title: Central inhibition of IKKβ/NF-κB signaling attenuates high-fat diet-induced obesity and glucose intolerance.
abstract: Metabolic inflammation in the central nervous system might be causative for the development of overnutrition-induced metabolic syndrome and related disorders, such as obesity, leptin and insulin resistance, and type 2 diabetes. Here we investigated whether nutritive and genetic inhibition of the central IκB kinase β (IKKβ)/nuclear factor-κB (NF-κB) pathway in diet-induced obese (DIO) and leptin-deficient mice improves these metabolic impairments. A known prominent inhibitor of IKKβ/NF-κB signaling is the dietary flavonoid butein. We initially determined that oral, intraperitoneal, and intracerebroventricular administration of this flavonoid improved glucose tolerance and hypothalamic insulin signaling. The dose-dependent glucose-lowering capacity was profound regardless of whether obesity was caused by leptin deficiency or high-fat diet (HFD). To confirm the apparent central role of IKKβ/NF-κB signaling in the control of glucose and energy homeostasis, we genetically inhibited this pathway in neurons of the arcuate nucleus, one key center for control of energy homeostasis, via specific adeno-associated virus serotype 2-mediated overexpression of IκBα, which inhibits NF-κB nuclear translocation. This treatment attenuated HFD-induced body weight gain, body fat mass accumulation, increased energy expenditure, and reduced arcuate suppressor of cytokine signaling 3 expression, indicative for enhanced leptin signaling. These results reinforce a specific role of central proinflammatory IKKβ/NF-κB signaling in the development and potential treatment of DIO-induced comorbidities.
authors: Department of Animal Physiology, Faculty of Biology, Philipps-University Marburg, Marburg, Germany.
authors: Jonas
authors: J
authors: Benzler
authors: Institute for Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Philipps-University Marburg, Marburg, Germany.
authors: Goutham K
authors: GK
authors: Ganjam
authors: Department of Animal Physiology, Faculty of Biology, Philipps-University Marburg, Marburg, Germany.
authors: Dominik
authors: D
authors: Pretz
authors: Department of Animal Physiology, Faculty of Biology, Philipps-University Marburg, Marburg, Germany.
authors: Rebecca
authors: R
authors: Oelkrug
authors: Department of Animal Physiology, Faculty of Biology, Philipps-University Marburg, Marburg, Germany.
authors: Christiane E
authors: CE
authors: Koch
authors: Department of Animal Physiology, Faculty of Biology, Philipps-University Marburg, Marburg, Germany.
authors: Karen
authors: K
authors: Legler
authors: Department of Animal Physiology, Faculty of Biology, Philipps-University Marburg, Marburg, Germany.
authors: Sigrid
authors: S
authors: Stöhr
authors: Institute for Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Philipps-University Marburg, Marburg, Germany.
authors: Carsten
authors: C
authors: Culmsee
authors: Metabolic Health Group, Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, U.K.
authors: Lynda M
authors: LM
authors: Williams
authors: Department of Animal Physiology, Faculty of Biology, Philipps-University Marburg, Marburg, Germany Centre for Neuroendocrinology, Department of Physiology, School of Medical Sciences, University of Otago, Dunedin, New Zealand alexander.tups@otago.ac.nz.
authors: Alexander
authors: A
authors: Tups
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001823:Body Composition / Q000502:physiology; D002460:Cell Line; D004041:Dietary Fats / Q000009:adverse effects*; D018149:Glucose Intolerance; D051550:I-kappa B Kinase / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D016328:NF-kappa B; D051550:I-kappa B Kinase