Childhood obesity has increased precipitously to the point that almost 20% of children between the ages of 2 and 19 have been diagnosed with obesity. While obesity is a complex metabolic disorder, one contributing factor is diet, particularly a diet high in fat. Among many problems associated with diet-induced obesity, the impact on skeletal health is often overlooked. In addition to increased stress on the skeleton due to excess weight, obesity also disrupts the endocrine and immune systems that, in turn, can secondarily alter skeletal growth. Obesity during the early years of childhood is particularly detrimental because the skeleton is highly sensitive to damaging changes during a critical early period of development.

The process by which bones grow in length is called endochondral ossification and occurs in the cartilaginous regions of long bones called the growth plate. During endochondral ossification, growth plate chondrocytes proliferate, enlarge, differentiate, and mineralize to elongate bones. One of the main modulators of these processes is insulin-like growth factor-1 (IGF-1), which has both endocrine and paracrine/autocrine functions. Paradoxically, children with obesity have normal to low levels of endocrine IGF-1 despite exhibiting accelerated bone growth.

The objective of this dissertation is to determine how excess dietary fat alters IGF-1 bioactivity in the growth plate. The overall hypothesis is that a high-fat diet has both direct and indirect effects on IGF-1 stimulated growth plate activity. The first aim of this dissertation is to determine how a high-fat diet directly alters IGF-1 activity and cell proliferation in the growth plate where we hypothesize that a high-fat diet will increase direct IGF-1 activity in growth plate chondrocytes to accelerate postnatal bone elongation. The second aim of this dissertation is to determine the indirect mechanisms by which a high-fat diet alters IGF1-stimulated growth plate activity. We hypothesize that a high-fat diet has secondary effects on IGF-1 signaling through its effects on IGF binding proteins and inflammatory cytokines.

These experiments are important for understanding how early environmental exposures, such as diet, can impact bone growth in a way that has lasting effects into adulthood. Elucidating the ways in which excess dietary fat can alter IGF-1 activity in the growth plate in both a direct and indirect function can lead to a more targeted approach in identifying children at high risk of developing obesity before problems escalate to adulthood.