title: Central administration of interleukin-4 exacerbates hypothalamic inflammation and weight gain during high-fat feeding.
abstract: In peripheral tissues, the link between obesity and insulin resistance involves low-grade inflammation induced by macrophage activation and proinflammatory cytokine signaling. Since proinflammatory cytokines are also induced in the hypothalamus of animals placed on a high-fat (HF) diet and can inhibit neuronal signal transduction pathways required for normal energy homeostasis, hypothalamic inflammation is hypothesized to contribute to the pathogenesis of diet-induced obesity (DIO). We addressed this hypothesis by perturbing the inflammatory milieu of the hypothalamus in adult male Wistar rats using intracerebroventricular (icv) administration of interleukin-4 (IL-4), a Th2 cytokine that promotes alternative activation (M2) of macrophages and microglia. During HF feeding, icv IL-4 administration increased hypothalamic proinflammatory cytokine gene expression and caused excess weight gain. Intracerebroventricular pretreatment with PS1145, an inhibitor of IKKbeta (a key intracellular mediator of inflammatory signaling), blocked both IL-4 effects, suggesting a causal relationship between IL-4-induced weight gain and hypothalamic inflammation. These observations add to growing evidence linking hypothalamic inflammation to obesity pathogenesis.
authors.affiliation: UW Medicine at South Lake Union, Department of Medicine, Diabetes and Obesity Center of Excellence, University of Washington, 815 Mercer St., Seattle, WA 98109, USA.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Oh-I
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Thaler
authors.forename: Kayoko
authors.initials: K
authors.lastname: Ogimoto
authors.forename: Brent E
authors.initials: BE
authors.lastname: Wisse
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Morton
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000502:physiology; D004041:Dietary Fats / Q000008:administration & dosage* / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D007031:Hypothalamus / Q000503:physiopathology*; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D007249:Inflammation / Q000503:physiopathology*; D007328:Insulin / Q000097:blood; D015847:Interleukin-4 / Q000494:pharmacology*; D020738:Leptin / Q000097:blood; D008262:Macrophage Activation / Q000502:physiology; D008297:Male; D009765:Obesity / Q000503:physiopathology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013047:Specific Pathogen-Free Organisms
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D006575:Heterocyclic Compounds, 3-Ring; D007328:Insulin; D020738:Leptin; C456319:PS1145; D011725:Pyridines; D015847:Interleukin-4; D051550:I-kappa B Kinase