title: Activation of AMPK Stimulates Neurotensin Secretion in Neuroendocrine Cells.
abstract: AMP-activated protein kinase (AMPK), a critical fuel-sensing enzyme, regulates the metabolic effects of various hormones. Neurotensin (NT) is a 13-amino acid peptide predominantly localized in enteroendocrine cells of the small bowel and released by fat ingestion. Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with an increased risk of diabetes, cardiovascular disease, and mortality; however, the mechanisms regulating NT release are not fully defined. We previously reported that inhibition of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) increases NT secretion and gene expression through activation of the MEK/ERK pathway. Here, we show that activation of AMPK increases NT secretion from endocrine cell lines (BON and QGP-1) and isolated mouse crypt cells enriched for NT-positive cells. In addition, plasma levels of NT increase in mice treated with 5-aminoimidazole-4-carboxamide riboside, a pharmacologic AMPK activator. Small interfering RNA-mediated knockdown of AMPKα decrease, whereas overexpression of the subunit significantly enhances, NT secretion from BON cells treated with AMPK activators or oleic acid. Similarly, small interfering RNA knockdown of the upstream AMPK kinases, liver kinase B1 and Ca(2+) calmodulin-dependent protein kinase kinase 2, also attenuate NT release and AMPK phosphorylation. Moreover, AMPK activation increases NT secretion through inhibition of mTORC1 signaling. Together, our findings show that AMPK activation enhances NT release through inhibition of mTORC1 signaling, thus demonstrating an important cross talk regulation for NT secretion.
authors.affiliation: Department of Surgery (J.L., J.S., B.M.E.) and Lucille P. Markey Cancer Center (J.L., J.S., H.L.W., T.W., B.M.E.), University of Kentucky, Lexington, Kentucky 40536; and Department of Surgery (C.M.T.), The University of Texas Medical Branch, Galveston, Texas 77555.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Surgery (J.L., J.S., B.M.E.) and Lucille P. Markey Cancer Center (J.L., J.S., H.L.W., T.W., B.M.E.), University of Kentucky, Lexington, Kentucky 40536; and Department of Surgery (C.M.T.), The University of Texas Medical Branch, Galveston, Texas 77555.
authors.forename: Jun
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Surgery (J.L., J.S., B.M.E.) and Lucille P. Markey Cancer Center (J.L., J.S., H.L.W., T.W., B.M.E.), University of Kentucky, Lexington, Kentucky 40536; and Department of Surgery (C.M.T.), The University of Texas Medical Branch, Galveston, Texas 77555.
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Weiss
authors.affiliation: Department of Surgery (J.L., J.S., B.M.E.) and Lucille P. Markey Cancer Center (J.L., J.S., H.L.W., T.W., B.M.E.), University of Kentucky, Lexington, Kentucky 40536; and Department of Surgery (C.M.T.), The University of Texas Medical Branch, Galveston, Texas 77555.
authors.forename: Todd
authors.initials: T
authors.lastname: Weiss
authors.affiliation: Department of Surgery (J.L., J.S., B.M.E.) and Lucille P. Markey Cancer Center (J.L., J.S., H.L.W., T.W., B.M.E.), University of Kentucky, Lexington, Kentucky 40536; and Department of Surgery (C.M.T.), The University of Texas Medical Branch, Galveston, Texas 77555.
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Townsend
authors.affiliation: Department of Surgery (J.L., J.S., B.M.E.) and Lucille P. Markey Cancer Center (J.L., J.S., H.L.W., T.W., B.M.E.), University of Kentucky, Lexington, Kentucky 40536; and Department of Surgery (C.M.T.), The University of Texas Medical Branch, Galveston, Texas 77555.
authors.forename: B Mark
authors.initials: BM
authors.lastname: Evers
mesh_terms: D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D055099:Neuroendocrine Cells / Q000187:drug effects / Q000378:metabolism*; D009496:Neurotensin / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering; D012265:Ribonucleotides / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D034741:RNA, Small Interfering; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D009496:Neurotensin; D000263:Adenylate Kinase; C031143:AICA ribonucleotide