MITO-OB-RES: Human Mitochondrial Stress-driven Obesity Resistance

Sponsor

Rigshospitalet, Denmark (Other)

Overall Status

Recruiting

CT.gov ID

NCT06080568

Collaborator

University of Copenhagen (Other)

Enrollment

Location

Anticipated Duration (Months)

1.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Mitochondrial Diseases Mitochondrial Myopathies Mitochondrial Disorder

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 Design

Study Type:

Observational

Anticipated Enrollment :

30 participants

Observational Model:

Case-Control

Time Perspective:

Cross-Sectional

Official Title:

Energy Balance and Mitochondrial Function in Human Genetic Models of Mitochondrial Stress-mediated Obesity Resistance

Anticipated Study Start Date :

Oct 1, 2023

Anticipated Primary Completion Date :

Dec 1, 2025

Anticipated Study Completion Date :

Dec 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Mitochondrial myopathy Individuals with pathogenic mtDNA mutations
Control Individuals without mtDNA mutations

Outcome Measures

Primary Outcome Measures

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
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
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

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
Plasma adipokines modulating appetite and energy expenditure [Baseline]
Plasma levels of leptin and adiponectin are measured in the fasting state
Muscle mitochondrial leak respiration [Baseline]
Mitochondrial O2 flux is measured by high-resolution respirometry in permeabilized muscle fibers
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

Other Outcome Measures

Body composition [Baseline]
Fat free mass and fat mass are determined by dual-energy X-ray absorptiometry
Physical activity level [Baseline]
Physical activity level is measured by wrist-worn accelerometers
Self-reported physical activity [Baseline]
Self-reported physical activity is measured by the International Physical Activity Questionnaire - Short Form (IPAQ-SF)
Cardiorespiratory fitness [Baseline]
Pulmonary maximal oxygen uptake (VO2max) is determined during an incremental exercise test to exhaustion

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Eligibility criteria for individuals with mitochondrial DNA mutations

Inclusion criteria:

Known mtDNA point mutations

Exclusion criteria:

Use of antiarrhythmic medications or other medications which, in the opinion of the investigators, have the potential to affect outcome measures.
Diagnosed severe heart disease, dysregulated thyroid gland conditions, or other dysregulated endocrinopathies, or other conditions which, in the opinion of the investigators, have the potential to affect outcome measures.
Pregnancy

Eligibility criteria for controls

Exclusion criteria:

Current and regular use of antidiabetic medications or other medications which, in the opinion of the investigators, have the potential to affect outcome measures.
Diagnosed heart disease, symptomatic asthma, liver cirrhosis or -failure, chronic kidney disease, dysregulated thyroid gland conditions or other dysregulated endocrinopathies, or other conditions which, in the opinion of the investigators, have the potential to affect outcome measures
Daily use of tobacco products
Excessive alcohol consumption
Pregnancy