Induced Caspase Activation and Fat Cell Apoptosis in Mice
The iDimerize Inducible Homodimerization technology is used to rewire the apoptosis pathway, and generate transgenic mice capable of conditional ablation of fat cells. Authors show that induced caspase-8 dimerization leads to systemic fat apoptosis. Paper: Pajvani et al. (2005) Nat. Med. 11(23):797–803.
Advantages of inducible dimerization
- Induction is systemic and reversible
- Lacks toxicity of constitutive models
- Induce at any developmental stage
- Remove ligand to study phenotype reversibility
FAT-ATTAC (fat apoptosis through targeted activation of caspase-8) mice with transgenes under the control of adipocytes-specific promoter were created. The catalytic domain of human caspase-8 was fused with a DmrB domain and a membrane-targeting domain. Caspase-8 dimerization was induced by intraperitoneal injections with B/B Homodimerizer ligand.*
FAT-ATTAC mice receiving injections of ligand showed a loss of white and brown fat, plus a marked drop in the adipocyte-specific markers adiponectin and resistin, within 7 days of treatment.
Mice lost 12% of their total mean body weight by the 10th week of treatment.
Phenotype recovered to normal state within 2 months of stopping treatment.
Studies are presented using iDimerize components. For complete experimental details please refer to the original publication. The optimal position and copy number of fusion domains varies per study and must be determined empirically.