Fractalkine (CX3CL1) Is Involved in the Early Activation of Hypothalamic Inflammation in Experimental Obesity

Abstract

Hypothalamic inflammation is a common feature of experimental obesity. Dietary fats are important triggers of this process, inducing the activation of toll-like receptor-4 (TLR4) signaling and endoplasmic reticulum stress. Microglia cells, which are the cellular components of the innate immune system in the brain, are expected to play a role in the early activation of diet-induced hypothalamic inflammation. Here, we use bone marrow transplants to generate mice chimeras that express a functional TLR4 in the entire body except in bone marrow–derived cells or only in bone marrow–derived cells. We show that a functional TLR4 in bone marrow–derived cells is required for the complete expression of the diet-induced obese phenotype and for the perpetuation of inflammation in the hypothalamus. In an obesity-prone mouse strain, the chemokine CX3CL1 (fractalkine) is rapidly induced in the neurons of the hypothalamus after the introduction of a high-fat diet. The inhibition of hypothalamic fractalkine reduces diet-induced hypothalamic inflammation and the recruitment of bone marrow–derived monocytic cells to the hypothalamus; in addition, this inhibition reduces obesity and protects against diet-induced glucose intolerance. Thus, fractalkine is an important player in the early induction of diet-induced hypothalamic inflammation, and its inhibition impairs the induction of the obese and glucose intolerance phenotypes.

The body mass index (BMI) is significantly correlated with levels of cytokines and chemokines in cerebrospinal fluid

“…It is expressed in a number of cell types including forebrain neurons and has been shown to be involved in the activation of hypothalamic inflammation in experimental obesity [40]. Studies have shown that inflammatory activity affects the expression of beta-NGF in the brain.…”

Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy

“…The best duplex with sequence 5′-gcuuGcGAGAGGGuuuAAAdTsdT-3′ (sense) (where upper-case letters represent unmodified RNA [2'-OH] residues and lower-case letters represent residues with 2'-O-methyl modification) and 5′-UUuAAACCCUCUCGcAAGCdTsdT-3′ (anti-sense) was selected for largescale synthesis and subsequent nanoparticle formulation ( Figure 7B and Supplemental Figure 8B). Importantly, when we compared the knockdown efficiency of our siCX3CL1 (hereafter referred to as Axo-siCX3CL1) and another siRNA against CX3CL1 from a recent publication (61), there was a dramatic enhancement in silencing efficiency for Axo-siCX3CL1 (Supplemental Figure 8C).…”

MECHANISMS IN ENDOCRINOLOGY: Hypothalamic inflammation and nutrition

“…Inflammatory cytokines released by microglia in the hypothalamic microenvironment induce the expression of CX3CL1 (fractalkine) by neurons (31). Fractalkine produced in this context recruits peripheral monocytes to potentiate and perpetuate hypothalamic inflammation (31). An important aspect of diet-induced hypothalamic inflammation is that intracellular serine/ threonine kinases activated in response to inflammatory signals can target and inhibit key proteins of the leptin and insulin signaling systems, therefore establishing a mechanistic link between hypothalamic inflammation and the resistance to adipostatic signals (25).…”

“…Long-chain saturated fatty acids trigger hypothalamic inflammation by inducing the activation of toll-like receptor-4 (TLR4) signaling in microglia (15). Inflammatory cytokines released by microglia in the hypothalamic microenvironment induce the expression of CX3CL1 (fractalkine) by neurons (31). Fractalkine produced in this context recruits peripheral monocytes to potentiate and perpetuate hypothalamic inflammation (31).…”