Substance P promotes expansion of human mesenteric preadipocytes through proliferative and antiapoptotic pathways

Kara Gross, Iordanes Karagiannides, Thomas Thomou, Wai Koon Hon, Collin Bowe, Ho Kim, Nino Giorgadze, Tamara Tchkonia, Tamara Pirtskhalava, James L Kirkland, Charalabos Pothoulakis

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

White adipose tissue is intimately involved in the regulation of immunity and inflammation. We reported that human mesenteric preadipocytes express the substance P (SP)-mediated neurokinin-1 receptor (NK-1R), which signals proinflammatory responses. Here we tested the hypothesis that SP promotes proliferation and survival of human mesenteric preadipocytes and investigated responsible mechanism(s). Preadipocytes were isolated from mesenteric fat biopsies during gastric bypass surgery. Proliferative and antiapoptotic responses were delineated in 3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), bromodeoxyuridine (BrdU), caspase-3, and TUNEL assays, as well as Western immunoanalysis. SP (10-7 M) increased MTS and proliferation (BrdU) and time dependently (15-30 min) induced Akt, EGF receptor, IGF receptor, integrin αVβ3, phosphatidylinositol 3-kinase, and PKC-θ phosphorylation. Furthermore, pharmacological antagonism of Akt and PKC-θ activation significantly attenuated SP-induced preadipocyte proliferation. Exposure of preadipocytes to the proapoptotic Fas ligand (FasL, 100 μM) resulted in nuclear DNA fragmentation (TUNEL assay), as well as increased cleaved poly (ADP-ribose) polymerase, cleaved caspase-7, and caspase-3 expression. Cotreatment with SP almost completely abolished these responses in a NK-1R-dependent fashion. SP (10-7 M) also time dependently stimulated expression 4E binding protein 1 and phosphorylation of p70 S6 kinase, which increased protein translation efficiency. SP increases preadipocyte viability, reduces apoptosis, and stimulates proliferation, possibly via cell cycle upregulation and increased protein translation efficiency. SP-induced proliferative and antiapoptotic pathways in fat depots may contribute to development of the creeping fat and inflammation characteristic of Crohn's disease.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume296
Issue number5
DOIs
StatePublished - May 2009

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Substance P
Neurokinin-1 Receptors
Fats
In Situ Nick-End Labeling
Protein Biosynthesis
Bromodeoxyuridine
Caspase 3
Phosphorylation
Phosphatidylinositol 3-Kinase
70-kDa Ribosomal Protein S6 Kinases
Inflammation
Caspase 7
White Adipose Tissue
Fas Ligand Protein
Gastric Bypass
Poly(ADP-ribose) Polymerases
DNA Fragmentation
Epidermal Growth Factor Receptor
Integrins
Crohn Disease

Keywords

  • Adipocyte
  • Akt
  • Creeping fat
  • Crohn's disease
  • Neuropeptide
  • Proliferation
  • Protein kinase C-θ

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

Substance P promotes expansion of human mesenteric preadipocytes through proliferative and antiapoptotic pathways. / Gross, Kara; Karagiannides, Iordanes; Thomou, Thomas; Hon, Wai Koon; Bowe, Collin; Kim, Ho; Giorgadze, Nino; Tchkonia, Tamara; Pirtskhalava, Tamara; Kirkland, James L; Pothoulakis, Charalabos.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 296, No. 5, 05.2009.

Research output: Contribution to journalArticle

Gross, Kara ; Karagiannides, Iordanes ; Thomou, Thomas ; Hon, Wai Koon ; Bowe, Collin ; Kim, Ho ; Giorgadze, Nino ; Tchkonia, Tamara ; Pirtskhalava, Tamara ; Kirkland, James L ; Pothoulakis, Charalabos. / Substance P promotes expansion of human mesenteric preadipocytes through proliferative and antiapoptotic pathways. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2009 ; Vol. 296, No. 5.
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