Fat cells are known for their energy storing capacity, but have also other important functions related to padding of the skeleton, thermal insulation and the control of whole body metabolism. The way lipids are stored changes drastically during ageing, with a general trend of increased adiposity. Especially lipids that accumulate ectopically in liver and muscle are associated with glucose intolerance, insulin resistance and hypertension, while fat cell accumulation in thymus and bone marrow correlate with the decline in adoptive immunity.
Especially as the expansion of bone marrow fat cells occurs at the cost of bone tissue volume, osteoporosis has been highlighted as the “obesity of the bone”. Osteoblasts, the cells which are involved in the life-long process of building bone, and fat cells originate from the same precursors, implicating that aging might cause a shift in the differentiation of stem cells from osteoblasts towards fat cells.
We used a human stem cell model system to study the formation of fat cells and osteoblasts in culture, and determined functional elements in the genome that control the dynamics in gene expression linked to cellular differentiation. Irrespective of stem cells are derived from bone marrow or adipose tissue, there are fewer hurdles in the path of becoming an osteoblast compared to the investments necessary for fat cell specification, both on level of gene expression and chromatin structure at the regulatory elements in the genome. We identified a set of stem cell factors that set the transcriptional stage for activating the osteogenic path while at the same time suppressing the fat cell lineage, explaining the close relationship of osteoblast and stem cells. The presence of such a transcriptional network actively suppressing fat cell formation highlights that fat cell differentiation is not by default the path of least resistance. However, conditions such as ageing and obesity that affect the integrity of the network are therefore likely to remove the brake which in turn gives rise to fat formation and lipid accumulation.