The first inkling that lipid droplets were more than a cell’s beer belly came in the early 1990s. Cell biologist Constantine Londos of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, and colleagues identified a novel protein, perilipin, on lipid droplets in fat precursor cells. They also discovered that the cells, when they are stimulated to metabolize the droplet’s fat reserves, attach phosphate groups to this protein, suggesting that the cells precisely control the protein’s activity during the process. Whereas perilipin is found almost exclusively in the lipid droplets of fat cells, other researchers soon identified two structurally related proteins—adipose differentiationrelated protein (ADRP or adipophilin) and TIP47—associated with lipid droplets in other types of cells. These three became the charter members of the PAT (perilipin/ADRP/TIP47) family of lipid-droplet proteins, whose ranks have since swollen to include more than half a dozen molecules spanning mammals, flies, and amoeba. Researchers in the late 1990s also found a handful of proteins in yeast lipid bodies that are involved in lipid production and degradation.

But what really grabbed everyone’s attention were the mutant mice reported in 2000 by Lawrence Chan, an endocrinologist at Baylor College of Medicine in Houston, Texas. Lacking all perilipin thanks to a mutation introduced by Chan’s team, these rodents ate more food than normal but burned off two-thirds of the fat a typical mouse would have gained on the same diet.“Their metabolic rate is as if they are exercising all the time,” says Chan. These perilipin knockout mice were a “big breakthrough,” says Londos.(His team reported creating its own strain of such mice a few months after Chan’s paper was published.) Biochemical experiments by Londos’s teams revealed that under normal circumstances, perilipin coats lipid droplets in fat cells and guards their luscious store of lipids. When cells are starved or chemically induced to chew up their fat, an enzyme drapes a phosphate group on perilipin. This changes the protein’s shape, exposing the droplet’s neutral lipids to degradative enzymes. Finding a way to keep perilipin phosphorylated might prove to be a useful antiobesity therapy, suggests Chan. Londos, however, cautions that “the freewheeling fat breakdown in the perilipin knockout animals” leads to free fatty acids in the blood, a precursor to insulin resistance. The functions of ADRP and TIP47 on lipid droplets are less well understood. Knocking out ADRP in rodents produced mice that seem to be healthy; cells in the animals compensated by overproducing TIP47, says Londos. His group has since deactivated the genes for both ADRP and TIP47 in mice, but they haven’t published