Obesity has increased dramatically worldwide. Being overweight or obese can lead to various conditions, including dyslipidaemia, hypertension, glucose intolerance and metabolic syndrome (MetS), which may further lead to type 2 diabetes mellitus (T2DM). Previous studies have identified a link between β-cell dysfunction and the severity of MetS, with multiple organs and tissues affected. Identifying the associations between pancreatic β-cell dysfunction and organs is critical. Research has focused on the interaction between the liver, gut and pancreatic β-cells. However, the mechanisms and related core targets are still not perfectly elucidated. The aims of this review were to summarize the mechanisms of β-cell dysfunction and to explore the potential pathogenic pathways and targets that connect the liver, gut, adipose tissue, muscle, and brain to pancreatic β-cell dysfunction.

Metabolism in each organ of multi-organ organisms, including humans, is regulated in a coordinated manner to dynamically maintain whole-body homeostasis. Metabolic information exchange among organs/tissues, i.e., inter-organ communication, which is necessary for this purpose, has been a subject of ongoing research. In particular, it has become clear that metabolism of energy, glucose, lipids, and amino acids is dynamically regulated at the whole-body level mediated by the nervous system, including afferent, central, and efferent nerves. These findings imply that the central nervous system obtains metabolic information from peripheral organs at all times and sends signals selectively to peripheral organs/tissues to maintain metabolic homeostasis, and that the liver plays an important role in sensing and transmitting information on the metabolic status of the body. Furthermore, the utilization of these endogenous mechanisms is expected to lead to the development of novel preventive/curative therapies for metabolic diseases such as diabetes and obesity.(This is a summarized version of the subject matter presented at Symposium 7 presented at the 43rd Annual Meeting of the Japanese Society of Inflammation and Regeneration.).

Autonomic nerves, sympathetic and parasympathetic, innervate organs and modulate their functions. It has become evident that afferent and efferent signals of the autonomic nervous system play important roles in regulating systemic metabolism, thereby maintaining homeostasis at the whole-body level. Vagal afferent nerves receive signals, such as nutrients and hormones, from the peripheral organs/tissues including the gastrointestinal tract and adipose tissue then transmit these signals to the hypothalamus, thereby regulating feeding behavior. In addition to roles in controlling appetite, areas in the hypothalamus serves as regulatory centers of both sympathetic and parasympathetic efferent fibers. These efferent innervations regulate the functions of peripheral organs/tissues, such as pancreatic islets, adipose tissues and the liver, which play roles in metabolic regulation. Furthermore, recent evidence has unraveled the metabolic regulatory systems governed by autonomic nerve circuits. In these systems, afferent nerves transmit metabolic information from peripheral organs to the central nervous system (CNS) and the CNS thereby regulates the organ functions through the efferent fibers of autonomic nerves. Thus, the autonomic nervous system regulates the homeostasis of systemic metabolism, and both afferent and efferent fibers play critical roles in its regulation. In addition, several lines of evidence demonstrate the roles of the autonomic nervous system in regulating and dysregulating the immune system. This review introduces variety of neuron-mediated inter-organ cross-talk systems and organizes the current knowledge of autonomic control/coordination of systemic metabolism, focusing especially on a liver-brain-pancreatic β-cell autonomic nerve circuit, as well as highlighting the potential importance of connections with the neuronal and immune systems.

In insulin-resistant states such as obesity, pancreatic β-cells proliferate to prevent blood glucose elevations. Failure of this β-cells proliferative response leads to the development of diabetes. On the other hand, when organs are damaged, cells proliferate to repair the organs. Therefore, these proliferations are compensatory mechanisms aimed at maintaining whole-body homeostasis. We previously discovered vagal signal-mediated systems regulating adaptive proliferation of β-cells and hepatocytes. Neuron-mediated liver-β-cell inter-organ crosstalk is involved in promotion of β-cell proliferation during obesity, and in this system, vagal signals directly stimulate β-cell proliferation. Meanwhile, in the liver, the multi-step mechanisms whereby vagal nerve signals activate hepatic resident macrophages are involved in hepatocyte proliferation after severe injury. Diabetes mellitus develops on the pathological basis of insufficient insulin action. Insulin action insufficiency is attributable to insulin resistance, i.e., the failure of insulin to exert sufficient effects, and/or to impairment of insulin secretion. Impairment of insulin secretion is attributable not only to the β-cell dysfunction but also to functional β-cell mass reduction. In this regard, there are already therapeutic options to increase insulin secretion from residual β-cells, such as sulfonyl urea and incretin-related drugs. In contrast, there are as yet no applicable therapeutic strategies to increase functional β-cell mass in vivo. Therefore, we have conducted the basic investigations to tackle this issue based on the discovery of neuron-mediated liver-β-cell inter-organ crosstalk. This review introduces vagal signal-mediated regulatory systems of adaptive cell proliferation in vivo and efforts to develop cell-increasing therapies based on vagal nerve-mediated cell proliferation.

In insulin-resistant states such as obesity, pancreatic β-cells proliferate to prevent blood glucose elevations. However, the mechanism(s) by which obesity induces compensatory β-cell responses is not fully understood. Recently, several studies have shown that signals from the liver, such as neuronal signals or humoral factors, regulate β-cell proliferation during obesity development. We previously reported a liver-brain-pancreas neuronal relay, consisting of afferent splanchnic nerves, the central nervous system and efferent vagal nerves, to promote this compensatory β-cell proliferation. Furthermore, we recently clarified the molecular mechanisms by which efferent vagal signals induce β-cell proliferation in this inter-organ neuronal network system. Herein, these liver-β-cell inter-organ networks are reviewed, focusing mainly on the neuronal network. The significance of the neuronal network system in the maintenance of glucose homeostasis is also discussed with reference to the relevant literature.

To date, various signal transducers, cytokines, growth factors, and hormones have been reported to play an important role in homeostasis of various organs. Various cells and organs are involved in the hepatic regeneration process, which proceeds as a result of the coordination of many factors. While these factors are well known to be involved in the liver regeneration after the liver injury, however, as the details of such mechanisms have not been sufficiently elucidated, the practical applicability of hepatic regeneration based on the action of these and cytokines growth factors is still unclear. In terms of the involvement of the autonomic nervous system in hepatic regeneration, cell proliferation resulting from direct signal transduction to the liver has also been reported and recent studies focusing on the inter-organ communication via neural network opened a novel aspect of this field for therapeutic applicability. Therefore, the appropriate understanding of the relationship between autonomic neural network and liver regeneration through various organs including brain, afferent nerve, efferent nerve, etc. is essential. This mini-review explains the principle of neural system involved in the inter-organ communication and its contribution on the liver regeneration upon the liver injury reviewing recent progress in this field.

The development of therapeutic options to promote hepatic regeneration following severe liver injury is essential. While humoral factors have been reported as mechanisms of liver regeneration, the contributions of interorgan communication to liver regeneration have not been reported. In this study, we examined the effect of a neural relay on liver regeneration via activation of serotonin release from the gastrointestinal (GI) tract. Our results demonstrated that the afferent visceral nerve from the liver activates the efferent vagus nerve from the brain, leading to activation of serotonin release from the GI tract and contributing to liver regeneration. While it is difficult to apply these results directly to human health, we believe that this study may represent a step toward developing essential therapeutics to promote liver regeneration.