title: CREB pathway links PGE2 signaling with macrophage polarization.
abstract: Obesity is thought to promote insulin resistance in part via activation of the innate immune system. Increases in proinflammatory cytokine production by M1 macrophages inhibit insulin signaling in white adipose tissue. In contrast, M2 macrophages have been found to enhance insulin sensitivity in part by reducing adipose tissue inflammation. The paracrine hormone prostaglandin E2 (PGE2) enhances M2 polarization in part through activation of the cAMP pathway, although the underlying mechanism is unclear. Here we show that PGE2 stimulates M2 polarization via the cyclic AMP-responsive element binding (CREB)-mediated induction of Krupple-like factor 4 (KLF4). Targeted disruption of CREB or the cAMP-regulated transcriptional coactivators 2 and 3 (CRTC2/3) in macrophages down-regulated M2 marker gene expression and promoted insulin resistance in the context of high-fat diet feeding. As re-expression of KLF4 rescued M2 marker gene expression in CREB-depleted cells, our results demonstrate the importance of the CREB/CRTC pathway in maintaining insulin sensitivity in white adipose tissue via its effects on the innate immune system.
authors.affiliation: Peptide Biology Laboratories, The Salk Institute, La Jolla, CA 92037-1002; Department of Endocrinology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200092, China; bluan@tongji.edu.cn montminy@salk.edu.
authors.forename: Bing
authors.initials: B
authors.lastname: Luan
authors.affiliation: Peptide Biology Laboratories, The Salk Institute, La Jolla, CA 92037-1002;
authors.forename: Young-Sil
authors.initials: YS
authors.lastname: Yoon
authors.affiliation: Department of Genetics, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6145.
authors.forename: John
authors.initials: J
authors.lastname: Le Lay
authors.affiliation: Department of Genetics, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6145.
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
authors.affiliation: Peptide Biology Laboratories, The Salk Institute, La Jolla, CA 92037-1002;
authors.forename: Susan
authors.initials: S
authors.lastname: Hedrick
authors.affiliation: Peptide Biology Laboratories, The Salk Institute, La Jolla, CA 92037-1002; bluan@tongji.edu.cn montminy@salk.edu.
authors.forename: Marc
authors.initials: M
authors.lastname: Montminy
mesh_terms: D000818:Animals; D016764:Cell Polarity; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D015232:Dinoprostone / Q000494:pharmacology*; D006801:Humans; D007333:Insulin Resistance; D015847:Interleukin-4 / Q000494:pharmacology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000502:physiology; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology
chemical_list: C493245:CRTC2 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; D015847:Interleukin-4; D015232:Dinoprostone
keywords: CREB/CRTC; M2 macrophage; cAMP; insulin resistance