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

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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 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
JournalEndocrinology
Volume152
Issue number6
DOIs
StatePublished - Jun 1 2011
Externally publishedYes

Fingerprint

Neurokinin-1 Receptors
High Fat Diet
Substance P
Adipose Tissue
Insulin
Glucose
Knockout Mice
Obesity
Leptin
Weight Gain
Adiponectin Receptors
Fats
Neurokinin-1 Receptor Antagonists
Glucose Intolerance
JNK Mitogen-Activated Protein Kinases
Heat-Shock Proteins
Adipocytes
Protein Kinases
Type 2 Diabetes Mellitus
Protein Kinase C

ASJC Scopus subject areas

  • Endocrinology

Cite this

Karagiannides, I., Stavrakis, D., Bakirtzi, K., Kokkotou, E., Pirtskhalava, T., Nayeb-Hashemi, H., ... 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. https://doi.org/10.1210/en.2010-1345

Substance P (SP)-neurokinin-1 receptor (NK-1R) alters adipose tissue responses to high-fat diet and insulin action. / Karagiannides, Iordanes; Stavrakis, Dimitris; Bakirtzi, Kyriaki; Kokkotou, Efi; Pirtskhalava, Tamara; Nayeb-Hashemi, Hamed; Bowe, Collin; Bugni, James M.; Nuno, Miriam A; Lu, Bao; Gerard, Norma P.; Leeman, Susan E.; Kirkland, James L.; Pothoulakis, Charalabos.

In: Endocrinology, Vol. 152, No. 6, 01.06.2011, p. 2197-2205.

Research output: Contribution to journalArticle

Karagiannides, I, Stavrakis, D, Bakirtzi, K, Kokkotou, E, Pirtskhalava, T, Nayeb-Hashemi, H, Bowe, C, Bugni, JM, Nuno, MA, Lu, B, Gerard, NP, Leeman, SE, Kirkland, JL & Pothoulakis, C 2011, 'Substance P (SP)-neurokinin-1 receptor (NK-1R) alters adipose tissue responses to high-fat diet and insulin action', Endocrinology, vol. 152, no. 6, pp. 2197-2205. https://doi.org/10.1210/en.2010-1345
Karagiannides I, Stavrakis D, Bakirtzi K, Kokkotou E, Pirtskhalava T, Nayeb-Hashemi H et al. Substance P (SP)-neurokinin-1 receptor (NK-1R) alters adipose tissue responses to high-fat diet and insulin action. Endocrinology. 2011 Jun 1;152(6):2197-2205. https://doi.org/10.1210/en.2010-1345
Karagiannides, Iordanes ; Stavrakis, Dimitris ; Bakirtzi, Kyriaki ; Kokkotou, Efi ; Pirtskhalava, Tamara ; Nayeb-Hashemi, Hamed ; Bowe, Collin ; Bugni, James M. ; Nuno, Miriam A ; Lu, Bao ; Gerard, Norma P. ; Leeman, Susan E. ; Kirkland, James L. ; Pothoulakis, Charalabos. / Substance P (SP)-neurokinin-1 receptor (NK-1R) alters adipose tissue responses to high-fat diet and insulin action. In: Endocrinology. 2011 ; Vol. 152, No. 6. pp. 2197-2205.
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