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.

This study investigates the physiological role of ghrelin receptor signaling in individuals with obesity receiving stable treatment with semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist known to suppress appetite and induce weight loss. Ghrelin is the only known circulating orexigenic gut hormone, and its activity is mediated via the growth hormone secretagogue receptor (GHSR). Whether ghrelin signaling continues to contribute meaningfully to appetite regulation during pharmacological GLP-1 receptor activation remains unknown.

Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous inverse agonist and competitive antagonist of the GHSR. LEAP2 provides a highly specific and transient means of blocking ghrelin receptor activity in humans, enabling mechanistic exploration of its physiological relevance. Previous studies have demonstrated that LEAP2 infusion reduces ad libitum food intake and postprandial glucose excursions in both lean and obese individuals. However, the role of ghrelin signaling under conditions of GLP-1-induced appetite suppression has not been elucidated.

The SILENCED study is a randomized, double-blind, placebo-controlled, crossover trial. Twenty-four participants with obesity who are weight-stable and on a stable dose of ≥1 mg/week semaglutide for at least 3 months will complete two experimental study days. Each participant will receive a 6-hour intravenous infusion of either LEAP2 or placebo (saline) on separate days. During each visit, appetite-related measures, food intake, glucose metabolism, gastrointestinal motility, growth hormone levels, and energy expenditure will be assessed.

The primary outcome is total energy intake during a standardized ad libitum meal. Secondary and exploratory outcomes include visual analogue scale ratings of appetite, gastric emptying assessed via paracetamol absorption, postprandial glucose and hormone responses, and indirect calorimetry measurements.

This study is expected to provide novel insight into whether ghrelin receptor signaling continues to play a functional role in appetite and metabolism under pharmacological GLP-1 receptor activation. The findings may inform the development of future combination therapies targeting multiple appetite-regulating pathways in the treatment of obesity.

Inclusion Criteria:

• 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.
• Informed oral and written consent

Exclusion Criteria:

• 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)
• Any ongoing medication that investigator evaluates would interfere with study participation
• Any physical or psychological condition that investigators evaluate would interfere with study participation including any acute or chronic illnesses.
• Regular tobacco smoking and/or use of other nicotine products
• Glycated haemoglobin HbA1c > 48 and/or type 1 or type 2 diabetes medical treatment
• Women of childbearing potential who are not using effective contraception
• Pregnancy or breastfeeding

At this stage, no final decision has been made regarding sharing of individual participant data (IPD). While sharing de-identified data could contribute to scientific transparency, reproducibility, and collaborative advancement in obesity and metabolic research, several factors must be considered. These include ethical and legal obligations related to participant confidentiality, the need for appropriate data-use agreements, and institutional policies on data governance. The possibility of sharing IPD will be revisited upon study completion, in alignment with sponsor requirements, ethical approvals, and journal publication policies