The study finds that a hormonal cocktail routinely used in the lab induces a key genetic switch in the transition from fat-cell precursors to full-blown fat, researchers at University of Michigan Life Sciences Institute report in the September Cell Metabolism.

"The body needs fat cells, both as a storage depot for fuel and as cells that sense hormonal and energy status and in response, secrete hormones that maintain whole-body energy balance," said study author Alan Saltiel. "However, you don't want too many, big fat cells. It's a careful balance, and many diseases are associated with either extreme."

Lipodystrophies are disorders characterized by fat deficiency, Saltiel said. While obesity and lipodystrophy represent opposite ends of the spectrum, both are characterized by other metabolic disorders, such as insulin resistance, he added.

The generation of fat begins before birth and continues throughout life. The first step in fat production involves proliferation of mesenchymal stem cells, followed by differentiation into fat cell precursors called preadipocytes. Mesenchymal stem cells can differentiate into various cell types, including bone, cartilage, muscle, nerve, and fat.

Fat precursor cells then migrate and proliferate at the site of fat production, where they differentiate further to become spherical adipocytes.

"The multistep process is regulated by numerous hormones and is accompanied by dramatic changes in cell shape and gene expression," Saltiel said.

The team identified changes in the activity of hundreds of genes during the transition to fat cells, including a critical switch in gene activity--from integrin alpha 5 to integrin alpha 6. That switch allows preadipocytes to cease dividing and cluster, forming bona fide fat cells.

Integrins are a superfamily of cell surface proteins that are involved in binding to the extracellular matrix, a meshwork of protein and fiber supports outside of cells that can influence their behavior.

"Fat cells require contact in order to stretch and change shape--becoming round cells able to accumulate lots of lipids," said Saltiel. "Many things happen in the generation of fat cells, the transition from one integrin to another is a crucial step."

While there is no evidence as yet to suggest that changes in integrin function underlie metabolic disorders, the fuller understanding of what happens in fat formation opens new avenues for exploration, he said.

cellmetabolism/