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The chemokine CCL5, a key regulator of neuroinflammation and type 2 diabetes associated with diet-induced obesity

  • Stobbe, Katharina
Publication Date
Oct 31, 2019
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Obesity is defined by the excessive accumulation of body fat and accompanied by chronic low-grade inflammation of peripheral metabolic tissues, especially of adipose tissue. Adipocytes secrete inflammatory mediators such as cytokines and chemokines, which can act at the cerebral level and modulate neuronal activity. The hypothalamus is an important region of the brain, which contains neural networks involved in the control of energy metabolism and feeding behavior. Emerging evidence indicates that inflammation occurs also at the level of the hypothalamus. Our recent results showed that the chemokines can be involved in the deregulation of energy homeostasis. CCL5 is a chemoattractant cytokine well known for its role in cerebral and peripheral inflammation. Together with one of its cognate receptors, CCR5, it also contributes to neural function and diseases such as obesity, type 2 diabetes and neuropathic pain.We were interested in the inflammatory response of the hypothalamus and different adipose tissues to high-fat diet and its role in the development of diet-induced obesity. In particular, we are focusing on the role of the previously identified chemokine CCL5 and its receptor CCR5, in the central inflammation associated with the deregulation of energy metabolism and the pathogenesis of obesity.In this study, we tested the long-term effects of an obesogenic high-fat or standard diet on the development of obesity in adult CCL5-/-, CCR5-/- and wild-type mice. After 16 weeks of feeding, animals were sacrificed and peripheral and cerebral tissues collected. Metabolic parameters, locomotor activity, expression levels of pro-inflammatory mediators and peptides involved in feeding behavior were measured. We discovered that both CCL5-/- and CCR5-/- mice seem to be protected from weight gain and the associated impairment of glucose metabolism compared to WT mice. To evaluate the implication of CCL5 in neuropathic pain associated with diabetes, thermal pain sensitivity of CCL5-/- and CCR5-/- mice was measured in both conditions. Remarkably, in high fat diet condition, CCL5-/- mice displayed higher tolerance to heat pain compared to control mice.Furthermore, CCL5-/- mice show a different expression pattern of inflammatory markers and hypothalamic neuropeptides compared to control mice. In addition, we used RNA in situ hybridization (RNAScope® Technology) to verify the cellular localization of CCL5 and its receptor CCR5 in the hypothalamus of wild-type mice.Our results indicate that the absence of CCL5 and its receptor CCR5 protects against the development of obesity and type 2 diabetes and the absence of CCL5 abolishes the increased thermal pain sensitivity observed under high fat diet challenge. Thus, the CCL5 signaling cascade could represent a new putative target for the development of therapeutic strategies.

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