Joseane Morari, 1 Gabriel F. Anhe, 2 Lucas F. Nascimento, 1 Rodrigo F. de Moura, 1 Daniela Razolli, 1 Carina Solon, 1 Dioze Guadagnini, 3 Gabriela Souza, 1 Alexandre H. Mattos, 4 Natalia Tobar, 5 Celso D. Ramos, 5 Vinicius D. Pascoal, 4 Mario J. Saad, 3 Iscia Lopes-Cendes, 4 Juliana C. Moraes, 1 and Licio A. Velloso 1 Fractalkine (CX3CL1) Is Involved in the Early Activation of Hypothalamic Inflammation in Experimental Obesity Diabetes 2014;63:3770–3784 | DOI: 10.2337/db13-1495 Hypothalamic inflammation is a common feature of ex- perimental 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 ex- pression 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 hy- pothalamus 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 intoler- ance phenotypes. A complex network of neurons that are responsive to hormonal, neural, and nutritional cues tightly regulates body adiposity (1,2). Cells of the medium-basal hypothalamus act as first-order neurons in this system, and many genetic, pharmacological, and environmental approaches that lead to the damage or loss of some of these neurons can affect body energy homeostasis (1,2). In many experimental models, hy- pothalamic dysfunction that results from local inflammation plays a central role in the pathogenesis of obesity (3,4). In addition, recent studies using neuroimaging have provided strong evidence for the existence of inflammation and dys- function in the hypothalamus of obese humans (5,6). Dietary long-chain saturated fatty acids are the main triggers of hypothalamic inflammation in obesity (7). These fatty acids act through toll-like receptor 4 (TLR4) (7) and induce endoplasmic reticulum stress (4,7), leading to the activation of intracellular inflammatory signaling pathways through Jun NH 2 -terminal kinase (JNK), nuclear factor- kB, and protein kinase C-u (PKC-u) (3,4,8). The increased hypothalamic expression of inflammatory cytokines is de- tectable as early as 1 day after the introduction of a fat-rich diet to rodents (6). Upon prolonged high-fat feeding, sig- nals of cellular damage become evident, such as gliosis (6), apoptosis (9), and defects in the potential for neurogenic recovery (10). Thus, diet-induced hypothalamic inflamma- tion follows a classical path of the inflammatory response, which is detectable a few hours after the exposure to the threatening stimulus, and progresses with a wide array of damaging/recovering outcomes. An important missing link between the exposure to dietary fats and the induction and perpetuation of 1 Laboratory of Cell Signaling, University of Campinas, Campinas, Brazil 2 Department of Pharmacology, University of Campinas, Campinas, Brazil 3 Laboratory of Experimental Endocrinology, University of Campinas, Campinas, Brazil 4 Department of Medical Genetics, University of Campinas, Campinas, Brazil 5 Department of Radiology, University of Campinas, Campinas, Brazil Corresponding author: Licio A. Velloso, lavelloso.unicamp@gmail.com. Received 29 September 2013 and accepted 28 May 2014. This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1495/-/DC1. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. 3770 Diabetes Volume 63, November 2014 OBESITY STUDIES Downloaded from http://diabetesjournals.org/diabetes/article-pdf/63/11/3770/574221/3770.pdf by guest on 07 May 2023