AIMS/HYPOTHESIS: Glucagon-like peptide (GLP-1), an intestinal incretin produced in L cells through proglucagon processing, is released in response to meal intake. The intracellular mechanism by which L cells sense the organism energy level to coordinate the production of GLP-1 remains unclear. Mechanistic target of rapamycin (mTOR) is an intracellular fuel sensor critical for energy homeostasis. In this study, we investigated whether intestinal mTOR regulates GLP-1 production in L cells. METHODS: The effects of mTOR on GLP-1 production were examined in lean- or high-fat diet (HFD) induced diabetic C57/BL6, db/db, Neurog3-Tsc1(-/-) mice, and STC-1 cells. GLP-1 expression was investigated by real-time PCR and western blotting. Plasma GLP-1 and insulin were detected by enzyme immunoassay and radioimmunoassay, respectively. RESULTS: Fasting downregulated mTOR activity, which was associated with a decrement of intestinal proglucagon and circulating GLP-1. Upon re-feeding, these alterations returned to the levels of fed animals. In HFD induced diabetic mice, ileal mTOR signalling, proglucagon and circulating GLP-1 were significantly decreased. Inhibition of mTOR signalling by rapamycin decreased levels of intestinal and plasma GLP-1 in both normal and diabetic mice. Activation of the intestinal mTOR signalling by L-leucine or Tsc1 gene deletion increased levels of intestinal proglucagon and plasma GLP-1. Overexpression of mTOR stimulated proglucagon promoter activity and GLP-1 production, whereas inhibition of mTOR activity by overexpression of tuberous sclerosis 1 (TSC1) or TSC2 decreased proglucagon promoter activity and GLP-1 production in STC-1 cells. CONCLUSIONS/ INTERPRETATION: mTOR may link energy supply with the production of GLP-1 in L cells.
AIMS/HYPOTHESIS: Glucagon-like peptide (GLP-1), an intestinal incretin produced in L cells through proglucagon processing, is released in response to meal intake. The intracellular mechanism by which L cells sense the organism energy level to coordinate the production of GLP-1 remains unclear. Mechanistic target of rapamycin (mTOR) is an intracellular fuel sensor critical for energy homeostasis. In this study, we investigated whether intestinal mTOR regulates GLP-1 production in L cells. METHODS: The effects of mTOR on GLP-1 production were examined in lean- or high-fat diet (HFD) induced diabetic C57/BL6, db/db, Neurog3-Tsc1(-/-) mice, and STC-1 cells. GLP-1 expression was investigated by real-time PCR and western blotting. Plasma GLP-1 and insulin were detected by enzyme immunoassay and radioimmunoassay, respectively. RESULTS: Fasting downregulated mTOR activity, which was associated with a decrement of intestinal proglucagon and circulating GLP-1. Upon re-feeding, these alterations returned to the levels of fed animals. In HFD induced diabeticmice, ileal mTOR signalling, proglucagon and circulating GLP-1 were significantly decreased. Inhibition of mTOR signalling by rapamycin decreased levels of intestinal and plasma GLP-1 in both normal and diabeticmice. Activation of the intestinal mTOR signalling by L-leucine or Tsc1 gene deletion increased levels of intestinal proglucagon and plasma GLP-1. Overexpression of mTOR stimulated proglucagon promoter activity and GLP-1 production, whereas inhibition of mTOR activity by overexpression of tuberous sclerosis 1 (TSC1) or TSC2 decreased proglucagon promoter activity and GLP-1 production in STC-1 cells. CONCLUSIONS/ INTERPRETATION:mTOR may link energy supply with the production of GLP-1 in L cells.
Authors: Lotte Bjerre Knudsen; Lars Wichmann Madsen; Søren Andersen; Kasper Almholt; Anne S de Boer; Daniel J Drucker; Carsten Gotfredsen; Frederikke Lihme Egerod; Anne Charlotte Hegelund; Helene Jacobsen; Søren Dyring Jacobsen; Alan C Moses; Anne-Marie Mølck; Henriette S Nielsen; Jette Nowak; Helene Solberg; Tu D L Thi; Milan Zdravkovic; Ulrik Moerch Journal: Endocrinology Date: 2010-03-04 Impact factor: 4.736
Authors: Juris J Meier; Baptist Gallwitz; Stefan Salmen; Oliver Goetze; Jens J Holst; Wolfgang E Schmidt; Michael A Nauck Journal: J Clin Endocrinol Metab Date: 2003-06 Impact factor: 5.958
Authors: Lauren Barron; Raphael C Sun; Bola Aladegbami; Christopher R Erwin; Brad W Warner; Jun Guo Journal: Cell Mol Gastroenterol Hepatol Date: 2016-12-10