A LEAP2 Forward in Gut-Induced Metabolic Profiling

Abstract

INVITED COMMENTARY Diet- and exercise-induced weight loss has been established clinically to improve glycemic control. Interestingly, bariatric surgery has been reported to enhance glycemia above and beyond that of lifestyle treatment (1). In fact, bariatric surgery–induced effects on glucose control and reversal of diabetes are often seen prior to weight loss, with improved hepatic insulin sensitivity and pancreatic beta-cell insulin secretion occurring early, followed by improvements in skeletal muscle and adipose insulin action with weight loss (2). An additional mechanism contributing to this enhanced glucose control likely centers around the gut. Gut-derived mechanisms (eg, foregut vs hindgut hypothesis) posit that enteroendocrine factors, such as glucagon-like peptide-1 (GLP-1), glucose insulinotropic peptide (GIP), and/or bile acids, rise in support of not only pancreatic insulin secretion, but also satiety (3). In contrast, ghrelin is considered the only known orexigenic hormone from the periphery. Ghrelin is important for glucose control since it impacts insulin and growth hormone metabolism. Roux-en-Y gastric bypass (RYGB) is reported to lower fasting and/or postprandial ghrelin, whereas sleeve gastrectomy may largely impact fasting levels due to predominate removal of the fundus (3). These observations from surgery are prominent as caloric restriction by diet is often related to elevations in ghrelin and hunger compared with exercise-mediated improvements in appetite up to about 24 hours (4, 5). Despite these collective understandings on how lifestyle and/or bariatric surgery treatments affect gut-derived signatures, the exact mechanisms regulating changes in gut hormones as well as their systemic influence remain largely unclear. Novel work presented in this issue of the Journal of Clinical Endocrinology & Metabolism demonstrates the impact of RYGB on genome-wide expression patterns in enteroendocrine cells from human gut biopsies during and after surgery in patients with obesity and/or diabetes (6). Liver-expressed antimicrobial peptide 2 (LEAP2) mRNA in particular was upregulated from gut biopsies, while circulating fasting and postprandial plasma levels were unchanged. These gene expression data from the gut, nonetheless, are of potential clinical relevance since LEAP2 related peptide fragments have been proposed to oppose ghrelin via reciprocal effects on growth hormone secretagogue receptor (GHSR) activity. Indeed, during active weight loss LEAP2 has been reported to decline in an effort to foster the acyl-ghrelin effect on stimulating food intake, stimulate growth hormone secretion in circulation, as well as raise blood glucose to prevent hypoglycemia (7). In contrast, LEAP2 is elevated in obesity to likely limit ghrelin effect on food intake and maintain blood glucose (7). Adding to this physiologic understanding, work herein demonstrated that in vitro LEAP238-47 fragment had insulinotropic effects in a human pancreatic pseudo-islet glucose-stimulated insulin secretion assay, which were similar to that of GLP-1. Furthermore, this same LEAP238-47 fragment opposed the ghrelin receptor agonist, GHSR, as assessed in COS-7 cells. However, the utility of such findings in humans is uncertain, as LEAP238-47 infusion had no apparent insulin secretory changes during a graded glucose clamp in healthy, young male participants of normal weight status. Moreover, there were no glucoregulatory effect as determined by examination of plasma total ghrelin, substrate metabolism via indirect calorimetry, or perceived appetite by way of visual analog scale. While it would have been useful to determine acylated and des-ghrelin for bioactive property understanding as well as to have included female participants with glucose stable isotope infusion to depict hepatic glucose production compared with peripheral glucose disposal, these initial infusion findings suggest that LEAP238-47 may not directly impact glycemic control. It should be noted, however, that a single dose of LEAP2 was tested and glucagon as well as pharmacokinetics of LEAP2 were not investigated during the present study. The current work raises more questions than it necessarily provides answers—a sign of innovative work. Most notably, what regulates LEAP2 gene transcription in the gut? And would this be similar to that of the liver? In either case, since bariatric surgery restricts food intake, it would be reasonable to hypothesize that less food contact with enteroendocrine cells of the upper duodenum and/or expedited delivery of food to the distal region of the small intestine plays a role. This said, circadian rhythm and macronutrient per se are each considered modifiers of gut hormone secretion. Thus, given popularity of intermittent fasting, ketogenic, and/or plant-based diets today, it is worth considering whether nutrient timing and/or macronutrients per se contribute to LEAP2 gene expression and/or translation. Plasma levels were not altered in these patients undergoing bariatric surgery despite differences in gene expression. It is worth mentioning that the assay selected to test circulating LEAP2 was specific to LEAP238-77. This leads to basic science questions of what regulates LEAP2 fragmentation? Similar to other gut hormones (eg, GLP-1, ghrelin, and peptide YY), there exists bioactive forms. Understanding the regulator steps in converting LEAP2 to “active” molecules is critical toward moving the physiology field forward. It may also yield understanding potential targets of interest (eg, dipeptidyl peptidase-4 inhibitors and incretins) for health. Another point raised by the present work (6) is whether or not LEAP2 can affect human physiology independent of GHSR. For instance, a consideration of these bariatric and in vitro findings is the influence of physical activity on gut hormones. This is worth mentioning since exercise raises body temperature, increases vagal tone, and alters blood flow distribution away from the splanchnic region to skeletal muscle, creating a quasi-hypoxic state that can impact gut hormone secretion (8). These factors may be an alternative or additional means for translating LEAP2 expression to functional action in the blood. Whatever the mechanism for affecting LEAP2, it appears that this novel peptide may regulate ghrelin and insulin action during states of energy surplus/deficit. Therefore, the work of Hagemann and colleagues (6) helps to remind us that there are likely parallel hormones rather than just one working to affect energy homeostasis. Additional work such as this will continue to evolve our understanding of how treatments work for combating obesity/diabetes.