreases in GFAP + cells and synaptophysin expression in CA1, CA3 and DG in both sexes, whereas the pharmacological treatment reduced CB1 levels only in males. The decrease in GFAP + cells and synaptophysin together with the observed decreased DAPI labelling within pyramidal and granular cell layers suggest that blockade of leptin receptor at an early neonatal age impaired hippocampus development. Since not all the effects induced by leptin receptor blockade parallel MD effects, it seems that leptin deficiency is not the only factor involved in MD as regards its effects at the hippocampal level. The leptin antagonist also affected hypothalamic cell turnover and maturation in a sex specific manner with only females being affected in the parameters analysed (hypothalamic mRNA levels for brain-derived neurotrophic factor, cocaine and amphetamine regulated transcript, leptin receptor and nestin and vimentin levels). There was also an increase in cell death in the hypothalamus, with a shift towards an anti-apoptotic balance in the Bcl2/BAX ratio. Changes in leptin, at least at this postnatal age, may differentially affect hypothalamic development in males and females and this could explain some of the reported sexually dimorphic responses to modifications in the early nutritional environment.

Selected publications

PMarco EM,. García-Gutiérrez MS, Bermudez-Silva FJ, Moreira F, Guimarães F, Manzanares J, Viveros MP. Endocannabinoid system and psychiatry: in search of a neurobiological basis for detrimental and potential therapeutic effects (R). Frontiers in Behavioral Neuroscience. In the special issue entitled: "The endocannabinoid system: a key modulator of emotions and cognition" (in press)

Granado M,García-Cáceres C, de la Fuente-Martín E, Díaz F, Virginia Mela, Viveros MP;, Argente, Chowen J.A. Acute hyperleptinemia on postnatal day 2 decreases food intake in adulthood while leptin antagonism on postnatal days 9-10 reduces bodyweight and adipose tissue in adult rats. Endocrinology 2011, (A) in press

Llorente-Berzal A, Mela V, Borcel E, Valero M, López-Gallardo M, Viveros MP, Marco EM. Neurobehavioral and metabolic long-term consequences of neonatal maternal deprivation stress and adolescent olanzapine treatment in male and female rats. Neuropharmacology. 2011 Jul 28. [Epub ahead of print] (A)

Daniela Cota