The cardiac OT system is downregulated in DC [
74], MI [
24], and hypertension [
75] suggesting that OTR deficiency magnifies these pathologies. Lowered OT plasma levels are also linked to increased sensitivity of cardiovascular system to stress [
76]. Interestingly, down-regulation of the OT/OTR system (which includes natriuretic peptides (NPs) ANP, BNP) in the LV of ovariectomized rats can be effectively prevented by regular exercise training [
19]. Indeed, hypothalamic and LV mRNA levels of OT, OTR, and NPs were restored back to normal levels after 8-weeks of moderate intensity exercise training on a treadmill. We have investigated the effects of exercise training in the
db/db mice, a mouse model of diabetes and obesity used to study DC. These mice display genetic mutations in leptin receptor, resulting in a diabetic profile induced by hyperphagia. We have demonstrated that exercise training failed to upregulate of the OT/OTR system in hearts of
db/db mice. After eight weeks of moderate intensity treadmill running, mRNA expression of the OT/OTR system in
db/db hearts remained low and unchanged from pre-training levels [
74]. Expression of ANP and BNP was similarity low and even further decreased after exercise training, and training had no effect on the extent of obesity and blood glucose concentrations [
72], suggesting that the hyperglycemic state may contribute to reduced expression of OT and NPs. This hypothesis was suggested earlier by Kobayashi et al. [
77] indicating that acute hyperglycemic conditions and streptozotocin-induced type 1 diabetes reduced the expression of GATA4, a transcription factor associated with the synthesis of structural and cardioprotective genes, including OT/OTR and NPs [
78]. Hearts from
db/db mice exhibited low mRNA and protein levels of GATA4 [
79], and exercise training was beneficial in stimulating GATA4 protein expression, albeit in the absence of the OT/OTR system. Degradation of GATA4 by hyperglycemia is induced by ROS and ubiquitination by ubiquitin-proteaosomes [
80], and a benefit of exercise may be related to reduced expression of E3-ubiquitin ligase MURF1 [
81]. The possibility exists that GATA4 is not required and that expression of another transcription factor, such as GATA6 [
82], is involved in the synthesis of OT and NPs. The role of GATA4 and exercise training on the OT/OTR system is further complicated by our recent findings showing that expression of this transcription factor is not altered by the effects of hyperglycemia or obesity in hearts of
ob/ob mice [
83]. Eight weeks of spontaneous running in
ob/ob mice increased cardiac mRNA expression of GATA4, but disrupted glucose and triglyceride regulation. Consistent with the gene profile observed in
db/db mice after exercise training, expression of OTR, ANP, BNP, and C-type NP was reduced. One important aspect that arises from this
ob/ob study is whether leptin is key to this aberrant synthesis of the OT/OTR system. In addition to its well-established role in appetite control, leptin is known for stimulating running activity in mice [
84].