Abstract
Here, we provide a focused review of the evidence for the roles of the vagus nerve in mediating the regulatory effects of peripherally and centrally produced GLP-1 on eating behaviour and energy balance. We particularly focus on recent studies which have used selective genetic, viral, and transcriptomic approaches to provide important insights into the anatomical and functional organisation of GLP-1-mediated gut-brain signalling pathways. A number of these studies have challenged canonical ideas of how GLP-1 acts in the periphery and the brain to regulate eating behaviour, with important implications for the development of pharmacological treatments for obesity.
Abbreviations
FFA - free fatty acid
GLP-1 - glucagon-like peptide 1
NTS - nucleus tractus solitarius
PPG - preproglucagon
PVN - paraventricular nucleus of the hypothalamus
SGLT1 - sodium-dependent glucose transporter 1
INTRODUCTION
The prevalence of obesity is increasing at an alarming rate. This chronic relapsing disease is associated with co-morbidities including type 2 diabetes, cardiovascular disease, stroke and cancer, resulting in higher mortality rates amongst individuals living with obesity (Abdelaal et al., 2017; Bray et al., 2017). Although there is a consensus that increased energy intake, coupled with reduced energy expenditure, is the primary impetus for weight gain, lifestyle interventions aimed at reducing food intake and increasing exercise are largely ineffective in treating obesity (Grill, 2020). It appears that physiological mechanisms that prevent weight gain fail during the initial onset of obesity, yet defend against weight loss once obesity has developed. Although much attention has been given to the role of the brain in energy homeostasis, at present, remodelling of the gut through bariatric surgery is the only effective treatment for severe obesity. This implicates neuronal and/or hormonal gut-brain signalling mechanisms in the development of obesity, and suggests that targeting these mechanisms provides the most effective opportunities for obesity pharmacotherapy.
Glucagon-like peptide 1 (GLP-1), a gastrointestinal hormone and centrally produced neuromodulator, has received particular attention as a gut-brain signalling molecule that can be targeted for the treatment of metabolic diseases. GLP-1 is predominantly released from the gut in response to nutrient ingestion, with known roles in glucose homeostasis, gut motility and the regulation of eating. In humans and rodents, GLP-1 levels are reduced in obesity, while bariatric surgery dramatically increases post-prandial levels of GLP-1 (Chambers et al., 2014; Jiménez et al., 2014; Umeda et al., 2011) as early as a few days after the surgery (Le Roux et al., 2007). The level of circulating GLP-1 after bariatric surgery positively correlates with both improved insulin release (Umeda et al., 2011) and weight loss (Le Roux et al., 2007), while administration of the GLP-1 receptor antagonist exendin-(9-39) blocks the surgery-induced insulin response to an oral glucose load in both humans and rodents (Chambers et al., 2011; Salehi et al., 2011; Vidal et al., 2016). In line with the pleiotropic effects of GLP-1, pharmacological therapies aimed at increasing GLP-1 levels by stimulating GLP-1 secretion (Iwasaki et al., 2018; Vidal et al., 2016), inhibiting proteolytic breakdown of GLP-1 (Herman et al., 2006), or exogenous administration of GLP-1 analogues (Vilsbøll et al., 2012), are effective in promoting weight loss and improve a number of obesity-associated health risks (Campbell & Drucker, 2013; Kim et al., 2013).
GLP-1 is also produced centrally by neurons in the caudal brainstem, a key integration site for gut-brain signalling pathways which regulate energy homeostasis, particularly those mediated by the vagus nerve (Brierley et al., 2021; Holt, Richards, et al., 2019; Llewellyn-Smith et al., 2011; McLean et al., 2020). Here, we critically review evidence for the role(s) of the vagus nerve in mediating the regulatory effects of peripherally and centrally produced GLP-1 on eating behaviour and metabolism. We particularly highlight recent studies which have used selective genetic and viral approaches to provide important insights into the anatomical and functional organisation of GLP-1-mediated gut-brain signalling pathways. We discuss how these recent findings challenge canonical views of how GLP-1 regulates eating, and the implications of these findings for the development of pharmacological obesity treatments.
VAGAL-DEPENDENT ACTIONS OF GLP-1 IN THE PERIPHERY
2.1 GLP-1 production in the gut
Circulating GLP-1 levels are low under fasting conditions and increase threefold to fourfold in response to a meal (Ørskov et al., 1996). Consumption of food high in fats and/or carbohydrates is the primary physiological stimulus for GLP-1 secretion (Brubaker, 2006; Herrmann et al., 1995). This secretion is predominantly mediated by nutrient sensing in the gut, since direct infusion of individual macronutrients into the intestine is sufficient to increase circulating GLP-1 levels (Cordier-Bussat et al., 1998; Roberge & Brubaker, 1993; Rocca & Brubaker, 1999). Furthermore, orally consumed glucose elicits a rapid rise in GLP-1, however, bypassing the gastrointestinal tract with intravenous infusion of glucose is not sufficient to elicit this rise (Herrmann et al., 1995; Unger et al., 1968). Nutrient sensing in the gut is performed by specialised cells known as enteroendocrine cells, which are sparsely dispersed in the gastrointestinal epithelium. Enteroendocrine cells sense luminal content via long projections into the gut lumen and/or via post-absorptive mechanisms, resulting in the release of hormones that are produced and packaged into dense core vesicles, through a process of regulated exocytosis. L-cells are enteroendocrine cells which express the glucagon gene and prohormone convertase 1/3 enzyme, necessary for post-translational GLP-1 production, and account for 95% of circulating GLP-1 (Song et al., 2019)...
ACKNOWLEDGEMENTS
The authors would like to thank Stefan Trapp for helpful comments provided during the preparation of this manuscript.