title: Atypical protein kinase C activity in the hypothalamus is required for lipopolysaccharide-mediated sickness responses.
abstract: By activating the Toll-like receptor 4-nuclear factor-kappaB signal transduction pathway, the bacterial endotoxin lipopolysaccharide (LPS) induces anorexia, weight loss, fever, and other components of the sickness response. By comparison, the hormones leptin and insulin cause anorexia without sickness via a central mechanism involving the phosphatidylinositol-3 kinase signaling pathway. In the current study, we investigated whether a common Toll-like receptor 4 and phosphatidylinositol-3 kinase signaling intermediate, atypical protein kinase Czeta/lambda (aPKC), contributes to changes of energy balance induced by these stimuli. Immunohistochemistry analysis revealed that aPKC is expressed in the arcuate and paraventricular nuclei of the hypothalamus, key sites of leptin, insulin, and LPS action. Although administration of LPS, insulin, and leptin each acutely increased hypothalamic aPKC activity at doses that also reduce food intake, LPS treatment caused over 10-fold greater activation of hypothalamic a PKC signaling than that induced by leptin or insulin. Intracerebroventricular pretreatment with an aPKC inhibitor blocked anorexia induced by LPS but not insulin or leptin. Similarly, LPS-induced hypothalamic inflammation (as judged by induction of proinflammatory cytokine gene expression) and neuronal activation in the paraventricular nucleus (as judged by c-fos induction) were reduced by central aPKC inhibition. Although intracerebroventricular aPKC inhibitor administration also abolished LPS-induced fever, it had no effect on sickness-related hypoactivity or weight loss. We conclude that although hypothalamic aPKC signaling is not required for food intake inhibition by insulin or leptin, it plays a key role in inflammatory anorexia and fever induced by LPS.
authors.affiliation: Division of Metabolism, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Thaler
authors.forename: Sun Ju
authors.initials: SJ
authors.lastname: Choi
authors.forename: Mini P
authors.initials: MP
authors.lastname: Sajan
authors.forename: Kayoko
authors.initials: K
authors.lastname: Ogimoto
authors.forename: Hong T
authors.initials: HT
authors.lastname: Nguyen
authors.forename: Miles
authors.initials: M
authors.lastname: Matsen
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Benoit
authors.forename: Brent E
authors.initials: BE
authors.lastname: Wisse
authors.forename: Robert V
authors.initials: RV
authors.lastname: Farese
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D000855:Anorexia / Q000139:chemically induced / Q000201:enzymology*; D002460:Cell Line; D016207:Cytokines / Q000235:genetics; D004435:Eating / Q000187:drug effects; D005334:Fever / Q000139:chemically induced / Q000201:enzymology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000201:enzymology / Q000473:pathology; D007328:Insulin / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta
chemical_list: D016207:Cytokines; D007328:Insulin; D007527:Isoenzymes; D020738:Leptin; D008070:Lipopolysaccharides; D011493:Protein Kinase C; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta; C115015:PKC-3 protein