Adipokines, Obesity, and Sex: Implications for the Central Control of Cardiovascular Function

In addition to the storage of lipids, adipose tissue contributes to energy homeostasis by producing multiple adipokines, such as leptin and nesfatin‐1, that regulate food intake and energy expenditure. Plasma levels of these adipokines, which inhibit appetite, increase as a function of adipocyte mass, thus decreasing food intake during times of energy excess. In addition to modulating energy intake, adipokines also impact cardiovascular function, particularly through activation of the sympathetic nervous system. Like leptin, nesfatin‐1 interacts with the central melanocortin system to exert its hypertensive effects. Interestingly, melanocortin neurons are heavily influenced by sex hormones, particularly estrogen, which regulates the responsiveness and activity of these neurons. The functional implication of this observation is that females may respond to the hypertensive effects of adipokines, like nesfatin‐1, differently than males. We previously reported that male rats exhibit significant, dose‐related increases in blood pressure following injection of nesfatin‐1 into the lateral cerebroventricle, and that this effect could be blocked by pretreatment with a melanocortin receptor antagonist. In contrast, the hypertensive effect of nesfatin‐1 in females appears to be dependent upon sex hormone levels, as the response to nesfatin‐1 was significantly attenuated in rats in proestrus and estrus (high estrogen). As with males, the hypertensive effect of nesfatin‐1 in females in diestrus (low estrogen) was blocked by pretreatment with the melanocortin receptor antagonist, SHU9119. However, a completely sexually dimorphic effect was observed with respect to nesfatin‐1's effect on angiotensin II‐stimulated drinking and blood pressure. Whereas nesfatin‐1 significantly inhibited angiotensin II‐induced water drinking in males, nesfatin‐1 enhanced angiotensin II's effects on water drinking and blood pressure in females. We propose that these sex‐related differences in the hypertensive effects of nesfatin‐1 are due to the modulatory activity of estrogen on nesfatin‐1‐responsive melanocortin neurons, and that loss of estrogen, as observed in menopause, will lead to enhanced nesfatin‐1 signaling and hypertension. Future studies investigating the ability of chronically administered nesfatin‐1 to promote hypertension using telemetric monitoring of blood pressure will be necessary to evaluate whether persistently high nesfatin‐1 levels alter cardiovascular function. Support or Funding Information National Institutes of Health, HL121456