Human Mitochondrial Stress-driven Obesity Resistance

Study Overview
=================
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.

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

Conditions
-----------------
Mitochondrial Diseases, Mitochondrial Myopathies, Mitochondrial Disorder

Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Mitochondrial myopathy<br>Individuals with pathogenic mtDNA mutations | |
| Control<br>Individuals without mtDNA mutations | |

What is the study measuring?
-----------------
Primary Outcome Measures

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

Secondary Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Energy balance, Energy expenditure, Appetite, Energy intake, Mitochondrial dysfunction