Bone Marrow Adipose Tissue as a New Parameter in Relation to Bone and Energy Metabolism in Obesity and Type 2 Diabetes Mellitus
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 45
- 试验地点
- 3
- 主要终点
- Change From Baseline in Mean L2-L4 Vertebral Bone Marrow Adipose Tissue Proton Density Fat Fraction
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 21 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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
- •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
- •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
结局指标
主要结局
Change From Baseline in Mean L2-L4 Vertebral Bone Marrow Adipose Tissue Proton Density Fat Fraction
时间窗: Baseline, 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 Index
时间窗: Baseline, 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 adaptation
时间窗: Baseline 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.
次要结局
- Change from baseline in metabolomic and lipidomic profile of bone marrow and plasma(Baseline and Week 24)
- Change From Baseline in Total Hip Bone Mineral Density(Baseline, Week 24, and Week 48)
- Change From Baseline in Lumbar Spine Bone Mineral Density(Baseline, Week 24, and Week 48)
- Change From Baseline in Femoral Neck Bone Mineral Density(Baseline, Week 24, and Week 48)
研究者
Vit Zikan
Head of the Metabolic Bone Centre and Principal Investigator
General University Hospital, Prague