GLP-1, the gut-brain, and brain-periphery axes

Abstract

Glucagon-like peptide 1 (GLP-1) is a gut hormone which directly binds to the GLP-1 receptor located at the surface of the pancreatic β-cells to enhance glucose-induced insulin secretion. In addition to its pancreatic effects, GLP-1 can induce metabolic actions by interacting with its receptors expressed on nerve cells in the gut and the brain. GLP-1 can also be considered as a neuropeptide synthesized by neuronal cells in the brain stem that release the peptide directly into the hypothalamus. In this environment, GLP-1 is assumed to control numerous metabolic and cardiovascular functions such as insulin secretion, glucose production and utilization, and arterial blood flow. However, the exact roles of these two locations in the regulation of glucose homeostasis are not well understood. In this review, we highlight the latest experimental data supporting the role of the gut-brain and brain-periphery axes in the control of glucose homeostasis. We also focus our attention on the relevance of β-cell and brain cell targeting by gut GLP-1 for the regulation of glucose homeostasis. In addition to its action on β-cells, we find that understanding the physiological role of GLP-1 will help to develop GLP-1-based therapies to control glycemia in type 2 diabetes by triggering the gut-brain axis or the brain directly. This pleiotropic action of GLP-1 is an important concept that may help to explain the observation that, during their treatment, type 2 diabetic patients can be identified as 'responders' and 'non-responders'.

Figure 1. Schematic representation of the structure of proglucagon and its post-translational processing in different tissues

In the pancreas, post-translational processing of proglucagon leads to the generation of glycentin related polypeptide (GRPP), glucagon, intervening peptide (IP-1), and a major proglucagon fragment (MPF). In the brain and the gut, post-translational processing of proglucagon liberates GLP-1, GLP-2, IP-2, glicentin, and oxyntomodulin.. Proconvertases and carboxypeptidases are responsible for the processing of the mature peptides. Numbers represent the position of amino acids following the signal peptide (not shown).

Figure 2. The gut-to-brain and the brain-to-periphery axes are part of GLP-1 metabolic and vascular functions

In response to glucose and lipid, GLP-1 is secreted by the intestine into the mesenteric capillaries and released into the hepatoportal vein. This activates termination ends from the vagus nerve to generate a neural signal towards the brain stem. The corresponding nuclei, such as the nucleus of the solitary tract nucleus (NTS) and the area postrema (AP), send axons to the hypothalamus, which release GLP-1 and activate the receptors. Then, a new signal is sent towards peripheral tissues through the autonomic nervous system (ANS) to regulate numerous functions. In blood and tissues, DPP-4 continuously degrades GLP-1. The remaining hormone could reach β-cells and enhance glucose-induced insulin secretion through the direct route, or by targeting the brain, through the indirect route.

Figure 3. Schematic brain GLP-1 receptors localization in the mouse brain

GLP-1 receptors have been primarily identified in the paraventricular (PVN), dorsomedian (DMN), and arcuate (ARC) hypothalamic nuclei. In the brainstem, they were also localized in the nucleus of the tractus solitarius (NTS) and the area postrema (AP). These two last areas in the brainstem also contain the cell bodies of neurons synthesizing the GLP-1 which projects into the hypothalamus. All these localizations contribute to the metabolic effects described in the figure. Ventricles are represented in blue. CC: central canal. 3V: third ventricle. LV: lateral ventricle. 3drV: dorsal third ventricle.