Human Mitochondrial Stress-driven Obesity Resistance

Recruiting

• Conditions: Mitochondrial Diseases; Mitochondrial Disorder; Mitochondrial Myopathies

• Registration Number: NCT06080568
• Lead Sponsor: Rigshospitalet, Denmark

Brief Summary

The overarching aim of this observational study is to determine alterations in energy balance while exploring the underlying cellular mechanisms in human genetic models of mitochondrial stress.

In a case-control design, individuals with pathogenic mitochondrial DNA mutations will be compared to healthy controls matched for sex, age, and physical activity level. Participants will attend a screening visit and an experimental trial including assessments of energy expenditure, appetite sensation, energy intake, and muscle and subcutaneous adipose tissue biopsy samples.

Detailed Description

Background: Pre-clinical models of mitochondrial stress are resistant to diet-induced obesity. Likewise, humans with primary mitochondrial diseases present a high prevalence of underweight (42%) as compared to a very low prevalence of obesity (2%). In this direction, recent data show a lower BMI across 17 cohorts of patients with mitochondrial diseases compared to national averages, suggesting mitochondrial stress-induced increments in resting energy expenditure as the primary driver of the lean phenotype. In recent years, the study of humans with genetic mutations has shown enormous potential to establish the mechanistic link between two physiological variables; indeed, if the mutation has a functional impact on one of those variables, then the direction of causality can be readily ascribed. Taken together, studies integrating assessments of energy balance with mitochondrial phenotyping in patients with rare mitochondrial disorders hold the potential to uncover putative mechanisms conferring protection from obesity in humans.

Objective: To determine alterations in energy expenditure/intake while exploring the underlying cellular mechanisms in individuals harboring mitochondrial DNA (mtDNA) mutations associated with mitochondrial stress.

Study design: Case-control study in individuals with mtDNA mutations (n=15) and healthy controls (n=15) matched for sex, age, and physical activity level.

Endpoint: Differences between individuals with mtDNA mutations and controls.

Study Timeline

• Study First Submitted: 2023-09-29
• Study First Submitted QC: 2023-10-06
• Study First Posted: 2023-10-12
• Study Start: 2023-10-20
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-30
• Last Update Posted: 2025-02-03
• Primary Completion: 2025-12
• Study Completion: 2025-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Appetite	Before (baseline) and 60-180 minutes after ingestion of a glucose solution as well as immediately after an ad libitum meal test	Subjective appetite sensations are measured in the fasting and fed state by visual analogue scale (VAS) ratings
Resting energy expenditure	Before (baseline) and 60-180 minutes after ingestion of a glucose solution	Resting energy expenditure is measured in the fasting and fed state by indirect calorimetry
Energy intake	180 minutes after ingestion of a glucose solution	Energy intake is measured by quantifying the amount of food ingested during an ad libitum meal test

Secondary Outcome Measures

Name	Time	Method
Plasma adipokines modulating appetite and energy expenditure	Baseline	Plasma levels of leptin and adiponectin are measured in the fasting state
Muscle mitochondrial efficiency	Baseline	Mitochondrial P/O ratio is measured by high-resolution respirometry in isolated mitochondria
Muscle mitochondrial membrane potential	Baseline	Mitochondrial membrane potential is measured by high-resolution fluorometry in isolated mitochondria
Plasma hormones and cytokines modulating appetite and energy expenditure	Before (baseline) and 0-180 minutes after ingestion of a glucose solution	Plasma levels of FGF21, GDF15, GLP-1, PYY, ghrelin, glucagon, and GIP are measured in the fasting and fed state
Muscle mitochondrial leak respiration	Baseline	Mitochondrial O2 flux is measured by high-resolution respirometry in permeabilized muscle fibers

Trial Locations

Locations (1)

Rigshospitalet; 🇩🇰 Copenhagen, Denmark