The Bone-Fat-Pancreas Axis in Children
Condition: Bone Mineral Density; Body Fat Distribution; Insulin Homeostasis
Study type: Observational

Summary: 
      The overarching hypothesis of this proposal is that obesity and positive energy balance in
      children promote both low bone mass accrual and risk for diabetes through events that are
      mechanistically associated and that involve bone as an endocrine organ. Recent studies
      conducted in mice have uncovered the presence of a unique "bone-fat-pancreas" axis that
      regulates energy homeostasis, coordinates energy partitioning between bone and adipose
      tissue, and impacts insulin sensitivity. The adipocyte-derived hormone leptin, elevated
      levels of which reflect both adiposity and positive energy balance, inhibits bone formation
      via sympathetic activation. Decreased bone formation in turn depresses insulin sensitivity
      and secretion via decreased production of undercarboxylated osteocalcin (unOC), a novel
      bone-derived hormone. Although data from mice are compelling, this novel pathway has not been
      widely tested in humans. Sparse data from adult men and women suggest that this axis is
      active in humans, and that unOC is regulated in part by exercise. No data are available
      regarding the bone-fat-pancreas axis in children. Because the foundations of body composition
      trajectories and metabolic "programming" are established early in the life course, childhood,
      particularly during early stages of growth and development, is an especially salient time
      period for evaluating the bone-fat-pancreas axis. With this pilot grant, we propose to gather
      evidence that these interrelationships exist in children. The data from this project will be
      used to prepare an NIH R01 proposal to conduct a lifestyle-based intervention in children
      aimed both at reducing risk for osteoporosis and type 2 diabetes, and at identifying the role
      of unOC in metabolism and tissue partitioning.

      Hypothesis 1: Obesity and positive energy balance in children decrease bone mass via elevated
      leptin.

      Specific Aim 1: Determine the association between bone mass by DXA and serum leptin
      concentration in lean and obese children. We predict that body weight will be positively
      associated with bone mass, but that at any given body weight, bone mass will be lower in
      obese children, and that this difference will be explained by leptin.

      Hypothesis 2: Leptin-mediated suppression of unOC decreases insulin secretion through action
      on the β-cell, and decreases insulin sensitivity by inhibiting secretion of adiponectin from
      adipose tissue.

      Specific Aim 2: Determine the association between insulin secretion during oral glucose
      tolerance test (OGTT; from C-peptide modeling) and serum unOC in lean and obese children.
      Determine the association between insulin sensitivity during OGTT (derived from mathematical
      modeling) and serum unOC in lean and obese children. Obese children are less insulin
      sensitive, and in an absolute sense, secrete more insulin. However, we predict that at any
      given degree of insulin sensitivity, insulin secretion will be lower in obese children, and
      that this difference will be explained by unOC. unOC will be inversely associated with serum
      leptin, and will be positively associated with adiponectin and insulin sensitivity.

      Hypothesis 3: Physical activity prevents leptin suppression of unOC and partitions energy
      towards bone mineral at the expense of bone marrow adipose tissue.

      Specific Aim 3: Assess the interrelationships among physical activity using accelerometry,
      bone mass using DXA and bone marrow adipose tissue using magnetic resonance imaging. We
      predict that at any given level of serum leptin, active children will have greater unOC.
      Further, we predict that at any given body weight, active children will have greater bone
      mass and lesser bone marrow adipose tissue than inactive children.
    


Observational model: Cohort
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Healthy European American (Caucasian) girls aged five to ten years
      
Biospecimen description: 
      Samples will be labeled with the study protocol number, a unique identifier, and the date of
      collection.

      Specimens will be obtained by the nursing staff at the PCIR. The PCIR processing lab will
      process the samples, which will then be stored in a locked freezer at -80oC in the restricted
      access CNRU Metabolism Core lab (WEBB 337).
    
Keywords: osteocalcin; insulin; body composition; bone mineral density; Evaluate the effect of osteocalcin on bone mineral density; Evaluate the effect of osteocalcin on body fat distribution; Evaluate the effect of osteocalcin on insulin homeostasis