The Influence of the Sympathetic Nervous System on Cardiometabolic Health in Response to Weight Gain or Weight Loss

Figures

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  Figure 1. Putative mechanisms linking changes in weight with sympathetic nervous activation. The roles of insulin and hyperinsulinemia are likely important, given their critical role in metabolic syndrome development [18]. The pathways represented share a common role in engaging the liver and pancreas, leading to the development of hyperinsulinemia and insulin resistance. (a) Sympathetic nervous activation occurs as an adaptive response to overeating [19]. (b) The precipitating factor in the development of obesity-related illness is insulin resistance, driving hyperinsulinemia, sympathetic activation, and an increase in blood pressure [20]. (c) Increments in visceral fat result in increased release of adipokines, including leptin and non-esterified fatty acids (NEFAs), into circulation, which leads to insulin resistance and sympathetic nervous activation [21]. (d) Insulin resistance and the development of obesity-related illness are driven primarily by sympathetic nervous activation and increased norepinephrine release [22]. (e) An alteration in sympathetic drive to the liver with weight gain or diet change influences the hepatic uptake of glucose and impacts the development of insulin…

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  Figure 2. Diagram showing (top) the disposition of noradrenaline in postganglionic sympathetic nerve endings and post-synaptic cells (e.g., blood vessels, muscle cells, or cardiac myocytes) and (bottom) overflow into the systemic circulation under basal conditions and during the steady-state infusion of a tracer dose of tritium-labelled noradrenaline (3H-NA). The use of tritium enables the calculation of the rate of noradrenaline clearance from, and spillover into, plasma. At steady state, the rate of noradrenaline synthesis (a) equals the rate of noradrenaline turnover; where the noradrenaline turnover is equal to the sum of the rates of the spillover of noradrenaline into plasma (b), the extraneuronal uptake and metabolism of noradrenaline (c), and the intraneuronal metabolism of noradrenaline (d). The availability of noradrenaline for intraneuronal metabolism is determined by the balance between the entry of noradrenaline into the axoplasm, via the processes of reuptake (e) and leakage (g), and removal from the axoplasm by vesicular sequestration. Circulating 3H-NA may be extracted from plasma via the process of neuronal uptake (uptake 1; U1) and metabolised intraneuronally (f) or…

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  Figure 3. Schematic showing brain regions associated with changes in body weight and sympathetic nervous system activity. Key cortical and subcortical regions within the brain undergo structural and functional changes with weight gain or weight loss. Hypothalamic regions including arcuate, paraventricular, ventromedial, and dorsomedial nuclei are identified as targets for peripherally or centrally originating afferent and humoral signals involving adipokines, insulin, and glucose. Key brainstem regions including the nucleus tractus solitarius (NTS) and caudal and rostral ventrolateral medulla (CVLM and RVLM, respectively) are recognised as being involved in the generation of sympathetic nerve activity, with RVLM being the primary nucleus for outflow to renal, splanchnic, and muscle vascular beds. The cortical regions shown are known to be influenced by body weight; however, the pathways by which this occurs are not well understood. Abbreviations: CVLM, caudal ventrolateral medulla; NTS, nucleus tractus solitarius; RVLM, rostral ventrolateral medulla. Created in BioRender. Braun, J. (2025) https://BioRender.com/a80q797, accessed on 18 March 2025.

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  Figure 4. Schematic showing metabolic pathways associated with changes in body weight and sympathetic nervous system activity. Monosynaptic projections arising from brain regions including the rostral and caudal ventrolateral medulla, caudal raphe, and pontine noradrenergic A5 group, as well as the paraventricular nucleus of the hypothalamus, provide inputs to the sympathetic preganglionic neurones in the intermediolateral cell (IML) column of the spinal cord. Sympathetic postganglionic neurones then project them to target organs (solid arrows). Although sympathetic nervous-associated pathways vary between the weight-gain and weight-loss states, key effector organs and the corresponding adrenergic receptors in response to sympathetic activation are shown (dotted arrows). Created in BioRender. Braun, J. (2025) https://BioRender.com/t56w833, accessed on 18 March 2025.