Cardiovascular and Metabolic Crosstalk in the Brain: Leptin and Resistin

Abstract

Leptin and resistin are cytokines whose plasma levels correlate with adiposity. Leptin is a hormone synthesised and released from adipocytes and can be transported into the brain. Resistin is produced in adipocytes in rodents and in macrophages in humans, particularly macrophages that have infiltrated adipose tissue. Both hormones can act within the brain to influence sympathetic nerve activity. Leptin appears to have a generalised sympatho-excitatory actions whilst resistin appears to increase sympathetic nerve activity affecting the cardiovascular system but inhibits sympathetic nerve activity to brown adipose tissue, which contrasts with leptin. Since both hormones can be elevated in conditions of metabolic dysfunction, interactions/crosstalk between these two hormones in the brain is a real possibility. This review describes the current knowledge regarding such crosstalk within the central nervous system. The evidence suggests that with respect to sympathetic nerve activity, crosstalk between leptin and resistin can elicit enhanced sympatho-excitatory responses to the kidneys. In contrast, with respect to food intake, resistin has weaker effects, but in regard to insulin secretion and thermogenesis, leptin and resistin have opposing actions. Thus, in conditions in which there is increased resistin and leptin levels, the result of crosstalk in the central nervous system could contribute to worse cardiovascular and metabolic complications.

Keywords: central nervous system; interactions; leptin; metabolic syndrome; resistin; sympathetic nerve activity.

FIGURE 1

% Change in renal sympathetic nerve activity (RSNA) over time following intracerebroventricular administration of vehicle, resistin, leptin, alone and in combination. Note the enhanced increase in RSNA when leptin and resistin were administered in combination. Modified from Habeeballah et al. (2016). * represent significantly greater than leptin or resistin administered alone.

FIGURE 2

Average number of activated neurons per section in the arcuate nucleus (ARC) and paraventricular nucleus (PVN) in the hypothalamus in control or following administration of leptin or resistin alone or in combination. Modified from Kosari et al. (2012). * represent significantly greater than control. # represents significantly greater than leptin or resistin administered alone. Note that only in the ARC was there a greater number of activated neurons following leptin and resistin combined compared to when each was administered alone.

FIGURE 3

Maximum% change in renal sympathetic nerve activity in rats fed normal chow or a moderately high fat diet (22% fat) following intracerebroventricular saline, leptin or resistin alone or in combination. Note there was no influence of the diet. Modified from Habeeballah et al. (2017).

FIGURE 4

Diagrammatic depiction of the potential centrally mediated effects of increased leptin and resistin synthesis due to increased adiposity. Leptin and insulin can act in the brain to influence metabolic and cardiovascular outputs. Leptin elevates sympathetic nerve activity to the kidneys (RSNA), vasculature and to brown adipose tissue (BAT SNA). It also dramatically reduces food intake, body mass and decreases insulin secretion from the pancreas through actions in the brain. Resistin can act in the brain to increase sympathetic nerve activity to the kidneys and vasculature, but it decreases sympathetic nerve activity to brown adipose tissue. Resistin by acting in the brain increases insulin secretion and reduces food intake acutely (though less than leptin) and has little effect chronically. Thus, crosstalk within the brain between these two hormones could result in less thermogenesis (energy expenditure), a reduced anorexigenic effect, less insulin secretion but enhanced sympathetic nerve activity to the kidneys (and vasculature?) compared to the actions of leptin alone. This would result in increased metabolic and cardiovascular complications in conditions in which there is increased leptin and resistin. Black arrows signify direction and relative magnitude of change.