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Overview of autonomic nervous system innervation of organs and tissues important for metabolic regulation. For vagal innervation, the line thickness roughly reflects the number of afferent and efferent axons in the respective branches, as mainly observed in rats. There are not sufficient data available for similar analyses in the sympathetic and dorsal root systems. AMB, nucleus ambiguous; DMV, dorsal motor nucleus of the vagus; DRG, dorsal root ganglia; NTS, nucleus tractus solitarius.
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With few effective treatments available, the global rise of metabolic diseases, including obesity, type 2 diabetes mellitus, and cardiovascular disease, seems unstoppable. Likely caused by an obesogenic environment interacting with genetic susceptibility, the pathophysiology of obesity and metabolic diseases is highly complex and involves crosstalk...
Citations
... The vagus nerve serves as a major neuroanatomical connection between the GI tract and the brain (4). Its cell bodies reside in the nodose ganglia, and their axons project bidirectionally to both the brainstem and the gut (5). Peripheral terminals of the vagus nerve are distributed throughout the mucosal and muscular layers of the GI tract. ...
The stomach has emerged as a crucial endocrine organ in the regulation of feeding since the discovery of ghrelin. Gut-derived hormones, such as ghrelin and cholecystokinin, can act through the vagus nerve. We previously reported the satiety effect of hypothalamic clusterin, but the impact of peripheral clusterin remains unknown. In this study, we administered clusterin intraperitoneally to mice and observed its ability to suppress fasting-driven food intake. Interestingly, we found its synergism with cholecystokinin and antagonism with ghrelin. These effects were accompanied by increased c-fos immunoreactivity in nucleus tractus solitarius, area postrema, and hypothalamic paraventricular nucleus. Notably, truncal vagotomy abolished this response. The stomach expressed clusterin at high levels among the organs, and gastric clusterin was detected in specific enteroendocrine cells and the submucosal plexus. Gastric clusterin expression decreased after fasting but recovered after 2 hours of refeeding. Furthermore, we confirmed that stomachspecific overexpression of clusterin reduced food intake after overnight fasting. These results suggest that gastric clusterin may function as a gut-derived peptide involved in the regulation of feeding through the gut-brain axis.
... Non-communicable chronic metabolic diseases, such as diabetes mellitus, obesity, nonalcoholic fatty liver disease and hyperlipidemias, have become important public health problems worldwide (COSTELLO; SCHONES, 2018). They have a complex and multifactorial etiology that can include a sedentary lifestyle, unhealthy diets, reduced energy expenditure, intestinal problems and genetic susceptibility (FÄNDRIKS, 2017;BERTHOUD;NEUHUBER, 2019). ...
... Non-communicable chronic metabolic diseases, such as diabetes mellitus, obesity, nonalcoholic fatty liver disease and hyperlipidemias, have become important public health problems worldwide (COSTELLO; SCHONES, 2018). They have a complex and multifactorial etiology that can include a sedentary lifestyle, unhealthy diets, reduced energy expenditure, intestinal problems and genetic susceptibility (FÄNDRIKS, 2017;BERTHOUD;NEUHUBER, 2019). ...
Changes in the global economy contribute to a sedentary lifestyle and higher caloric intake, increasing the incidence of metabolic diseases. It is estimated that the number of individuals diagnosed with metabolic diseases will increase by 25% by 2030 and 51% by 2045. Natural products have been tested in metabolic diseases with positive results, as shown by bergenin. Thus, this work aimed to evaluate the possible effects of bergenin in models of metabolic disease through in silico and in vitro experimental procedures. Bergenin showed the ability to inhibit protein glycation by 19.88 ± 4.22% in the oxidative pathway and 8.32 ± 1.85% in the non-oxidative pathway. This study showed for the first time that bergenin has the potential to inhibit the α-amylase enzyme (33.89 ± 0.96%) using in silico and in vitro assays. Bergenin was not able to significantly inhibit lipid uptake by the Oil Red method. After these results, it is understood that bergenin has the potential to be better studied as a therapeutic option in metabolic diseases. However, additional in vivo studies are needed to better elucidate the possible pharmacological effects of bergenin in metabolic diseases.
... Afferent signals arrive from peripheral organs, including the gastrointestinal tract where nutrients are absorbed, or from other tissues such as adipose tissue, liver, and pancreas. One important area for nutrients, including glucose sensing, is the hepatic portal vein, which is innervated by both spinal and vagal afferents (5)(6)(7). Sensory signals through the dorsal root ganglia or the left nodose ganglion are relayed to the dorsal vagal complex. A recent study conducted in rats used herpes simplex virus-1 (an anterograde, transsynaptic viral tracer) to define sensory pathways from the hepatic portal and superior mesenteric veins (8). ...
The prevalence of metabolic disorders, including type 2 diabetes mellitus, continues to increase worldwide. Although newer and more advanced therapies are available, current treatments are still inadequate and the search for solutions remains. The regulation of energy homeostasis including glucose metabolism, involves an exchange of information between the nervous systems and peripheral organs and tissues; therefore, developing treatments to alter central and/or peripheral neural pathways could be an alternative solution to modulate whole-body metabolism. Liver glucose production and storage are major mechanisms controlling glycemia, and the autonomic nervous system plays an important role in the regulation of hepatic functions. Autonomic nervous system imbalance contributes to excessive hepatic glucose production, and thus to the development and progression of type 2 diabetes mellitus. At cellular levels, change in neuronal activity is one of the underlying mechanisms of autonomic imbalance; therefore, modulation of the excitability of neurons involved in autonomic outflow governance has the potential to improve glycemic status. Tissue-specific subsets of pre-autonomic neurons differentially control autonomic outflow, therefore, detailed information about neural circuits and properties of liver-related neurons is necessary for the development of strategies to regulate liver functions via the autonomic nerves. This review provides an overview of our current understanding of the hypothalamus - ventral brainstem - liver pathway involved in the sympathetic regulation of the liver, outlines strategies to identify organ-related neurons, and summarizes neuronal plasticity during diabetic conditions with particular focus on liver-related neurons in the paraventricular nucleus.
... В исследованиях последних лет выдвигалась гипотеза о том, что вагальная дисфункция играет роль в развитии ожирения и метаболического синдрома [34], но в целом в клинической практике в настоящее время вовлечению хемосенсорных систем в эти заболевания уделяется мало внимания. Возможное объяснение заключается в том, что функции этих систем не считаются жизненно необходимыми для человека и, следовательно, их исследование занимает незначительное положение в рамках рутинного медицинского обследования [23]. ...
Obesity is currently a major global public health problem. As a result, in recent decades there has been a growing interest in studying the impact of this disease on the functioning of the central nervous system. One of the least understood aspects is the impact that obesity has on sensory systems.The olfactory and gustatory systems are closely related to various vital functions, such as the nocifensors activation, the stimulation of digestive reflexes. In addition, these sensory systems are known to play an important role in the mechanisms of food consumption through the regulation of appetite and satiety, influencing food choice and, therefore, they are involved in the development of obesity. A number of clinical studies have shown that obese patients are more likely to suffer from hyposmia compared to lean people of the same age.The reasons why this relationship exists remain largely unclear. The aim of this review is to assess the available data on this topic and to identify new promising areas for further research. The review was conducted in the PubMed databases for 2017–2023.
... The sensory vagal nerve terminals in the GIT are heterogenous in nature conveying both chemosensory, from nutrients and gut hormones, and mechanosensory signals to the brainstem [138,139]. Postprandial gut hormones and nutrients suppress food intake by transmitting information via the sensory vagal afferent terminals to the NTS, a crucial entry point in the brain for visceral information [140,141]. CCK, one of the first gut peptides to be identified to mediate satiety, elicits its actions by acting on the CCK-A receptors that are abundantly expressed on the vagal afferents and the cell bodies of the nodose ganglia [140,[142][143][144]. Additionally other receptors involved in regulating satiety, such as the LepR, are also expressed on these cell bodies [145]. As a result, circulating signals such as leptin can also act along with CCK on the nodose ganglia, to synergistically suppress food intake [146,147]. ...
Precise neural regulation is required for maintenance of energy homeostasis. Essential to this are the hypothalamic and brainstem nuclei which are located adjacent and supra-adjacent to the circumventricular organs. They comprise multiple distinct neuronal populations which receive inputs not only from other brain regions, but also from circulating signals such as hormones, nutrients, metabolites and postprandial signals. Hence, they are ideally placed to exert a multi-tier control over metabolism. The neuronal sub-populations present in these key metabolically relevant nuclei regulate various facets of energy balance which includes appetite/satiety control, substrate utilization by peripheral organs and glucose homeostasis. In situations of heightened energy demand or excess, they maintain energy homeostasis by restoring the balance between energy intake and expenditure. While research on the metabolic role of the central nervous system has progressed rapidly, the neural circuitry and molecular mechanisms involved in regulating distinct metabolic functions have only gained traction in the last few decades. The focus of this review is to provide an updated summary of the mechanisms by which the various neuronal subpopulations, mainly located in the hypothalamus and the brainstem, regulate key metabolic functions.
... The vagus nerve functions as the bridge for the brain-gut axis and has the primary role of immunomodulation in the GI tract. The vagal CAP synapses directly on the enteric neurons and modulates macrophages to reduce TNF-α synthesis (Berthoud and Neuhuber, 2019). The immunomodulation by the vagal afferent route is mediated through the HPA axis ( Figure 1). ...
Vagus nerve stimulation (VNS) is a technology that provides electrical stimulation to the cervical vagus nerve and can be applied in the treatment of a wide variety of neuropsychiatric and systemic diseases. VNS exerts its effect by stimulating vagal afferent and efferent fibers, which project upward to the brainstem nuclei and the relayed circuits and downward to the internal organs to influence the autonomic, neuroendocrine, and neuroimmunology systems. The neuroimmunomodulation effect of VNS is mediated through the cholinergic anti-inflammatory pathway that regulates immune cells and decreases pro-inflammatory cytokines. Traditional and non-invasive VNS have Food and Drug Administration (FDA)-approved indications for patients with drug-refractory epilepsy, treatment-refractory major depressive disorders, and headaches. The number of clinical trials and translational studies that explore the therapeutic potentials and mechanisms of VNS is increasing. In this review, we first introduced the anatomical and physiological bases of the vagus nerve and the immunomodulating functions of VNS. We covered studies that investigated the mechanisms of VNS and its therapeutic implications for a spectrum of brain disorders and systemic diseases in the context of neuroimmunomodulation.
... Most vagal axons transmit sensory information from viscera to the brain and are the subject of other recent reviewse.g., [5,6]. Also, since vagal efferent anatomy and function have been extensively reviewed elsewhere, e.g., [6][7][8][9][10][11][12][13][14][15], this review focuses instead on recent insights into the molecular organization of the efferent vagus gained from single-cell genomics and genetic technology. ...
... The larger of these two nuclei, the dorsal motor nucleus of the vagus (DMV), contains around 13,800 vagal efferent neurons in humans [16] and about one-tenth as many in mice [17]. DMV efferent neurons are the parasympathetic preganglionic neurons for the heart, esophageal smooth muscle, and abdominal organs including the stomach, pancreas, gall bladder, and intestines [9] (Fig. 1). The smaller vagal efferent nucleus, the nucleus ambiguus (nAmb), contains only 587 neurons in mice [17]. ...
The vagus nerve vitally connects the brain and body to coordinate digestive, cardiorespiratory, and immune functions. Its efferent neurons, which project their axons from the brainstem to the viscera, are thought to comprise "functional units" - neuron populations dedicated to the control of specific vagal reflexes or organ functions. Previous research indicates that these functional units differ from one another anatomically, neurochemically, and physiologically but have yet to define their identity in an experimentally tractable way. However, recent work with genetic technology and single-cell genomics suggests that genetically distinct subtypes of neurons may be the functional units of the efferent vagus. Here we review how these approaches are revealing the organizational principles of the efferent vagus in unprecedented detail.
... Regarding vagal afferents, fibers were noticed around larger portal triads in the hilum of different liver lobes, around the extrahepatic part of the portal vein, and around almost all paraganglia adjacent to the hepatic branch of the vagus and the hilum. 41,44 Overall, (mainly afferent) parasympathetic hepatic innervations may be restricted to hilar structures, while a direct hepatic cholinergic innervation is doubtful. Some authors propose an indirect vagal control of the liver, by affecting the sympathetic celiac ganglion or microganglia around the celiac artery. ...
Abbreviations: VMN/PVN, hypothalamic ventromedial nucleus/paraventricular nucleus; VLM/VMM, ventrolateral medulla/ventromedial medulla; SMG/CG, superior mesenteric ganglion/caeliac ganglia; NTS, nucleus of the solitary tract; NG, nodose ganglion.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder. Increased sympathetic (noradrenergic) nerve tone has a complex role in the etiopathomechanism of NAFLD, affecting the development/progression of steatosis, inflammation, fibrosis, and liver hemodynamical alterations. Also, lipid sensing by vagal afferent fibers is an important player in the development of hepatic steatosis. Moreover, disorganization and progressive degeneration of liver sympathetic nerves were recently described in human and experimental NAFLD. These structural alterations likely come along with impaired liver sympathetic nerve functionality and lack of adequate hepatic noradrenergic signaling. Here, we first overview the anatomy and physiology of liver nerves. Then, we discuss the nerve impairments in NAFLD and their pathophysiological consequences in hepatic metabolism, inflammation, fibrosis, and hemodynamics. We conclude that further studies considering the spatial-temporal dynamics of structural and functional changes in the hepatic nervous system may lead to more targeted pharmacotherapeutic advances in NAFLD.
... The sensory vagal nerve terminals in the GIT are heterogenous in nature conveying both chemosensory, from nutrients and gut hormones, and mechanosensory signals to the brainstem [105,106]. Postprandial gut hormones and nutrients suppress food intake by transmitting information via the sensory vagal afferent terminals to the NTS, a crucial entry point in the brain for visceral information [107,108]. CCK, one of the first gut peptides to be identified to mediate satiety, elicits its actions by acting on the CCK-A receptors that are abundantly expressed on the vagal afferents and the cell bodies of the nodose ganglia [107,[109][110][111]. Additionally other receptors involved in regulating satiety, such as the LepR, are also expressed on these cell bodies [112]. As a result, circulating signals such as leptin can also act along with CCK on the nodose ganglia, to synergistically suppress food intake [113,114]. ...
Keywords: Obesity; hypothalamus; appetite; glucose homeostasis; weight-loss drugs; AGRP; POMC; NTS; incretins.
... 2,3,9,62 HPV-to-Brain Pathways for Food Intake Control How are signals from HPV glucose sensors transmitted to the brain to exert effects on food intake? The HPV is innervated by both vagal 63,64 and spinal 65 afferents. Accordingly, it is thought that glucose sensors in the HPV likely signal via the vagus nerve 66,67 or through spinal afferents 68 to the brain and ultimately manifest physiological or behavioral effects. ...
The detection of nutrients in the gut influences ongoing and future feeding behavior as well as the development of food preferences. In addition to nutrient sensing in the intestine, the hepatic portal vein plays a considerable role in detecting ingested nutrients and conveying this information to brain nuclei involved in metabolism, learning, and reward. Here, we review mechanisms underlying hepatic portal vein sensing of nutrients, particularly glucose, and how this is relayed to the brain to influence feeding behavior and reward. We additionally highlight several gaps where future research can provide new insights into the effects of portal nutrients on neural activity in the brain and feeding behavior.
