This clinical study investigates how blocking the hunger-related ghrelin receptor affects appetite and metabolism in individuals with obesity who are treated with semaglutide (a GLP-1 receptor agonist). LEAP2, a naturally occurring hormone that inhibits the ghrelin receptor, is used as the investigational compound. The objective of the study is to clarify how the ghrelin system functions when appetite is suppressed by semaglutide treatment. Participants will receive either LEAP2 or placebo during two experimental visits in a randomized, double-blind, crossover design. The investigators will assess food intake, appetite sensations, glucose metabolism, and hormonal responses. By examining the interaction between semaglutide and ghrelin signaling, the study aims to improve understanding of how multiple appetite-regulating systems interact and whether additional hunger signals remain active during GLP-1 treatment. The findings may inform the development of future treatments for individuals with obesity.
Age between 18 and 65 years old
Body mass index (BMI) above ≥ 25 kg/m2
Ongoing semaglutide treatment with a stable dose of ≥ 1 mg once weekly for a minimum of 3 months prior to inclusion
Weight stability, defined as a maximum variation of ±3% between the highest and lowest recorded body weight during the 3 months prior to inclusion.
Anaemia
Alanine aminotransferase (ALAT) > 2 times normal value
History of hepatobiliary and/or gastrointestinal disorder
Kidney disease (serum creatinine above normal range and/or urine albumin-creatinine ratio 30mg/g confirmed with two measurements)
Crossover
Liver-Expressed Antimicrobial Peptide 2 (LEAP2)
Biological/VaccineContinuous intravenous infusion of LEAP2 (Liver-Expressed Antimicrobial Peptide 2), an endogenous inverse agonist and competitive antagonist of the ghrelin receptor (GHSR), administered at 40 pmol/kg/min for 6 hours. LEAP2 inhibits ghrelin-mediated signaling involved in hunger regulation, gastric motility, and growth hormone secretion. This intervention enables investigation of the physiological relevance of ghrelin receptor activity during semaglutide-induced appetite suppression
Placebo (saline)
Other interventionContinuous intravenous infusion of isotonic saline (0.9% sodium chloride) for 6 hours. This placebo comparator is used to match the volume, rate, and duration of the active intervention (LEAP2) in a randomized, double-blind, crossover design. The placebo enables assessment of the physiological effects of ghrelin receptor blockade by LEAP2 in individuals with obesity treated with semaglutide
Food intake
Difference in total energy intake during a standardized ad libitum meal. Energy intake will be quantified as kilojoules (kJ) and kJ per kilogram of body weight consumed during the meal
Composite score of sensation of hunger, fullness (reverse corded) and prospective food intake.
Visual analogue scales (VASs) assessing appetite, satiety and hunger sensations (from 0 to 10 cm on a scale = from mimimum to maximum sensation)
Gastric emptying
Paracetamol concentration in plasma after intake of 1.5 g paracetamol
Plasma concentrations of glucose
Plasma glucose
Circulating levels of growth hormone and IGF-1
Blood samples
Sensation of nausea, thirst, and comfort
VAS
Circulating levels of LEAP2, insulin, glucagon, and other hormones and signaling molecules regulating glucose metabolism, gastrointestinal motility, energy expenditure and eating behaviour
Blood samples
Lipids and other metabolism markers
Blood samples
Energy expenditure
Indirect calorimetry
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