TLR4-interactor with leucine-rich repeats (TRIL) is involved in diet-induced hypothalamic inflammation

Alexandre Moura-Assis,Pedro A S Nogueira,Joana M Gaspar,Jose C De-Lima-Junior,Licio A Velloso,Fernando M Simabuco,Jose Donato Jr

doi:10.1038/s41598-021-97291-7

Alexandre Moura-Assis, Pedro A S Nogueira + Show 5 more

Open Access

https://doi.org/10.1038/s41598-021-97291-7

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Abstract

Obesity and high-fat diet (HFD) consumption result in hypothalamic inflammation and metabolic dysfunction. 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.

Highlights

Obesity and high-fat diet (HFD) consumption result in hypothalamic inflammation and metabolic dysfunction
We show that knockdown of hypothalamic toll-like receptor-4 (TLR4)-interactor with leucine-rich repeats (Tril) protects mice from diet-induced body mass gain and systemic glucose intolerance
Tril mRNA expression was detected in 44% of POMC neurons and only 25% of AgRP neurons (Fig. 1A,B); the major Tril overlap with POMC neurons was further confirmed in hypothalamic slices from POMC-GFP mice

Summary

Introduction

Obesity and high-fat diet (HFD) consumption result in hypothalamic inflammation and metabolic dysfunction. 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. 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 TLR4-interactor with leucine-rich repeats (Tril) is a single transmembrane spanning 89 kDa protein that contains 13 leucine-rich repeats and is highly expressed in the b rain[6] It plays an important role mediating TLR4 signal transduction, and whole-body Tril knockout results in defective inflammatory cytokine production in response to LPS and E. coli, in the central nervous system (CNS)[7]. We show that knockdown of hypothalamic Tril protects mice from diet-induced body mass gain and systemic glucose intolerance

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