Oxyntomodulin increases intrinsic heart rate in mice independent of the glucagon-like peptide-1 receptor.
Oxyntomodulin (OXM), a postprandially released intestinal hormone, inhibits food intake via the glucagon-like peptide-1 receptor (GLP-1R). Although OXM may have clinical value in treating obesity, the cardiovascular effects of OXM are not well understood. Using telemetry to measure heart rate (HR), body temperature (Tb), and activity in conscious and freely moving mice, we tested 1) whether OXM affects HR and 2) whether this effect is mediated by the GLP-1R. We found that peripherally administered OXM significantly increased HR in wild-type mice, raising HR by >200 beats/min to a maximum of 728 +/- 11 beats/min. To determine the extent to which the sympathetic nervous system mediates the tachycardia of OXM, we delivered this hormone to mice deficient in dopamine-beta-hydroxylase [Dbh(-/-) mice], littermate controls [Dbh(+/-) mice], and autonomically blocked C57Bl mice. OXM increased HR equally in all groups (192 +/- 13, 197 +/- 21, and 216 +/- 11 beats/min, respectively), indicating that OXM elevated intrinsic HR. Intrinsic HR was also vigorously elevated by OXM in Glp-1R(-/-) mice (200 +/- 28 beats/min). In addition, peripherally administered OXM inhibited food intake and activity levels in wild-type mice and lowered Tb in autonomically blocked mice. None of these effects were observed in Glp-1R(-/-) mice. These data suggest multiple modes of action of OXM: 1) it directly elevates murine intrinsic HR through a GLP-1R-independent mechanism, perhaps via the glucagon receptor or an unidentified OXM receptor, and 2) it lowers food intake, activity, and Tb in a GLP-1R-dependent fashion.
Sowden
Gillian L
GL
Department of Biology, Williams College, Williamstown, MA 01267, USA.
Drucker
Daniel J
DJ
Weinshenker
David
D
Swoap
Steven J
SJ
D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001831:Body Temperature / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology; D004299:Dopamine beta-Hydroxylase / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004562:Electrocardiography; D004837:Epinephrine / Q000172:deficiency / Q000502:physiology; D000077270:Exenatide; D005260:Female; D005934:Glucagon / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009638:Norepinephrine / Q000172:deficiency / Q000502:physiology; D053772:Oxyntomodulin / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013686:Telemetry; D014688:Venoms / Q000494:pharmacology
C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D053772:Oxyntomodulin; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D005934:Glucagon; D000077270:Exenatide; D004299:Dopamine beta-Hydroxylase; D009638:Norepinephrine; D004837:Epinephrine