Clinical trial

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

Recruiting now · Not applicable · 1 countries · Registry ID NCT07731438

Recruiting nowNot applicableInterventional

What this study is about

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.

A promising-looking record is not the same as confirmed eligibility. The study team must review the full criteria and current recruitment status.

Basic eligibility

Age21 Years to 55 Years

SexAll

Healthy volunteersAccepted

ConditionObesity

Full registry 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

Treatments and study arms

Caloric Restriction

Behavioral

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 outcomes

Change From Baseline in Mean L2-L4 Vertebral Bone Marrow Adipose Tissue Proton Density Fat FractionBaseline, Week 24, and Week 48

Vertebral bone marrow adipose tissue proton density fat fraction will be measured in the L2, L3, and L4 vertebral bodies using the mDIXON Quant MRI sequence. The mean value across the three vertebral bodies will be reported as a percentage.

Change From Baseline in Mean L2-L4 Vertebral Bone Marrow Adipose Tissue Unsaturation IndexBaseline, Week 24, and Week 48

The lipid composition of vertebral bone marrow adipose tissue will be measured in the L2, L3, and L4 vertebral bodies using proton magnetic resonance spectroscopy. A prespecified unsaturation index will be calculated from the unsaturated and total lipid signals. The mean value across the three vertebral bodies will be reported.

Change from baseline in BM-MSC and AT-MSC potency, differentiation, senescence, and metabolic adaptationBaseline and Week 24

Change from baseline to Week 24 in characteristics of bone marrow-derived mesenchymal stem cells (BM-MSCs) and adipose tissue-derived mesenchymal stem cells (AT-MSCs). Potency is assessed using the colony-forming unit-fibroblast (CFU-F) assay and proliferation rate. Osteogenic differentiation is assessed by alkaline phosphatase (ALP) activity and expression of ALPL and RUNX2; adipogenic differentiation is assessed by Nile Red staining and expression of ADIPOQ and LEP. Senescence is assessed by senescence-associated β-galactosidase activity and expression of p16INK4a and p21. Metabolic adaptation is assessed by extracellular flux analysis of mitochondrial respiration and glycolytic capacity and by insulin-signaling activation. For each parameter, the outcome is the change from baseline to Week 24, compared between BM-MSCs and AT-MSCs.