Identification and Metabolic Profiling of a Novel Human Gut-derived LEAP2 Fragment

Abstract

Context The mechanisms underlying Roux-en-Y gastric bypass (RYGB) surgery-induced weight loss and the immediate postoperative beneficial metabolic effects associated with the operation remain uncertain. Enteroendocrine cell (EEC) secretory function has been proposed as a key factor in the marked metabolic benefits from RYGB surgery. Objective To identify novel gut-derived peptides with therapeutic potential in obesity and/or diabetes by profiling of EEC-specific molecular changes in obese patients following RYGB-induced weight loss. Subjects and Methods Genome-wide expression analysis was performed in isolated human small intestinal EECs obtained from 20 gut-biopsied obese subjects before and after RYGB. Targets of interest were profiled for preclinical and clinical metabolic effects. Results RYGB consistently increased expression levels of the inverse ghrelin receptor agonist, liver-expressed antimicrobial peptide 2 (LEAP2). A secreted endogenous LEAP2 fragment (LEAP238-47) demonstrated robust insulinotropic properties, stimulating insulin release in human pancreatic islets comparable to the gut hormone glucagon-like peptide-1. LEAP238-47 showed reciprocal effects on growth hormone secretagogue receptor (GHSR) activity, suggesting that insulinotropic action of the peptide may be directly linked to attenuation of tonic GHSR activity. The fragment was infused in healthy human individuals (n=10), but no glucoregulatory effect was observed in the chosen dose as compared to placebo. Conclusions Small intestinal LEAP2 expression was upregulated after RYGB. The corresponding circulating LEAP238-47 fragment demonstrated strong insulinotropic action in vitro, but failed to elicit glucoregulatory effects in healthy human subjects.

A LEAP2 Forward in Gut-Induced Metabolic Profiling

“…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.…”

“…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.…”

“…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.…”

The ups and downs of growth hormone secretagogue receptor signaling

“…The proposed proLEAP2 processing enzyme is furin, a calcium-dependent serine endoprotease that cleaves peptides at the C-terminal end of paired basic residues and usually processes precursors in the constitutive secretory pathway [50]. A recent study found that LEAP2 is also processed into LEAP2 [38][39][40][41][42][43][44][45][46][47] in the intestinal epithelium of humans and mice [51]. LEAP2's amino acid sequence is highly conserved in mammals, particularly the N-terminal end, where the initial six residues are identical across species [52,53].…”

Human liver‐expressed antimicrobial peptide 2 elevation in the cerebrospinal fluid in bacterial meningitis

“…LEAP2 suppressed food intake and growth hormone release and maintained viable glucose levels during chronic caloric restriction in mice (Ge et al., 2018). The six N‐terminal amino acids of LEAP2 are crucial for GHSR1a binding, and its 10‐amino‐acid N‐terminal fragment stimulated insulin release from human pancreatic islets (Hagemann et al., 2020; Wang et al., 2019). Plasma LEAP2 concentrations in humans increased with body weight gain and elevations of blood glucose and decreased with fasting and weight loss surgery (Mani et al., 2019).…”