[Hypothalamic inflammation and energy balance deregulations: focus on chemokines.]
The hypothalamus is a key brain region in the regulation of energy balance. It especially controls food intake and both energy storage and expenditure through integration of humoral, neural and nutrient-related signals and cues. Hypothalamic neurons and glial cells act jointly to orchestrate, both spatially and temporally, regulated metabolic functions of the hypothalamus. Thus, the existence of a causal link between hypothalamic inflammation and deregulations of feeding behavior, such as involuntary weight-loss or obesity, has been suggested. Among the inflammatory mediators that could induce deregulations of hypothalamic control of the energy balance, chemokines represent interesting candidates. Indeed, chemokines, primarily known for their chemoattractant role of immune cells to the inflamed site, have also been suggested capable of neuromodulation. Thus, chemokines could disrupt cellular activity together with synthesis and/or secretion of multiple neurotransmitters/mediators that are involved in the maintenance of energy balance. Here, we relate, on one hand, recent results showing the primary role of the central chemokinergic signaling CCL2/CCR2 for metabolic and behavioral adaptation to high-grade inflammation, especially loss of appetite and weight, through its activity on hypothalamic neurons producing the orexigenic peptide Melanin-Concentrating Hormone (MCH) and, on the other hand, results that suggest that chemokines could also deregulate hypothalamic neuropeptidergic circuits to induce an opposite phenotype and eventually participate in the onset/development of obesity. In more details, we will emphasize a study recently showing, in a model of high-grade acute inflammation of LPS injection in mice, that central CCL2/CCR2 signaling is of primary importance for several aspects explaining weight loss associated with inflammation: after LPS injection, animals lose weight, reduce their food intake, increase their fat oxidation (thus energy consumption from fat storage)...These inflammation-induced metabolic and behavioral changes are reduced when central CCR2 signaling is disrupted either pharmacologically (by a specific inhibitor of CCR2) or genetically (in mice deficient for CCR2). This underlines the importance of this signaling in inflammation-related weight loss. We further determined that the LPS-induced and CCR2-mediated weight loss depends on the direct effect of CCR2 activation on MCH neurons activity. Indeed, the MCH neurons express CCR2, and the application of CCL2 on brain slices revealed that activation of CCR2 actually depolarizes MCH neurons and induces delays and/or failures of action potential emission. Furthermore, CCL2 is able to reduce KCl-evoked MCH secretion from hypothalamic explants. Taken together, these results demonstrate the role of the central CCL2/CCR2 signaling in metabolic and behavioral adaptation to inflammation. On the other hand, this first description of how the chemokinergic system can actually modulate the activity of the hypothalamic regulation of energy balance, but also some less advanced studies and some unpublished data, suggest that some other chemokines, such as CCL5, could participate in the development of the opposite phenotype, that is to say obesity.
Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, France - Helmholtz Diabetes Center (HDC) & German Center for Diabetes Research (DZD), Helmholtz Zentrum München & Division of Metabolic Diseases, Technische Universität München, Munich, Germany.
Ophélia
O
Le Thuc
Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, France.
Carole
C
Rovère
D000818:Animals; D018925:Chemokines / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology; D006801:Humans; D007027:Hypothalamic Diseases / Q000150:complications* / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism / Q000473:pathology; D007249:Inflammation; D008659:Metabolic Diseases / Q000209:etiology*; D051379:Mice; D009765:Obesity / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D015431:Weight Loss / Q000235:genetics / Q000276:immunology
D018925:Chemokines