Substance P (SP)-neurokinin-1 receptor (NK-1R) alters adipose tissue responses to high-fat diet and insulin action

Iordanes Karagiannides, Dimitris Stavrakis, Kyriaki Bakirtzi, Efi Kokkotou, Tamara Pirtskhalava, Hamed Nayeb-Hashemi, Collin Bowe, James M. Bugni, Miriam A Nuno, Bao Lu, Norma P. Gerard, Susan E. Leeman, James L. Kirkland, Charalabos Pothoulakis

Research output: Contribution to journalArticle

23 Scopus citations


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 wildtype (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 Cθ 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.

Original languageEnglish (US)
Pages (from-to)2197-2205
Number of pages9
Issue number6
StatePublished - Jun 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology

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    Karagiannides, I., Stavrakis, D., Bakirtzi, K., Kokkotou, E., Pirtskhalava, T., Nayeb-Hashemi, H., Bowe, C., Bugni, J. M., Nuno, M. A., Lu, B., Gerard, N. P., Leeman, S. E., Kirkland, J. L., & Pothoulakis, C. (2011). Substance P (SP)-neurokinin-1 receptor (NK-1R) alters adipose tissue responses to high-fat diet and insulin action. Endocrinology, 152(6), 2197-2205.