Bone Marrow Adipose Tissue in Relation to Bone and Energy Metabolism in Obesity and Type 2 Diabetes Mellitus

Official title

Bone Marrow Adipose Tissue as a New Parameter in Relation to Bone and Energy Metabolism in Obesity and Type 2 Diabetes Mellitus

Overview

This interventional study is part of a broader research project entitled "Bone Marrow Adipose Tissue in Relation to Bone and Energy Metabolism in Obesity and Type 2 Diabetes Mellitus." The broader project includes both a cross-sectional study evaluating bone marrow adipose tissue and bone marrow mesenchymal stem cells in people with different metabolic and bone disorders and the present dietary intervention study. The interventional study investigates whether caloric restriction changes bone marrow adipose tissue, bone health, whole-body metabolism, and the molecular and cellular characteristics of bone marrow mesenchymal stem cells in obese non-diabetic premenopausal women. A group of lean healthy premenopausal women will serve as a comparison group. Participants in the intervention group will undergo an eight-week formula-based very-low-calorie diet using Cambridge Weight Plan products, providing approximately 2.5-3.35 MJ (600-800 kcal) per day, followed by a dietary weight-maintenance phase. Participants will receive nutritional counselling, and dietary adherence, body weight, physical activity, and clinical status will be monitored during scheduled study visits. Clinical and laboratory assessments will be conducted at baseline and after 2, 6, and 12 months. Assessments will include magnetic resonance imaging and proton magnetic resonance spectroscopy of the lumbar spine to measure the amount and lipid composition of vertebral bone marrow adipose tissue. Bone mineral density and body composition will be measured using dual-energy X-ray absorptiometry, with particular attention to bone mineral density at the total hip and femoral neck. Additional measurements will include body weight, waist and hip circumference, body composition, physical activity, and fasting blood tests evaluating bone turnover, glucose and lipid metabolism, inflammatory markers, hormones, and adipokines. Bone marrow aspirates and abdominal subcutaneous adipose tissue biopsies will be obtained at baseline and after six months. Bone marrow-derived and adipose tissue-derived mesenchymal stem cells will be examined for changes in cellular composition, gene-expression profiles, metabolic activity, oxidative stress, differentiation capacity, and senescence-related characteristics. Single-cell RNA sequencing will be used to characterize specific bone marrow mesenchymal stem cell subpopulations. Bone marrow plasma and other biological samples will also undergo metabolomic, lipidomic, and proteomic profiling using high-resolution mass spectrometry. These analyses will be used to identify extracellular molecules and molecular patterns associated with glucose and lipid metabolism, inflammation, cellular senescence, and the response to caloric restriction. The study aims to determine whether diet-induced weight loss can improve the bone marrow microenvironment and modify vertebral bone marrow fat, bone parameters, and the metabolic and senescent phenotype of mesenchymal stem cells. The findings may help identify imaging, cellular, and molecular markers of obesity-related bone fragility.

Detailed description

Bone marrow contains not only blood-forming cells but also adipose tissue and mesenchymal stromal cells that can develop into bone-forming cells or fat cells. Bone marrow adipose tissue (BMAT) is increasingly recognized as an active component of the bone marrow environment that may influence bone remodeling, skeletal strength, and whole-body metabolism. In people with obesity, fracture risk may be increased even when bone mineral density is normal or elevated. This suggests that changes in bone quality, bone marrow fat, and the function of bone marrow mesenchymal stromal cells (BM-MSCs) may contribute to obesity-related bone fragility.

The present application describes only the interventional study, which is part of a broader research project entitled "Bone Marrow Adipose Tissue in Relation to Bone and Energy Metabolism in Obesity and Type 2 Diabetes Mellitus." The broader project also includes a cross-sectional study evaluating BMAT and BM-MSC characteristics in participants with different metabolic and skeletal conditions. However, the cross-sectional component is not included in this application and is therefore not described further here.

The interventional study will investigate whether weight loss induced by caloric restriction modifies the bone marrow environment in obese non-diabetic premenopausal women. Lean healthy premenopausal women will serve as a comparison group. Participants in the intervention group will follow a formula-based very-low-calorie diet using Cambridge Weight Plan formula products, providing approximately 2.5-3.35 MJ (600-800 kcal) per day for 8 weeks. This will be followed by a 4-month low-calorie diet phase and subsequently by a weight-maintenance phase. Participants will receive nutritional counselling, and dietary adherence, body weight, physical activity, and clinical status will be monitored during scheduled study visits.

The study will evaluate whether the dietary intervention changes the amount and lipid composition of vertebral BMAT and whether these changes are associated with changes in bone and metabolic parameters. Vertebral BMAT will be assessed in the lumbar spine using magnetic resonance imaging and proton magnetic resonance spectroscopy. These methods allow non-invasive measurement of bone marrow fat content and assessment of its saturated and unsaturated lipid fractions.

Bone mineral density and body composition will be assessed using dual-energy X-ray absorptiometry, with particular attention to the total hip and femoral neck. Abdominal adipose tissue distribution will be evaluated using magnetic resonance imaging. Blood samples will be used to assess glucose and lipid metabolism, bone turnover, inflammatory markers, hormones, and adipokines.

Bone marrow aspirates and subcutaneous adipose tissue samples will be collected at baseline and after 6 months to study BM-MSCs and adipose tissue-derived mesenchymal stromal cells. Laboratory analyses will examine their cellular composition, ability to differentiate into bone-forming and fat cells, metabolic activity, oxidative stress, cellular senescence, gene-expression profiles, and other molecular characteristics. Single-cell RNA sequencing will be used to characterize specific BM-MSC subpopulations and identify transcriptional profiles associated with metabolic activity and cellular senescence.

Bone marrow plasma and other biological samples will also undergo metabolomic, lipidomic, and proteomic profiling to identify molecules associated with the bone marrow microenvironment, metabolic status, bone health, and the response to caloric restriction.

By integrating imaging, clinical, biochemical, cellular, and molecular data, the interventional study aims to determine whether diet-induced weight loss can improve the bone marrow environment and modify factors associated with obesity-related bone fragility. The findings may support the identification of new imaging, cellular, and molecular biomarkers of bone health and provide a scientific basis for future strategies to prevent or treat metabolic bone complications associated with obesity.

Interventions

• Behavioral Caloric Restriction
  Participants will follow a formula-based very-low-calorie diet (Cambridge Weight Plan) providing approximately 600-800 kcal per day (2.5-3.35 MJ per day) for 8 weeks. This will be followed by a 4-month low-calorie diet phase and subsequently by a weight-maintenance phase. Participants will receive nutritional counselling, and dietary adherence, body weight, physical activity, and clinical status will be monitored during scheduled study visits.

Primary outcome measures

• Change From Baseline in Mean L2-L4 Vertebral Bone Marrow Adipose Tissue Proton Density Fat Fraction [Time frame: Baseline, Week 24, and Week 48]
• Change From Baseline in Mean L2-L4 Vertebral Bone Marrow Adipose Tissue Unsaturation Index [Time frame: Baseline, Week 24, and Week 48]
• Change from baseline in BM-MSC and AT-MSC potency, differentiation, senescence, and metabolic adaptation [Time frame: Baseline and Week 24]

Secondary outcome measures (4)

• Change from baseline in metabolomic and lipidomic profile of bone marrow and plasma [Time frame: Baseline and Week 24]
• Change From Baseline in Total Hip Bone Mineral Density [Time frame: Baseline, Week 24, and Week 48]
• Change From Baseline in Lumbar Spine Bone Mineral Density [Time frame: Baseline, Week 24, and Week 48]
• Change From Baseline in Femoral Neck Bone Mineral Density [Time frame: Baseline, Week 24, and Week 48]

Eligibility criteria

Interventional Study: Effect of Caloric Restriction on BMAT/BM-MSCs Phenotype

Inclusion criteria

• Premenopausal women and age-eligible men assigned to either the obese intervention group or the lean control group
• Obese intervention group:
• Body mass index (BMI) of 30-42 kg/m²
• Fasting plasma glucose less than 6.4 mmol/L
• Age 25-55 years
• Lean control group:
• BMI of 19-25 kg/m²
• Fasting plasma glucose less than 6.4 mmol/L
• Age 25-50 years

Exclusion criteria

• Diabetes mellitus
• Secondary osteoporosis
• History of severe neuropathic disease
• Hyperparathyroidism
• Hyperthyroidism
• Immobilization
• Alcoholism
• Chronic gastrointestinal disease
• Significant chronic renal impairment, including any of the following:
• Chronic kidney disease
• Serum creatinine greater than 110 µmol/L
• Estimated glomerular filtration rate (eGFR) less than 1 mL/s/1.73 m²
• Proteinuria
• Diabetic nephropathy
• Chronic hepatic impairment
• Unstable cardiovascular disease
• Uncontrolled hypertension
• Current or recent use of any of the following medications:
• Bisphosphonates
• Estrogen
• Denosumab
• Gonadotropin-releasing hormone (GnRH) analogs
• Glucocorticoids at a dose equivalent to at least 5 mg of prednisone daily for at least 1 month
• Phenytoin
• Thiazolidinediones
• Insulin
• Adrenal or anabolic steroids
• Anticonvulsants
• Anticoagulants
• Pharmacological doses of vitamin D or vitamin A supplements
• Contraindications to magnetic resonance imaging (MRI), including:
• Pacemaker
• Metallic implants incompatible with MRI
• Claustrophobia

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Basic science

Study locations

Czechia · 3 centers

• General University Hospital in Prague — Prague
• Institute of Endocrinology, Prague, a state-funded organization established by the Ministr — Prague
• Institute of Physiology of the Czech Academy of Sciences — Prague

Publications

• Tencerova M, Frost M, Figeac F, Nielsen TK, Ali D, Lauterlein JL, Andersen TL, Haakonsson AK, Rauch A, Madsen JS, Ejersted C, Hojlund K, Kassem M. Obesity-Associated Hypermetabolism and Accelerated Senescence of Bone Marrow Stromal Stem Cells Suggest a Potential Mechanism for Bone Fragility. Cell Rep. 2019 May 14;27(7):2050-2062.e6. doi: 10.1016/j.celrep.2019.04.066. PMID 31091445

Identifiers

NCT: NCT07731438 · NU23-01 00125

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗