In the present study we showed that chronic delivery of adiponectin into the CNS of normotensive as well as hypertensive rats did not significantly alter BP or HR. Except for a small, non-significant, reduction in whole-body oxygen consumption we also found no major alterations in motor activity, food intake, body weight and fasting insulin, glucose and leptin levels in SD rats fed high fat-high fructose diet. However, in the SHR group chronic ICV adiponectin treatment markedly reduced food intake and caused modest weight loss that was accompanied by a significant reduction in fasting insulin levels suggesting an improvement of glucose homeostasis.
Previous studies have shown that acute adiponectin injection into the CNS may alter food intake and energy expenditure [9
]. Our results, however, suggest that chronic activation of adiponectin receptors in the CNS does not appear to play a major role in regulating body weight homeostasis either by altering appetite or energy expenditure in a HFD rodent model. Of note, chronic adiponectin reduced food intake in SHRs. The mechanisms by which adiponectin reduces food intake in SHRs but not in SD rats are still unclear. One possible explanation is that despite the high fat-high fructose feeding SD rats remain sensitive to the endogenous circulating levels of adiponectin and further increases in adiponectin by exogenous infusion into the CNS exert little additional effect. However, SHRs exhibit impaired adiponectin signaling [16
], and increasing brain adiponectin levels beyond the endogenous levels by direct ICV infusion may have resulted in more pronounced effect in these animals.
ICV adiponectin treatment also improved insulin sensitivity in SHRs and had a tendency to reduce fasting plasma insulin levels in HFD SD rats. It is important to note that despite been fed standard chow and weighing less than HFD rats, SHRs exhibited 2-fold greater fasting insulin levels at baseline which corroborates previous studies that showed insulin resistance in SHRs [16
]. Therefore, one may speculate that adiponectin treatment may exert its beneficial effects on metabolic parameters such as insulin sensitivity in states of established insulin-resistance, while these effects are not as evident under normal circumstances. Another factor that may help explain the lack of a major impact of adiponectin treatment on energy balance and metabolic profile in HFD rats is that we delivered adiponectin directly into the CNS. It is possible that most of the effects of adiponectin are mediated by its peripheral actions rather than being mediated via activation of its receptors in the brain. Our study, however, was designed to investigate only the brain effects of adiponectin on energy balance and metabolic function and additional studies are needed to test this hypothesis.
A unique aspect of our study is that we evaluated the chronic effects of central adiponectin delivery on long-term control of BP and HR in both normotensive and hypertensive rats using state-of the-art telemetry technique to measure BP and HR 24-hours a day. Contrary to our original hypothesis, we observed no significant impact of chronic increases in CNS adiponectin levels on BP and HR. Previous studies have shown that adiponectin deficiency predisposes to salt-sensitive hypertension, whereas acute adiponectin injection in the CNS reduces renal SNS activity and lowers BP [18
]. One potential explanation for lack of a chronic brain-mediated effect of adiponectin on cardiovascular regulation may be that long-term activation of adiponectin receptors in the CNS leads to compensatory changes that offset adiponectin’s ability to lower SNS activity. Adiponectin may also exert opposing effects on BP regulation by acting in different areas of the brain. For example, injections of adiponectin into the area postrema in anesthetized rats depolarizes neuronal cells causing a significantly increase in blood pressure [3
], while microinjection of adiponectin in the medial nucleus of the tractus solitarius decreases BP [5
]. Thus, acute ICV injection of adiponectin may exert a rapid effect to reduce SNS activity and BP by acting in certain areas of the brain but when more homogenous activation of adiponectin receptors occurs with prolonged delivery of adiponectin, as in the case of the present study, then no sustained effect of adiponectin on SNS activity and BP is observed. Since adiponectin is produced by adipocytes and reaches the brain via diffusion from the blood into the cerebral spinal fluid, it is likely that many areas of the brain involved in the regulation of cardiovascular function are exposed to adiponectin. Therefore, our observations using chronic intracerebroventricular delivery of adiponectin may better represent the long-term physiologic effects of adiponectin on BP and HR regulation.
It is also possible that adiponectin may exert a more prolonged effect on cardiovascular function by its peripheral actions including improved endothelial function. For instance, adiponectin KO mice develop larger infarcts associated with myocardial cell apoptosis and TNF-α production that can be reversed by adenovirus-mediated delivery of adiponectin in these mice [17
]. Adiponectin KO mice also exhibit reduced mRNA levels of endothelial nitric oxide synthase in aorta and kidneys, suggesting impaired nitric oxide (NO) production, and adiponectin treatment increased NO production in vascular endothelial cells [12
]. Taken together, adiponectin may exert rapid beneficial effects on BP regulation via a brain-mediated mechanism leading to acute reduction in SNS activity, while its long-term effects on cardiovascular function are mediated by a more slow progressive improvement on endothelial function. Our studies suggest, however, that direct CNS actions of adiponectin do not play a major role in long-term blood pressure regulation.