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Involvement of CXCL12/CXCR4 pathway in monocyte chemotaxis and postnatal neurogenesis during hypothalamic inflammation and of maternal obesity in monocyte sexual dimorphism.

Abstract

The prevalence of obesity has been increasing worldwide, reaching all age groups, including women of reproductive age. In obesity, there is a chronic low-grade inflammatory state that involves the chemotaxis of immune cells to various tissues. In mice, a few days of a high-fat diet (HFD) triggers an inflammatory response in the hypothalamus, the main regulatory center of energy homeostasis. After a few weeks, when the hypothalamic inflammation is already established, monocyte chemotaxis and reduction in postnatal neurogenesis are observed, with suppressed turnover of neurons involved in energy balance. Bioinformatic analysis of the transcriptome of CCR2+ monocytes isolated from the hypothalamus of HFD-fed mice shows thousands of differentially expressed genes involved in the chemotaxis, with an important sexual dimorphism, especially the chemokine Cxcl12 and its receptor Cxcr4. In the arcuate nucleus of the hypothalamus (ARC) and median eminence (ME), Cxcl12 is widely expressed in endothelial cells, while Cxcr4 is mainly expressed by tanycytes. The involvement of the CXCL12/CXCR4 pathway in HFD-induced hypothalamic inflammation remains barely explored. In this study, we will investigate whether endothelial Cxcl12 expression in hypothalamic blood capillaries is modulated by HFD, as well as the underlying molecular mechanisms and whether CXCL12/CXCR4 pathway is involved in monocyte chemotaxis or the impaired adult neurogenesis. To date, it is also unknown in which period of life the sexual dimorphism of the CCR2+ monocytes transcriptome is originated, nor if this is modulated by maternal obesity. Therefore, we will evaluate whether maternal obesity during gestation and neonatal life modifies the CCR2+ monocyte transcriptome in offspring, and the serum profile of chemokines and chemotaxis-related markers in these animals. We will also verify whether these offspring, when exposed to HFD in adulthood, are more susceptible to monocyte chemotaxis in the hypothalamus. Through an observational clinical study, we will assess whether maternal obesity modifies the serum profile of chemokines and chemotaxis-related markers in newborns. Our data will allow identifying, in an unprecedented way, the role of the CXCL12/CXCR4 pathway in hypothalamic inflammation, contributing to the knowledge advance about the enrollment of endothelial cells and tanycytes in this brain area. In addition, the proposed translational approach will contribute to obtaining unprecedented data on the effects of maternal obesity and early infancy on the transcriptome of CCR2+ monocytes, the origin of their sexual dimorphism, and the serum profile of chemokines in neonates. These data will promote an advance in the identification of new biomarkers that predispose the development of inflammatory diseases, such as obesity and its comorbidities, from the beginning of life. (AU)

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