title: Substance P (SP)-neurokinin-1 receptor (NK-1R) alters adipose tissue responses to high-fat diet and insulin action.
abstract: Peripheral administration of a specific neurokinin-1 receptor (NK-1R) antagonist to mice leads to reduced weight gain and circulating levels of insulin and leptin after high-fat diet (HFD). Here, we assessed the contribution of substance P (SP) and NK-1R in diet-induced obesity using NK-1R deficient [knockout (KO)] mice and extended our previous findings to show the effects of SP-NK-1R interactions on adipose tissue-associated insulin signaling and glucose metabolic responses. NK-1R KO and wild-type (WT) littermates were fed a HFD for 3 wk, and obesity-associated responses were determined. Compared with WT, NK-1 KO mice show reduced weight gain and circulating levels of leptin and insulin in response to HFD. Adiponectin receptor mRNA levels are higher in mesenteric fat and liver in NK-1 KO animals compared with WT, after HFD. Mesenteric fat from NK-1R KO mice fed with HFD has reduced stress-activated protein kinase/c-Jun N-terminal kinase and protein kinase C activation compared with WT mice. After glucose challenge, NK-1R KO mice remove glucose from the circulation more efficiently than WT and pair-fed controls, suggesting an additional peripheral effect of NK-1R-mediated signaling on glucose metabolism. Glucose uptake experiments in isolated rat adipocytes showed that SP directly inhibits insulin-mediated glucose uptake. Our results further establish a role for SP-NK-1R interactions in adipose tissue responses, specifically as they relate to obesity-associated pathologies such as glucose intolerance and insulin resistance. Our results highlight this pathway as an important therapeutic approach for type 2 diabetes.
authors.affiliation: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, South MacDonald Research Laboratories Building 1240, Los Angeles, California 90095-7019, USA. ikaragiannidis@mednet.ucla.edu
authors.forename: Iordanes
authors.initials: I
authors.lastname: Karagiannides
authors.forename: Dimitris
authors.initials: D
authors.lastname: Stavrakis
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Bakirtzi
authors.forename: Efi
authors.initials: E
authors.lastname: Kokkotou
authors.forename: Tamara
authors.initials: T
authors.lastname: Pirtskhalava
authors.forename: Hamed
authors.initials: H
authors.lastname: Nayeb-Hashemi
authors.forename: Collin
authors.initials: C
authors.lastname: Bowe
authors.forename: James M
authors.initials: JM
authors.lastname: Bugni
authors.forename: Miriam
authors.initials: M
authors.lastname: Nuño
authors.forename: Bao
authors.initials: B
authors.lastname: Lu
authors.forename: Norma P
authors.initials: NP
authors.lastname: Gerard
authors.forename: Susan E
authors.initials: SE
authors.lastname: Leeman
authors.forename: James L
authors.initials: JL
authors.lastname: Kirkland
authors.forename: Charalabos
authors.initials: C
authors.lastname: Pothoulakis
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D004041:Dietary Fats / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D020738:Leptin / Q000097:blood / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D011916:Rats, Inbred F344; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013373:Substance P / Q000378:metabolism*; D015430:Weight Gain
chemical_list: D004041:Dietary Fats; D007328:Insulin; D020738:Leptin; D018040:Receptors, Neurokinin-1; D013373:Substance P; D005947:Glucose