Obesity: sex and sympathetics

Abstract

Obesity increases sympathetic nerve activity (SNA) in men, but not women. Here, we review current evidence suggesting that sexually dimorphic sympathoexcitatory responses to leptin and insulin may contribute. More specifically, while insulin increases SNA similarly in lean males and females, this response is markedly amplified in obese males, but is abolished in obese females. In lean female rats, leptin increases a subset of sympathetic nerves only during the high estrogen proestrus reproductive phase; thus, in obese females, because reproductive cycling can become impaired, the sporadic nature of leptin-induced sympathoexcitaton could minimize its action, despite elevated leptin levels. In contrast, in males, obesity preserves or enhances the central sympathoexcitatory response to leptin, and current evidence favors leptin's contribution to the well-established increases in SNA induced by obesity in men. Leptin and insulin increase SNA via receptor binding in the hypothalamic arcuate nucleus and a neuropathway that includes arcuate neuropeptide Y (NPY) and proopiomelanocortin (POMC) projections to the paraventricular nucleus. These metabolic hormones normally suppress sympathoinhibitory NPY neurons and activate sympathoexcitatory POMC neurons. However, obesity appears to alter the ongoing activity and responsiveness of arcuate NPY and POMC neurons in a sexually dimorphic way, such that SNA increases in males but not females. We propose hypotheses to explain these sex differences and suggest areas of future research.

Keywords: Arcuate nucleus; Hypertension; Insulin; Leptin; Neuropeptide Y; Paraventricular nucleus; Sympathetic nerve activity.

Fig. 1

Hypothalamic sites and neuropathways by which leptin and insulin increase sympathetic nerve activity (SNA) in both males and females. a Leptin binds to leptin receptors (LepR) in several hypothalamic sites to increase SNA, including the arcuate nucleus (ArcN), ventromedial hypothalamus (VMH), dorsomedial hypothalamus (DMH), and lateral hypothalamus (LH). LepR binding in all these sites then triggers neuronal pathways that appear to converge in the paraventricular nucleus (PVN); ArcN neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons relay the signal from the ArcN to the PVN. Downstream, the rostral ventrolateral medulla (RVLM) is activated, which then excites preganglionic sympathetic neurons in the spinal cord. b Insulin acts in only one site, the ArcN, to increase SNA, via a neuropathway that includes ArcN NPY and POMC projections to the PVN, which then activate PVN glutamatergic neurons that project to the RVLM. Green (top) represents neurons that project to the RVLM. Red (a) is LepR. Red (b) is InsR

Fig. 2

Relationships between leptin and food intake (inhibitory) and sympathetic nerve activity (SNA; excitatory) in males (left) and females (right), and how these relationships are altered by obesity. Top panel: food intake. In both males and females, a loss or decrease of leptin or leptin receptors increases food intake, producing obesity. Increases in leptin can inhibit food intake, but, in general, high doses are required. In females, leptin’s anorexic effect is enhanced by estradiol (E2). In obese males and females (red lines), the relationship between leptin and food intake is reset to a higher leptin level. In males, increases in leptin no longer inhibit food intake (“leptin resistance”), but blockade of endogenous leptin receptors increases food intake (i.e. endogenous leptin continues to suppress appetite). In females, leptin resistance takes longer to develop, presumably due to suppression of reproductive cycling and decreases in E2. However, whether endogenous leptin continues to suppress food intake in females has not been investigated. Dashed lines indicate hypothetical relationships that require further experimentation. Middle panel: lumbar SNA (LSNA): Leptin increases LSNA in both lean males and females; however, in females, this effect requires proestrus levels of E2. It is unlikely that basal levels of endogenous leptin support (L)SNA in either males or females. In obese males, leptin’s sympathoexcitatory effect is preserved or enhanced and likely contributes to the increased basal SNA observed with obesity in male humans and experimental animals. In contrast, in obese females, suppression of reproductive cycling and estrogen levels likely in parallel suppresses leptin’s sympathoexcitatory effect. This sex difference (enhanced leptin SNA increases in obese males, but reduced leptin effects in obese females), may contribute to the observation that obesity increases SNA in men, but not women. Bottom panel: Summary of known and hypothetical changes in food intake and SNA with increases and decreases in leptin levels or actions in both lean and obese males and females

Fig. 3

Obesity alters the sympathoexcitatory response to insulin in a sexually dimorphic way. Intracerebroventricular (icv) insulin increases lumbar sympathetic nerve activity (LSNA) similarly in lean [control diet (CON) or resistant to obesity development when consuming a high fat diet (OR)] males and females throughout the reproductive cycle. However, while obesity (obesity prone; OP) markedly amplifies the sympathoexcitatory response to icv insulin in males, in females, insulin’s action is abolished. Data adapted from [84]

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