Sympathetic circuits regulating hepatic glucose metabolism: where we stand

Abstract

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.

Neural Circuits Underlying Reciprocal Cardiometabolic Crosstalk: 2023 Arthur C. Corcoran Memorial Lecture

“…53 To this end, it regulates key processes in adipose tissue (eg, increasing thermogenesis and lipolysis), the liver (eg, promoting glycogenolysis), skeletal muscle (eg, enhancing glucose metabolism and access to substrate), and the pancreas (eg, inhibiting insulin release). [54][55][56] Metabolic functions are also influenced by the PNS through its inhibition of hepatic glucose production, pancreatic release of insulin, stimulation of nutrient absorption and utilization by the digestive organs, such as the stomach and intestines, facilitation of glycogenesis in the liver and muscles, as well as lipogenesis in adipose tissue. 43,54 It should be noted that the interplay between the SNS and PNS in metabolic homeostasis is dynamic and context dependent.…”

Hypoxia sensing in the body: An update on the peripheral and central mechanisms

“…These neurons receive synaptic projections from multiple brainstem and forebrain regions, including the respiratory neurons of the preBötC, indicating that this region integrates sympathetic control with other physiological systems (Guyenet, 2006 ). The sympathetic nervous system also regulates the energy expenditure and O 2 demand of the body by controlling peripheral (e.g., cutaneous) blood flow and heat exchange with the environment, regulating non‐shivering thermogenesis through innervations to the brown adipose tissue and stimulating lipolysis and glycogenolysis (Madden & Morrison, 2005 ; Zsombok et al., 2023 ).…”