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1 Department of Biology, Williams College, Williamstown, Massachusetts, United States
2 Banting and Best Diabetes Centre, University of Toronto, Toronto General Hospital, Toronto, Canada
3 Human Genetics, Emory University, Atlanta, Georgia, United States
* To whom correspondence should be addressed. E-mail: sswoap{at}williams.edu.
Oxyntomodulin (OXM), a postprandially released intestinal hormone, inhibits food intake via the glucagon-like peptide-1 receptor (GLP-1R). While 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 wildtype mice, raising HR by over 200 bpm to a maximum of 728 ± 11 bpm. To determine the extent to which the sympathetic nervous system (SNS) mediates the tachycardia of OXM, this hormone was delivered to mice deficient in dopamine 
hydroxylase (Dbh -/- mice), littermate controls (Dbh +/- mice), and autonomically-blocked C57Bl mice. OXM increased HR equally in all groups (192 ± 13, 197 ± 21, 216 ± 11 bpm, respectively), indicating that OXM elevated intrinsic HR. Intrinsic HR was also vigorously elevated by OXM in Glp-1R -/- mice (200 ± 28 bpm). In addition, peripherally-administered OXM inhibited food intake and activity levels in wildtype 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
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