Fatty acid-induced effect on glucagon secretion is mediated via fatty acid oxidation.
BACKGROUND
While the effect of fatty acids and ectopic triglyceride storage in pancreatic beta cells has been well-defined, only limited information is available on alpha cells. This study evaluates the long-term impact of fatty acids on alpha cell function and proliferation as well as fatty acid oxidation.


METHODS
Clonal alpha cells were cultured with fatty acids in the presence of high glucose for up to 3 days. The influence of fatty acids on glucagon secretion, glucagon content and triglyceride accumulation from 24 to 72 h was investigated. After a - 72 h culture, cell proliferation, carnitine palmitoyl transferase-1 mRNA level and the effect of etomoxir were also elucidated.


RESULTS
Fatty acids stimulated glucagon secretion and increased triglyceride accumulation in a time- and dose-dependent manner, but inhibited alpha cell proliferation. Lower concentrations (0.125-0.25 mM) of fatty acids significantly increased glucagon secretion at 48 and 72 h, but did not affect triglyceride content. However, a marked increment in triglyceride accumulation occurred in the presence of 0.5 mM fatty acids. Fatty acids caused an up-regulation of the expression of carnitine palmitoyl transferase-1 gene. Etomoxir (1 microM) reversed fatty acid-induced glucagon hypersecretion, but did not inhibit carnitine palmitoyl transferase-1 mRNA level.


CONCLUSIONS
Our data indicates that compared with triglyceride accumulation, glucagon secretion is more sensitive to changes in fatty acid concentration. The effect of fatty acids on the glucagon response is mediated through their oxidation. The high carnitine palmitoyl transferase-1 gene expression and the accumulation of triglyceride may initially be a compensatory oxidation reaction to elevated fatty acids.
Hong
Jing
J
Department of Endocrinology and Metabolism, Aarhus Sygehus THG, Aarhus University Hospital, Tage-Hansens Gade 2, 8000 Aarhus C, Denmark.
Jeppesen
Per Bendix
PB
Nordentoft
Iver
I
Hermansen
Kjeld
K
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis; D004852:Epoxy Compounds / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D051379:Mice; D019301:Oleic Acid / Q000494:pharmacology*; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004852:Epoxy Compounds; D005227:Fatty Acids; D014280:Triglycerides; D019301:Oleic Acid; D019308:Palmitic Acid; D004247:DNA; D005934:Glucagon; D002334:Carnitine O-Palmitoyltransferase; C054207:etomoxir