Chronic Exposure to TNFα Impairs Secretion of Glucagon-Like Peptide-1.
Obesity is associated with systemic inflammation and elevated levels of TNFα, leading to impaired glucose tolerance. In humans, obesity is also associated with reduced nutrient-stimulated secretion of the intestinal incretin hormone, glucagon-like peptide-1 (GLP-1). We hypothesized that TNFα plays a direct role in the impairment of GLP-1 secretion from the enteroendocrine L-cell and that blocking TNFα can restore both GLP-1 secretion and glucose homeostasis. Expression of the TNFα receptor subytpe-1 was detected in the human NCI-H716 and murine GLUTag L-cell models and in mouse ileal sections. Although TNFα acutely increased GLP-1 release from NCI-H716 cells (P < .05-.001), preincubation with TNFα for 24 hours reduced proglucagon mRNA (P < .05) and GLP-1 cellular (P < .05) levels without affecting cell viability. Furthermore, both NCI-H716 and GLUTag cells pretreated with TNFα for 24 hours no longer responded to known GLP-1 secretagogues, an effect that was reversed by coincubation with the Nuclear Factor Kappa B inhibitor, 5-aminosalicylic acid, in the NCI-H716 cells. Mice given a high-fat diet (HFD) for 12 weeks developed impaired glucose tolerance, hyperinsulinemia, and increased TNFα mRNA expression in fat and ileal tissue. Hyperglycemia and hyperinsulinemia were reduced in HFD mice treated with the anti-TNFα biological, etanercept, for 2 weeks. In primary intestinal cultures from these animals, HFD control mice had impaired GLP-1 secretion, and this was not observed in the HFD etanercept-derived cultures (P < .05). In conclusion, chronic exposure to TNFα directly impairs GLP-1 secretion at the level of the intestinal L-cell, an effect that is reversed by anti-TNFα therapy in association with improved glucose tolerance.
Departments of Physiology (J.G., M.S., W.Z., H.M.S., S.C.W., S.-S.B., P.L.B.) and Medicine (P.L.B.), University of Toronto, Toronto, Ontario, M5S 1A8 Canada; and Centre for Microvascular Medicine (S.-S.B.), University of Toronto and Li Ka Shing Knowledge Institute at St Michael's Hospital, Toronto, Ontario, M5B 1T8 Canada.
Jeffrey
J
Gagnon
Departments of Physiology (J.G., M.S., W.Z., H.M.S., S.C.W., S.-S.B., P.L.B.) and Medicine (P.L.B.), University of Toronto, Toronto, Ontario, M5S 1A8 Canada; and Centre for Microvascular Medicine (S.-S.B.), University of Toronto and Li Ka Shing Knowledge Institute at St Michael's Hospital, Toronto, Ontario, M5B 1T8 Canada.
Meghan
M
Sauvé
Departments of Physiology (J.G., M.S., W.Z., H.M.S., S.C.W., S.-S.B., P.L.B.) and Medicine (P.L.B.), University of Toronto, Toronto, Ontario, M5S 1A8 Canada; and Centre for Microvascular Medicine (S.-S.B.), University of Toronto and Li Ka Shing Knowledge Institute at St Michael's Hospital, Toronto, Ontario, M5B 1T8 Canada.
Wen
W
Zhao
Departments of Physiology (J.G., M.S., W.Z., H.M.S., S.C.W., S.-S.B., P.L.B.) and Medicine (P.L.B.), University of Toronto, Toronto, Ontario, M5S 1A8 Canada; and Centre for Microvascular Medicine (S.-S.B.), University of Toronto and Li Ka Shing Knowledge Institute at St Michael's Hospital, Toronto, Ontario, M5B 1T8 Canada.
Holly M
HM
Stacey
Departments of Physiology (J.G., M.S., W.Z., H.M.S., S.C.W., S.-S.B., P.L.B.) and Medicine (P.L.B.), University of Toronto, Toronto, Ontario, M5S 1A8 Canada; and Centre for Microvascular Medicine (S.-S.B.), University of Toronto and Li Ka Shing Knowledge Institute at St Michael's Hospital, Toronto, Ontario, M5B 1T8 Canada.
Stuart C
SC
Wiber
Departments of Physiology (J.G., M.S., W.Z., H.M.S., S.C.W., S.-S.B., P.L.B.) and Medicine (P.L.B.), University of Toronto, Toronto, Ontario, M5S 1A8 Canada; and Centre for Microvascular Medicine (S.-S.B.), University of Toronto and Li Ka Shing Knowledge Institute at St Michael's Hospital, Toronto, Ontario, M5B 1T8 Canada.
Steffen-S
SS
Bolz
Departments of Physiology (J.G., M.S., W.Z., H.M.S., S.C.W., S.-S.B., P.L.B.) and Medicine (P.L.B.), University of Toronto, Toronto, Ontario, M5S 1A8 Canada; and Centre for Microvascular Medicine (S.-S.B.), University of Toronto and Li Ka Shing Knowledge Institute at St Michael's Hospital, Toronto, Ontario, M5B 1T8 Canada.
Patricia L
PL
Brubaker
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D019858:Enteroendocrine Cells / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D052336:Proglucagon / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D052336:Proglucagon; D052216:Glucagon-Like Peptide 1