title: Glucagon-like peptide 1 receptor induced suppression of food intake, and body weight is mediated by central IL-1 and IL-6.
abstract: Glucagon-like peptide 1 (GLP-1), produced in the intestine and the brain, can stimulate insulin secretion from the pancreas and alleviate type 2 diabetes. The cytokine interleukin-6 (IL-6) may enhance insulin secretion from β-cells by stimulating peripheral GLP-1 production. GLP-1 and its analogs also reduce food intake and body weight, clinically beneficial actions that are likely exerted at the level of the CNS, but otherwise are poorly understood. The cytokines IL-6 and interleukin 1β (IL-1β) may exert an anti-obesity effect in the CNS during health. Here we found that central injection of a clinically used GLP-1 receptor agonist, exendin-4, potently increased the expression of IL-6 in the hypothalamus (11-fold) and the hindbrain (4-fold) and of IL-1β in the hypothalamus, without changing the expression of other inflammation-associated genes. Furthermore, hypothalamic and hindbrain interleukin-associated intracellular signals [phosphorylated signal transducer and activator of transcription-3 (pSTAT3) and suppressor of cytokine signaling-1 (SOCS1)] were also elevated by exendin-4. Pharmacologic disruption of CNS IL-1 receptor or IL-6 biological activity attenuated anorexia and body weight loss induced by central exendin-4 administration in a rat. Simultaneous blockade of IL-1 and IL-6 activity led to a more potent attenuation of exendin-4 effects on food intake. Mice with global IL-1 receptor gene knockout or central IL-6 receptor knockdown showed attenuated decrease in food intake and body weight in response to peripheral exendin-4 treatment. GLP-1 receptor activation in the mouse neuronal Neuro2A cell line also resulted in increased IL-6 expression. These data outline a previously unidentified role of the central IL-1 and IL-6 in mediating the anorexic and body weight loss effects of GLP-1 receptor activation.
authors.affiliation: Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, SE-405 30 Gothenburg, Sweden.
authors.forename: Rozita
authors.initials: R
authors.lastname: Shirazi
authors.forename: Vilborg
authors.initials: V
authors.lastname: Palsdottir
authors.forename: Jim
authors.initials: J
authors.lastname: Collander
authors.forename: Fredrik
authors.initials: F
authors.lastname: Anesten
authors.forename: Heike
authors.initials: H
authors.lastname: Vogel
authors.forename: Fanny
authors.initials: F
authors.lastname: Langlet
authors.forename: Alexander
authors.initials: A
authors.lastname: Jaschke
authors.forename: Annette
authors.initials: A
authors.lastname: Schürmann
authors.forename: Vincent
authors.initials: V
authors.lastname: Prévot
authors.forename: Ruijin
authors.initials: R
authors.lastname: Shao
authors.forename: John-Olov
authors.initials: JO
authors.lastname: Jansson
authors.forename: Karolina Patrycja
authors.initials: KP
authors.lastname: Skibicka
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001069:Appetite Regulation / Q000502:physiology*; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology*; D055785:Gene Knockdown Techniques; D000067757:Glucagon-Like Peptide-1 Receptor; D007375:Interleukin-1 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000235:genetics
chemical_list: C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007375:Interleukin-1; D015850:Interleukin-6; D018027:Receptors, Glucagon; D017472:Receptors, Interleukin-1
keywords: DVC; POMC; hypothermia
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