Human Mitochondrial Stress-driven Obesity Resistance (MITO-OB-RES)

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

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.

Study Overview

• Status: Recruiting
• Conditions: 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 Type: Observational
• Enrollment (Estimated): 30

Contacts and Locations

• Study Contact: Name: Matteo Fiorenza, Ph.D.; Phone Number: +4535458748; Email: matteo.fiorenza@regionh.dk
• Study Contact Backup: Name: Tue Leth Nielsen, MD; Phone Number: +4535458748; Email: tue.leth.nielsen.01@regionh.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Rigshospitalet
    • Contact: Tue Leth Nielsen, MD; Phone Number: +4535458748; Email: tue.leth.nielsen.01@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Individuals with mitochondrial myopathy due to pathogenic mtDNA mutations are identified and recruited from the Copenhagen Neuromuscular Center or the Department of Clinical Genetics (Rigshospitalet).

Control volunteers are recruited via recruitment announcements in Denmark.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Mitochondrial myopathy; Individuals with pathogenic mtDNA mutations
Control; 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

Other Outcome Measures

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

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: University of Copenhagen
• Investigators: Principal Investigator: Matteo Fiorenza, Ph.D., Rigshospitalet, Denmark; Principal Investigator: John Vissing, MD, Rigshospitalet, Denmark; Principal Investigator: Signe Torekov, Ph.D., University of Copenhagen

Publications and helpful links

General Publications

• Guo Q, Xu Z, Zhou D, Fu T, Wang W, Sun W, Xiao L, Liu L, Ding C, Yin Y, Zhou Z, Sun Z, Zhu Y, Zhou W, Jia Y, Xue J, Chen Y, Chen XW, Piao HL, Lu B, Gan Z. Mitochondrial proteostasis stress in muscle drives a long-range protective response to alleviate dietary obesity independently of ATF4. Sci Adv. 2022 Jul 29;8(30):eabo0340. doi: 10.1126/sciadv.abo0340. Epub 2022 Jul 27.
• Yang M, Xu L, Xu C, Cui Y, Jiang S, Dong J, Liao L. The Mutations and Clinical Variability in Maternally Inherited Diabetes and Deafness: An Analysis of 161 Patients. Front Endocrinol (Lausanne). 2021 Nov 25;12:728043. doi: 10.3389/fendo.2021.728043. eCollection 2021.
• Sturm G, Karan KR, Monzel AS, Santhanam B, Taivassalo T, Bris C, Ware SA, Cross M, Towheed A, Higgins-Chen A, McManus MJ, Cardenas A, Lin J, Epel ES, Rahman S, Vissing J, Grassi B, Levine M, Horvath S, Haller RG, Lenaers G, Wallace DC, St-Onge MP, Tavazoie S, Procaccio V, Kaufman BA, Seifert EL, Hirano M, Picard M. OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases. Commun Biol. 2023 Jan 12;6(1):22. doi: 10.1038/s42003-022-04303-x.
• O'Rahilly S. "Treasure Your Exceptions"-Studying Human Extreme Phenotypes to Illuminate Metabolic Health and Disease: The 2019 Banting Medal for Scientific Achievement Lecture. Diabetes. 2021 Jan;70(1):29-38. doi: 10.2337/dbi19-0037.
• Saleheen D, Natarajan P, Armean IM, Zhao W, Rasheed A, Khetarpal SA, Won HH, Karczewski KJ, O'Donnell-Luria AH, Samocha KE, Weisburd B, Gupta N, Zaidi M, Samuel M, Imran A, Abbas S, Majeed F, Ishaq M, Akhtar S, Trindade K, Mucksavage M, Qamar N, Zaman KS, Yaqoob Z, Saghir T, Rizvi SNH, Memon A, Hayyat Mallick N, Ishaq M, Rasheed SZ, Memon FU, Mahmood K, Ahmed N, Do R, Krauss RM, MacArthur DG, Gabriel S, Lander ES, Daly MJ, Frossard P, Danesh J, Rader DJ, Kathiresan S. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature. 2017 Apr 12;544(7649):235-239. doi: 10.1038/nature22034.

Study record dates

Study Major Dates

• Study Start (Actual): October 20, 2023
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: September 29, 2023
• First Submitted That Met QC Criteria: October 6, 2023
• First Posted (Actual): October 12, 2023

Study Record Updates

• Last Update Posted (Estimated): November 20, 2023
• Last Update Submitted That Met QC Criteria: November 17, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Energy expenditure; Mitochondrial dysfunction; Appetite; Energy balance; Energy intake
• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Mitochondrial Diseases; Mitochondrial Myopathies
• Other Study ID Numbers: MITO-OB-RES

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No