Identification and Metabolic Profiling of a Novel Human Gut-derived LEAP2 Fragment
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Identification and Metabolic Profiling of a Novel Human Gut-derived LEAP2 Fragment. / Hagemann, Christoffer A.; Zhang, Chen; Hansen, Henrik H.; Jorsal, Tina; Rigbolt, Kristoffer T.G.; Madsen, Martin R.; Bergmann, Natasha C.; Heimbürger, Sebastian M.N.; Falkenhahn, Mechthilde; Theis, Stefan; Breitschopf, Kristin; Holm, Stephanie; Hedegaard, Morten A.; Christensen, Mikkel B.; Vilsbøll, Tina; Holst, Birgitte; Vrang, Niels; Jelsing, Jacob; Knop, Filip K.
In: The Journal of clinical endocrinology and metabolism, Vol. 106, No. 2, 2021, p. e966-e981.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Identification and Metabolic Profiling of a Novel Human Gut-derived LEAP2 Fragment
AU - Hagemann, Christoffer A.
AU - Zhang, Chen
AU - Hansen, Henrik H.
AU - Jorsal, Tina
AU - Rigbolt, Kristoffer T.G.
AU - Madsen, Martin R.
AU - Bergmann, Natasha C.
AU - Heimbürger, Sebastian M.N.
AU - Falkenhahn, Mechthilde
AU - Theis, Stefan
AU - Breitschopf, Kristin
AU - Holm, Stephanie
AU - Hedegaard, Morten A.
AU - Christensen, Mikkel B.
AU - Vilsbøll, Tina
AU - Holst, Birgitte
AU - Vrang, Niels
AU - Jelsing, Jacob
AU - Knop, Filip K.
PY - 2021
Y1 - 2021
N2 - 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 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: Roux-en-Y gastric bypass 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 the 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.
AB - 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 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: Roux-en-Y gastric bypass 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 the 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.
KW - bariatric surgery
KW - enteroendocrine cells
KW - gut hormone
KW - liver-expressed antimicrobial peptide 2
KW - obesity
KW - peptide fragment
U2 - 10.1210/clinem/dgaa803
DO - 10.1210/clinem/dgaa803
M3 - Journal article
C2 - 33135737
AN - SCOPUS:85100358583
VL - 106
SP - e966-e981
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 2
ER -
ID: 256939978