title: Substance P decreases fat storage and increases adipocytokine production in 3T3-L1 adipocytes.
abstract: Obesity, inflammation, and insulin resistance are closely linked. Substance P (SP), via its neurokinin 1 receptor (NK1R), mediates inflammatory and, possibly, neuroendocrine processes. We examined SP effects on lipid storage and cytokine production in 3T3-L1 adipocytes and adipose tissues. 3T3-L1 adipocytes and preadipocytes express NK1R, and 8 days of SP supplementation during differentiation to 3T3-L1 preadipocytes decreased lipid droplet accumulation. SP (10 nM, 24 h) increased lipolysis in primary adipocytes (138 ± 7%, P < 0.05) and reduced fatty acid uptake (-31 ± 7%, P < 0.05) and mRNA expression of the differentiation-related transcription factors peroxisome proliferator-activated receptor-γ type 2 (-64 ± 2%, P < 0.001) and CCAAT enhancer-binding protein (CEBP)-α (-65 ± 2%, P < 0.001) and the lipid storage genes fatty acid-binding protein type 4 (-59 ± 2%, P < 0.001) and diacylglycerol O-acyltransferase-1 (-45 ± 2%, P < 0.01) in 3T3-L1 adipocytes, while CD36, a fatty acid transporter (+82 ± 19%, P < 0.01), was augmented. SP increased secretion of complement C3 (148 ± 15%, P < 0.04), monocyte chemoattractant protein-1 (156 ± 16%, P < 0.03), and keratinocyte-derived chemokine (148 ± 18%, P = 0.045) in 3T3-L1 adipocytes and monocyte chemoattractant protein-1 (496 ± 142%, P < 0.02) and complement C3 (152 ± 25%, P < 0.04) in adipose tissue and primary adipocytes, respectively. These SP effects were accompanied by downregulation of insulin receptor substrate 1 (-82 ± 2%, P < 0.01) and GLUT4 (-76 ± 2%, P < 0.01) mRNA expression, and SP acutely blocked insulin-mediated stimulation of fatty acid uptake and Akt phosphorylation. Although adiponectin secretion was unchanged, mRNA expression was decreased (-86 ± 8%, P < 0.001). In humans, NK1R expression correlates positively with plasma insulin, fatty acid, and complement C3 and negatively with adiponectin, CEBPα, CEBPβ, and peroxisome proliferator-activated receptor-γ mRNA expression in omental, but not subcutaneous, adipose tissue. Our results suggest that, beyond its neuroendocrine and inflammatory effects, SP could also be involved in targeting adipose tissue and influencing insulin resistance.
authors.affiliation: Centre de Recherche Institut Universitaire de Cardiologie and Pneumologie de Quebec and Department of Medicine, Université Laval, Quebec, Quebec, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Miegueu
authors.forename: David H
authors.initials: DH
authors.lastname: St-Pierre
authors.forename: Marc
authors.initials: M
authors.lastname: Lapointe
authors.forename: Pegah
authors.initials: P
authors.lastname: Poursharifi
authors.forename: HuiLing
authors.initials: H
authors.lastname: Lu
authors.forename: Abhishek
authors.initials: A
authors.lastname: Gupta
authors.forename: Katherine
authors.initials: K
authors.lastname: Cianflone
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D054392:Adipokines / Q000096:biosynthesis*; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis; D002454:Cell Differentiation / Q000187:drug effects; D018932:Chemokine CCL2; D003176:Complement C3 / Q000378:metabolism; D051048:Diacylglycerol O-Acyltransferase / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000096:biosynthesis; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000096:biosynthesis; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000096:biosynthesis; D018040:Receptors, Neurokinin-1 / Q000096:biosynthesis; D013373:Substance P / Q000502:physiology*
chemical_list: D054392:Adipokines; D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D018932:Chemokine CCL2; D003176:Complement C3; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D047495:PPAR gamma; D018040:Receptors, Neurokinin-1; D013373:Substance P; D051048:Diacylglycerol O-Acyltransferase