COMPARATIVE GUT PHYSIOLOGY SYMPOSIUM: Comparative physiology of glucagon-like peptide-2: Implications and applications for production and health of ruminants12

Abstract

Glucagon-like peptide-2 (GLP-2) is a 33-amino acid peptide derived from proteolytic cleavage of proglucagon by prohormone convertase 1/3 in enteroendocrine L cells. Studies conducted in humans, in rodent models, and in vitro indicate that GLP-2 is secreted in response to the presence of molecules in the intestinal lumen, including fatty acids, carbohydrates, amino acids, and bile acids, which are detected by luminal chemosensors. The physiological actions of GLP-2 are mediated by its G protein-coupled receptor expressed primarily in the intestinal tract on enteric neurons, enteroendocrine cells, and myofibroblasts. The biological activity of GLP-2 is further regulated by dipeptidyl peptidase IV, which rapidly cleaves the N-terminus of GLP-2 that is responsible for GLP-2 receptor activation. Within the gut, GLP-2 increases nutrient absorption, crypt cell proliferation, and mesenteric blood flow and decreases gut permeability and motility, epithelial cell apoptosis, and inflammation. Outside the gut, GLP-2 reduces bone resorption, can suppress appetite, and is cytoprotective in the lung. Thus, GLP-2 has been studied intensively as a therapeutic to improve intestinal function of humans during parenteral nutrition and following small bowel resection and, more recently, as a treatment for osteoporosis and obesity-related disorders and to reduce cellular damage associated with inflammation of the gut and lungs. Recent studies demonstrate that many biological actions and properties of GLP-2 in ruminants are similar to those in nonruminants, including the potential to reduce intestinal nitro-oxidative stress in calves caused by parasitic diseases such as coccidiosis. Because of its beneficial impacts on nutrient absorption, gut healing, and normal gut development, GLP-2 therapy offers significant opportunities to improve calf health and production efficiency. However, GLP-2 therapies require an extended time course to achieve desired physiological responses, as well as daily administration because of the hormone's short half-life. Thus, practical means of administration and alternative strategies to enhance basal GLP-2 secretion (e.g., through specific feed additives), which are more likely to achieve consumer acceptance, are needed. Opportunities to address these challenges are discussed.

Glucagon-like peptide 2 and its beneficial effects on gut function and health in production animals

“…The effects of GLP-2 on the intestinal tract are quite extensive and diverse because GLP-2 has both direct and indirect effects (via intermediate factors) on target cells, including enterocytes, goblet cells, Paneth cells, stem and/ or progenitor cells, sensory and enteric neurons, subepithelial myofibroblasts, endothelial cells of blood vessels, and various enteroendocrine cells [30,52,58,59]; Figure 1. The effects of GLP-2 most commonly reported include increased intestinal weight and mucosal development (eg, increased enterocyte volume, microvillus and villus heights, and crypt depth), increased mesenteric blood flow, enhanced glucose and peptide transporter expression, or activity and digestive enzyme activity in the intestinal brush border, reduced gut motility, increased barrier function and/or reduced intestinal permeability, reduced intestinal inflammation and apoptosis of intestinal epithelial cells, and improved intestinal healing after injury (reviewed by [28,30]).…”

“…The effects of GLP-2 most commonly reported include increased intestinal weight and mucosal development (eg, increased enterocyte volume, microvillus and villus heights, and crypt depth), increased mesenteric blood flow, enhanced glucose and peptide transporter expression, or activity and digestive enzyme activity in the intestinal brush border, reduced gut motility, increased barrier function and/or reduced intestinal permeability, reduced intestinal inflammation and apoptosis of intestinal epithelial cells, and improved intestinal healing after injury (reviewed by [28,30]). The detailed cellular and signaling mechanisms underlying many of these responses have been characterized only recently.…”

“…The L cells comprise less than 5% of mucosal cells; however, the greatest percentage of L cells is located in the distal small intestine and colon [30]. Processing of proglucagon by prohormone convertase 1/3 in L cells concurrently produces the incretin hormone, GLP-1, in addition to an appetite regulator named oxyntomodulin [31], and 3 peptides called glicentin, glicentin-related pancreatic polypeptide, and intervening peptide 2 (IP-2; [32,33]), the functions of which are not well characterized.…”

“…Glucagon-like peptide 2 (GLP-2) is an enteric peptide gaining significant attention because of its roles in improving nutrient absorption, energy balance, and gut barrier function, and reducing intestinal inflammation and its subsequent impacts on human health (reviewed by [12,[27][28][29]) and production animals (reviewed by [22,30]). The purpose of this review is to summarize (1) the current understanding of GLP-2's functions and mechanisms of action; (2) the potential use of GLP-2 or stimulators of its release to improve health and production performance of food animals; and (3) recent findings suggesting the therapeutic potential of GLP-2 to reduce the pathogenesis of intestinal protozoan infections in dairy calves.…”

Gastroduodenal mucosal defense mechanisms

“…Activation of TASRs, FFARs, and GPBAR release several bioactive peptides, including the family of GLPs, which are generated through the activity of prohormone convertase 1/3, which proteolytically cleaves proglucagon to produce GLP-1 and GLP-2 in enteroendocrine L cells[9*]. GLP-1 is an important incretin released by L cells distributed throughout the gastrointestinal tract, conventionally thought to help mediate glycemic control.…”