Abstract
Anorexia nervosa (AN) is associated with low-grade systemic inflammation and altered gut microbiota. However, the molecular origin of the inflammation remains unknown. Toll-like receptors are key regulators of innate immune response and their activation seems also to be involved in the control of food intake. We used activity-based anorexia (ABA) model to investigate the role of TLR4 and its contribution in anorexia-associated low-grade inflammation. Here, we found that ABA affected early the intestinal inflammatory status and the hypothalamic response. Indeed, TLR4 was upregulated both on colonic epithelial cells and intestinal macrophages, leading to elevated downstream mucosal cytokine production. These mucosal changes occurred earlier than hypothalamic changes driving to increased levels of IL-1β and IL-1R1 as well as increased levels of plasma corticosterone. Paradoxically, TLR4-deficient mice exhibited greater vulnerability to ABA with increased mortality rate, suggesting a major contribution of TLR4-mediated responses during ABA-induced weight loss.
Highlights
Our study report increased hypothalamic IL1-βand IL-1R-1 expression during activity-based anorexia (ABA), which play a central role in the activation of hypothalamic pituitary axis (HPA) axis acting as essential mediators of the immune-induced glucocorticoid release[24]
Recent studies support the concept that high fat diet and bacteria interact to promote early inflammatory changes in the intestine that contribute to development of or susceptibility to obesity and insulin resistance[16,25]
Our results show for the first time TLR4-mediated intestinal inflammatory response associated to the ABA model that reproduces the Anorexia nervosa (AN) symptoms of body weight loss and physical hyperactivity[20,21]
Summary
Our hypothesis is that alterations of the gut barrier function could activate the intestinal immune response during the early period of food restriction, and could act as a trigger for systemic low-grade inflammation during AN. The present study aimed to analyze intestinal TLR4 signaling pathway activation during activity-based anorexia (ABA), as well as the hypothalamic immune response to early weight loss. We used TLR4 knockout (KO) mice to test the effect of TLR4 on ABA induction. We used the ABA model since it is one of the most widely used animal models for the study of AN20,21
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