Molecular Biology

20050619
Pajvani UB1, Trujillo ME, Combs TP, Iyengar P, Jelicks L, Roth KA, Kitsis RN, Scherer PE.
https://doi.org/10.1038/nm1262

Researchers genetically modified mice to have an engineered protein, FKBPv, on the surface of fat cells. These mice grow up just like normal mice. However, upon administering an agent, at any time during their life, these mice lose almost all of their fat cells.

The protein FKBPv is part of a Caspase. Caspases are used to invoke programmed cell death, a natural occurring phenomena.

Caspase 8 exists in a cell as inactive pairs, and need to be triggered to become active. Caspases can be activated by the removal of the prodomain, in this case FKBPv. FKBPv does not normally dimerize, or join together in pairs, but can be caused to dimerize in the presence of an FK1012 analog. Inactive Caspase pairs then merge in the process and begin to sever peptide bonds of the cell.

Thus, the surface of the fat cells, having the FKBPv protein, can be dismantled using the dimerizing agent FK1012-analog. When this happens, the mouse loses fat cells and becomes a very lean mouse. Mice with the inducible fat loss were given the name FAT-ATTAC mice (fat apoptosis through targeted activation of caspase 8).

• Cell death, or apoptosis, is a normal and desirable part of metabolism. For example, apoptosis helps clear tissues of cells that have degenerated and are performing poorly. Caspases, are normally involved in the execution of apoptosis (see video). Researchers modified Caspase 8 to include the FKBPv protein. When the FKBPv protein is released from the caspase, the caspase becomes an active catabolic enzyme and breaks down the fat cell via the caspase cascade
• Life is largely made of proteins. Proteins are often made from subunits or domains, that get reused in different types of proteins. Caspase 8, like all caspases, has subunits p10 and p20. In its inactive state, caspases also have a prodomain such as FKBP. In the genetically modified mice, these subunits were fused with the modified FKBPv, which has a 1000 fold higher affinity for the dimerizing agent, FK1012-analog.
• After 2 weeks of administering the dimerizing agent, the blood stream showed near knockout levels of cell signaling proteins normally produced by fat cells, such as leptin and other adipokines.
• Compared to genetically modified mice used in previous studies, FAT-ATTAC mice can be better subjects for study because they start off disease free, because fat loss can be easily induced at any stage of development, and because they recover from the fat loss and become normal again.

(UNDER CONSTRUCTION)

— Marcos Reyes 2019/07/15 02:56