Fig. 4

Proposed mechanisms to explain why obesity enhances the sympathoexcitatory response to insulin (and perhaps leptin) in males, but abolishes these responses in females. Left, males. In obese males, increased basal sympathetic nerve activity (SNA) is driven in part by suppressed tonic Neuropeptide Y (NPY) sympathoinhibition, and increased α-melanocyte stimulating hormone (α-MSH) excitation, of paraventricular (PVN) presympathetic neurons. Because the increase in SNA in response to PVN α-MSH agonists, like MTII, are the same in otherwise untreated obese male rats and in lean rats after blockade of PVN NPY Y1 receptors, the increased basal tone may be explained simply by the loss of tonic NPY inhibition of PVN presympathetic nerves and/or increased signaling upstream in arcuate nucleus (ArcN) proopiomelanocortin (POMC) neurons. In addition, therefore, the amplified SNA response to insulin in obese males is likely due to increased signaling in insulin-receptive POMC neurons. The mechanism for the enhanced insulin responsiveness is unknown, but may involve local ArcN actions of Angiotensin II (AngII) to inhibit NPY neurons and/or the inflammatory mediators like cytokines to excite POMC neurons. Right, females. In females, basal SNA may not increase, because tonic NPY sympathoinhibition is maintained and not inhibitable by insulin. The maintenance of NPY tone may be explained by the hypertensive actions of AngII becoming neutralized by the antihypertensive actions of Ang-(1-7), as in the periphery. However, future research is needed to address many of these mechanistic links in both obese male and female rodents, and when possible, in men and women