title: Interleukin-1β mediates macrophage-induced impairment of insulin signaling in human primary adipocytes.
abstract: Adipose tissue expansion during obesity is associated with increased macrophage infiltration. Macrophage-derived factors significantly alter adipocyte function, inducing inflammatory responses and decreasing insulin sensitivity. Identification of the major factors that mediate detrimental effects of macrophages on adipocytes may offer potential therapeutic targets. IL-1β, a proinflammatory cytokine, is suggested to be involved in the development of insulin resistance. This study investigated the role of IL-1β in macrophage-adipocyte cross-talk, which affects insulin signaling in human adipocytes. Using macrophage-conditioned (MC) medium and human primary adipocytes, we examined the effect of IL-1β antagonism on the insulin signaling pathway. Gene expression profile and protein abundance of insulin signaling molecules were determined, as was the production of proinflammatory cytokine/chemokines. We also examined whether IL-1β mediates MC medium-induced alteration in adipocyte lipid storage. MC medium and IL-1β significantly reduced gene expression and protein abundance of insulin signaling molecules, including insulin receptor substrate-1, phosphoinositide 3-kinase p85α, and glucose transporter 4 and phosphorylation of Akt. In contrast, the expression and release of the proinflammatory markers, including IL-6, IL-8, monocyte chemotactic protein-1, and chemokine (C-C motif) ligand 5 by adipocytes were markedly increased. These changes were significantly reduced by blocking IL-1β activity, its receptor binding, or its production by macrophages. MC medium-inhibited expression of the adipogenic factors and -stimulated lipolysis was also blunted with IL-1β neutralization. We conclude that IL-1β mediates, at least in part, the effect of macrophages on insulin signaling and proinflammatory response in human adipocytes. Blocking IL-1β could be beneficial for preventing obesity-associated insulin resistance and inflammation in human adipose tissue.
authors.affiliation: Department of Obesity and Endocrinology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Dan
authors.initials: D
authors.lastname: Gao
authors.affiliation: Department of Obesity and Endocrinology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Madi
authors.affiliation: Department of Obesity and Endocrinology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Cherlyn
authors.initials: C
authors.lastname: Ding
authors.affiliation: Department of Obesity and Endocrinology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Fok
authors.affiliation: Department of Obesity and Endocrinology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Steele
authors.affiliation: Department of Obesity and Endocrinology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Ford
authors.affiliation: Department of Obesity and Endocrinology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Leif
authors.initials: L
authors.lastname: Hunter
authors.affiliation: Department of Obesity and Endocrinology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom bing@liverpool.ac.uk.
authors.forename: Chen
authors.initials: C
authors.lastname: Bing
mesh_terms: D052438:Adipocytes, White / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D020170:Caspase 1 / Q000737:chemistry / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D002450:Cell Communication; D002460:Cell Line; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008066:Lipolysis / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D057134:Antibodies, Neutralizing; D061945:Caspase Inhibitors; D017077:Culture Media, Conditioned; D007004:Hypoglycemic Agents; C508585:IL1B protein, human; C507763:IL1RN protein, human; D007328:Insulin; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D020170:Caspase 1
keywords: IL-1β; cytokines; human adipocytes; insulin signaling; macrophages