TRH in mediating the bradycardia of caloric restriction

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DESCRIPTION (provided by applicant): The relationship between excess caloric intake and cardiovascular disease is well established, with increasing attention being paid to the cardiovascular disease risk linked to the tachycardia that is commonly seen in obese patients. Caloric restriction (CR) significantly ameliorates the elevated heart rate (HR) seen in obesity, as well as lowering resting HR in non-obese humans. The overall goal of this proposal is to elucidate the underlying mechanism(s) of the bradycardia induced by the reduction of caloric intake. The following specific aims will address important questions in cardiovascular biology concerning the roles of thyrotropin releasing hormone, thyroid hormones, the parasympathetic nervous system, and the sympathetic nervous system in the bradycardia of caloric restriction in mice. The first aim of this proposal is to directly test the hypothesis that alterations in both the sympathetic nervous system and parasympathetic nervous system outflow are responsible for the bradycardia associated with caloric restriction. The second aim of this proposal is to directly test the hypothesis that alterations in thyroid hormones do not play a role in the bradycardia of caloric restriction. The third and final aim of this proposal is to directly test the hypothesis that a change in TRH signaling is necessary for the bradycardia of caloric restriction. Successful completion of these goals will allow us to integrate what is currently known about how caloric intake is sensed in the hypothalamus with the effector pathways responsible for altered metabolism and cardiovascular control. HR measurements will be taken from mice using a telemetry-based system, where an EKG telemeter is placed in the abdominal cavity with electrical leads placed subcutaneously across the heart. The mice to be used in this proposal will be lacking an intact sympathetic nervous system (Dbh-/-), lacking parasympathetic nervous system to the heart (M2R-/-), hypothyroid, and lacking the neurotransmitter, TRH (Trh-/-). Resting and intrinsic HRs will be measured before and during a caloric restriction period.