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Hypercaloric diets rich, particularly high-fat diets (HFDs) induce hypothalamic neuroinflammation, which has been shown to precede peripheral inflammation, even after short-term exposure. However, the mechanisms initiating this central inflammatory response, especially the mediators involved, remain incompletely understood. In this study, we demonstrate that HFD consumption induces the expression of resistin in the hypothalamus. Resistin, an adipokine known to promote inflammation and insulin resistance, was found to modulate the expression profile of microRNAs in the hypothalamus. Notably, intracerebroventricular administration of resistin led to the upregulation of miR-155-5p in a TLR4-dependent manner. Consistently, HFD feeding elevated miR-155-5p levels in the mediobasal hypothalamus. Given the established role of miR-155-5p in promoting macrophage activation in peripheral tissues, we examined its expression in microglial cells. We found that both resistin and palmitate, a saturated fatty acid that mimics HFD-induced metabolic stress, increased miR-155-5p expression in the SIM-A9 microglial cell line, which is derived from mouse cerebral cortex tissue without transformation or artificial immortalization. Our findings reveal a novel resistin\/TLR4\/miR-155-5p signaling axis that may initiate hypothalamic neuroinflammation. Moreover, we show that the induction of miR-155-5p by resistin depends on activation of the NF-\u03baB, JNK, and p38 MAPK signaling pathways. To further explore this pathway, we performed High-Throughput Sequencing of RNA isolated by Cross-Linking Immunoprecipitation (HITS-CLIP) to identify miR-155-5p targets in SIM-A9 microglia and in the hypothalami of both male and female mice. This approach revealed several common targets, including <jats:italic>Quaking<\/jats:italic> and <jats:italic>Elmo1<\/jats:italic>, genes implicated in microglial phagocytosis and engulfment. These targets were validated, as transfection of SIM-A9 cells with a miR-155-5p mimic led to downregulation of their expression. Importantly, hypothalamic knockdown of miR-155-5p in both male and female mice improved glucose tolerance and restored <jats:italic>Quaking<\/jats:italic> expression in hypothalamic microglia. In conclusion, our data show that HFD promotes hypothalamic resistin expression, which in turn upregulates miR-155-5p via TLR4 and downstream signaling pathways, thereby contributing to hypothalamic neuroinflammation and disrupted glucose homeostasis. We identify the resistin\/TLR4\/miR-155-5p axis as a novel and critical pathway in the early events of diet-induced neuroinflammation.<\/jats:p>","DOI":"10.1186\/s12974-025-03522-3","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T20:01:15Z","timestamp":1754337675000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["The Resistin\/TLR4\/miR-155-5p axis: a novel signaling pathway in the onset of hypothalamic neuroinflammation"],"prefix":"10.1186","volume":"22","author":[{"given":"Marianne","family":"Pr\u00e9vost","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Cr\u00e9pin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah Al","family":"Rifai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghislaine","family":"Poizat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e9lanie","family":"Gon\u00e7alves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Femke","family":"van Barneveld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rozhina","family":"Shadpay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karim","family":"Taouis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laure","family":"Riffault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yacir","family":"Benomar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Taouis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,4]]},"reference":[{"key":"3522_CR1","doi-asserted-by":"publisher","first-page":"4109","DOI":"10.1210\/en.2010-0336","volume":"151","author":"PJ Thaler","year":"2010","unstructured":"Thaler PJ, Schwartz MW. 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