Neuroendocrinological and Epigenetic Mechanisms Subserving Autonomic Imbalance and HPA Dysfunction in the Metabolic Syndrome

Abstract

Impact of environmental stress upon pathophysiology of the metabolic syndrome (MetS) has been substantiated by epidemiological, psychophysiological, and endocrinological studies. This review discusses recent advances in the understanding of causative roles of nutritional factors, sympathomedullo-adrenal (SMA) and hypothalamic-pituitary adrenocortical (HPA) axes, and adipose tissue chronic low-grade inflammation processes in MetS. Disturbances in the neuroendocrine systems for leptin, melanocortin, and neuropeptide Y (NPY)/agouti-related protein systems have been found resulting directly in MetS-like conditions. The review identifies candidate risk genes from factors shown critical for the functioning of each of these neuroendocrine signaling cascades. In its meta-analytic part, recent studies in epigenetic modification (histone methylation, acetylation, phosphorylation, ubiquitination) and posttranscriptional gene regulation by microRNAs are evaluated. Several studies suggest modification mechanisms of early life stress (ELS) and diet-induced obesity (DIO) programming in the hypothalamic regions with populations of POMC-expressing neurons. Epigenetic modifications were found in cortisol (here HSD11B1 expression), melanocortin, leptin, NPY, and adiponectin genes. With respect to adiposity genes, epigenetic modifications were documented for fat mass gene cluster APOA1/C3/A4/A5, and the lipolysis gene LIPE. With regard to inflammatory, immune and subcellular metabolism, PPARG, NKBF1, TNFA, TCF7C2, and those genes expressing cytochrome P450 family enzymes involved in steroidogenesis and in hepatic lipoproteins were documented for epigenetic modifications.

Keywords: epigenetic programming; gene regulation; hypothalamic-pituitary adrenocortical axis; metabolic syndrome; microRNA; pathophysiology; stress neuropsychobiology; sympathetic autonomic nervous system.

Figure 1

Sympathetic and parasympathetic innervation of the coeliac and superior mesenteric plexus ganglia, and immune and cytokine mechanisms in cholinergic anti-inflammatory pathway. The acetylcholinergic anti-inflammatory pathway, the efferent arc of the inflammatory reflex (Section Inflammation and Arterial Rigidity; Tracey, 2002) converging in the spleen, has been discussed under the aspect of being a target for possible interventions counteracting autonomic imbalance in the metabolic syndrome related to chronic inflammation. Schematically depicted are innervations from the sympathetic and parasympathetic branches of the ANS, with their transmitters, into organ systems relevant for MetS. Left part panel (A): efferent fibers in the sympathetic branch with adrenoceptor type. Middle part panel (B): mixed sympathetic and vagal fiber connections into the coeliac and the superior mesenteric plexus ganglia innervating liver, pancreas and spleen. Right part panel (C): efferent fibers in the parasympathetic branch of the ANS. The insert panel (D) to the outer right hand side illustrates schematically the role of vagus stimulation-derived, yet noradrenergic transmission into liver and spleen, and the acetylcholinergic transmission between CD4⁺ T helper cells and macrophages in the spleen. Vagus departs the brainstem as its cranial nerve X, and vagal efferent outflow regulates visceral organs by counterbalancing sympathoexcitation, inhibiting cytokine release, and safeguarding against inflammatory damage to liver, pancreas, spleen, lungs, or kidneys in endotoxaemic states. The outflow of the vagus nerve triggers adrenergic neurons in the coeliac ganglion innervating the spleen further to liver and pancreas. Vagal influence to spleen T lymphocytes stimulates the release of the neurotransmitter acetylcholine (ACh), and activation of the α₇ subunit of the nicotinic ACh receptor (α₇ nAChR; Section Inflammation and Arterial Rigidity) expressed on cell membranes of splenic macrophages and other cytokine secreting cells. Vagal tone attenuates here production of the inflammatory response cytokine tumor necrosis factor alpha (TNFα) reciprocally related to sympathoexcitation (Zhang et al., ; Kisiswa et al., 2013). In the liver, noradrenergic innervation signals hepatic innate natural killer T cells (iNKT) (Van Kaer et al., 2013) to exert systemic immunosuppression. Increasing the vagal tone there induces a shift from pro-inflammatory T helper cell type 1 (T_H1) cytokines such as interferon-γ (IFN-γ) to anti-inflammatory T_H2-type cytokines, such as interleukin-10 (IL-10) (Tracey, , ; Rosas-Ballina et al., , ; Trakhtenberg and Goldberg, 2011). PVNH hypothalamic insulin promoter expressing neurons downregulate postprandial inflammation through cholinergic signaling in the spleen mediated by vagal outflow to the spleen, whereas vagotomy results in T2DM (Carvalheira et al., ; Wang L. et al., 2014). Vagus stimulation approaches for increasing vagal tone would therefore aim to counterbalance prolonged sympathoexcitation in MetS by supporting parasympathetic output. These could comprise, but are not limited to, device-based, pharmacological, and/or psychotherapeutic intervention approaches. With the advent of wearable transcutaneous stimulation devices, vagus nerve stimulation has become a convenient neuropsychological intervention method (Van Leusden et al., 2015). Drug discovery is still required to identify non-steroidal anti-inflammatory substances targeting the cholinergic pathway either peripherally (such as nicotinic α₇ nAChR agonist applications) and/or centrally (such as CNI-1493), or existing TNFα antagonists such as infliximab or etanercept. Possible behavioral interventions: Guided physical activity trainings, mindfulness-based psychotherapies, psychosomatic body-relaxation and/or balancing techniques, biofeedback training. Other: immunotherapy yet to be developed (Van Kaer et al., 2013). Medical illustrations by Corinna Naujok, Charité Media Centre Berlin, Virchow Campus.