Neuromodulation of metabolic functions: from pharmaceuticals to bioelectronics to biocircuits

Abstract

Neuromodulation of central and peripheral neural circuitry brings together neurobiologists and neural engineers to develop advanced neural interfaces to decode and recapitulate the information encoded in the nervous system. Dysfunctional neuronal networks contribute not only to the pathophysiology of neurological diseases, but also to numerous metabolic disorders. Many regions of the central nervous system (CNS), especially within the hypothalamus, regulate metabolism. Recent evidence has linked obesity and diabetes to hyperactive or dysregulated autonomic nervous system (ANS) activity. Neural regulation of metabolic functions provides access to control pathology through neuromodulation. Metabolism is defined as cellular events that involve catabolic and/or anabolic processes, including control of systemic metabolic functions, as well as cellular signaling pathways, such as cytokine release by immune cells. Therefore, neuromodulation to control metabolic functions can be used to target metabolic diseases, such as diabetes and chronic inflammatory diseases. Better understanding of neurometabolic circuitry will allow for targeted stimulation to modulate metabolic functions. Within the broad category of metabolic functions, cellular signaling, including the production and release of cytokines and other immunological processes, is regulated by both the CNS and ANS. Neural innervations of metabolic (e.g. pancreas) and immunologic (e.g. spleen) organs have been understood for over a century, however, it is only now becoming possible to decode the neuronal information to enable exogenous controls of these systems. Future interventions taking advantage of this progress will enable scientists, engineering and medical doctors to more effectively treat metabolic diseases.

Vagus nerve mediated liver-brain axis is a major regulator of the metabolic landscape in the liver

“…The liver is a central organ involved in carbohydrate and lipid metabolism, serving as a major energetic reservoir for other tissues [27] and the regulation of hepatic metabolic homeostasis is pivotal to whole-body metabolism. This balance is partially dependent on the sensing of metabolic states or nutrient availability and the release of neuroendocrine signals [28,29]. Most of these neural circuits are intrinsic to the vagus nerve, with vagal afferent fibers conveying sensory information as mechanical stretching, nutrients/metabolites and hormones, from gastrointestinal tract organs to the nucleus of the solitary tract (NTS) within the central nervous system [7,13,14,[30][31][32][33].…”

Closed-loop bioelectronic medicine for diabetes management

“…Successful advances are being made in the former, but full restoration of the functionality of the transplanted islets is still far from optimal. To address this issue, Seicol et al (2019) propose the development of biocircuit-augmented islet transplants containing mature, vascularized and neural innervated β-cells, where neurons will grow inside hydrogel-based micro tissue engineered neural network (micro-TENN) scaffolds (Seicol et al 2019). We proposed bringing this idea one step further and using closedloop neuromodulation of neural bio-circuits to restore the physiologic response to neural signalling that is present in healthy individuals (Güemes and Georgiou 2018).…”

Our natural “makeup” reveals more than it hides: Modeling the skin and its microbiome

“…Metabolic activities also play an important role in the pathogenesis of many diseases. Metabolism in immune cells (immunometabolism) is a major regulator of immune responses (Geltink, Kyle, & Pearce, 2018; Hotamisligil, 2017; O'Neill, Kishton, & Rathmell, 2016), further metabolic activity can also be altered by neuromodulation (Seicol, Bejarano, Behnke, & Guo, 2019). The host and microbiome's metabolic activities provide a platform for experimentally accessing interactions and mathematically modeling host–microbiome interactions.…”