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While the TLR4 activation by dietary fats is a well-characterized pathway involved in the neuronal and glial inflammation, the role of its accessory proteins in diet-induced hypothalamic inflammation remains unknown. Here, we demonstrate that the knockdown of TLR4-interactor with leucine-rich repeats (Tril), a functional component of TLR4, resulted in reduced hypothalamic inflammation, increased whole-body energy expenditure, improved the systemic glucose tolerance and protection from diet-induced obesity. The POMC-specific knockdown of Tril resulted in decreased body fat, decreased white adipose tissue inflammation and a trend toward increased leptin signaling in POMC neurons. Thus, Tril was identified as a new component of the complex mechanisms that promote hypothalamic dysfunction in experimental obesity and its inhibition in the hypothalamus may represent a novel target for obesity treatment.<\/jats:p>","DOI":"10.1038\/s41598-021-97291-7","type":"journal-article","created":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T10:06:24Z","timestamp":1631181984000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["TLR4-interactor with leucine-rich repeats (TRIL) is involved in diet-induced hypothalamic inflammation"],"prefix":"10.1038","volume":"11","author":[{"given":"Alexandre","family":"Moura-Assis","sequence":"first","affiliation":[]},{"given":"Pedro A. 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