Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy.
We describe the generation and characterization of the first inducible 'fatless' model system, the FAT-ATTAC mouse (fat apoptosis through targeted activation of caspase 8). This transgenic mouse develops identically to wild-type littermates. Apoptosis of adipocytes can be induced at any developmental stage by administration of a FK1012 analog leading to the dimerization of a membrane-bound, adipocyte-specific caspase 8-FKBP fusion protein. Within 2 weeks of dimerizer administration, FAT-ATTAC mice show near-knockout levels of circulating adipokines and markedly reduced levels of adipose tissue. FAT-ATTAC mice are glucose intolerant, have diminished basal and endotoxin-stimulated systemic inflammation, are less responsive to glucose-stimulated insulin secretion and show increased food intake independent of the effects of leptin. Most importantly, we show that functional adipocytes can be recovered upon cessation of treatment, allowing the study of adipogenesis in vivo, as well as a detailed examination of the importance of the adipocyte in the regulation of multiple physiological functions and pathological states.
Pajvani
Utpal B
UB
Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
Trujillo
Maria E
ME
Combs
Terry P
TP
Iyengar
Puneeth
P
Jelicks
Linda
L
Roth
Kevin A
KA
Kitsis
Richard N
RN
Scherer
Philipp E
PE
D017667:Adipocytes / Q000187:drug effects / Q000473:pathology; D000273:Adipose Tissue / Q000187:drug effects / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053181:Caspase 8; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D004435:Eating; D004789:Enzyme Activation; D018149:Glucose Intolerance / Q000235:genetics; D007249:Inflammation / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D020738:Leptin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008060:Lipodystrophy / Q000378:metabolism*; D008070:Lipopolysaccharides; D051379:Mice; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism
C463061:AP20187; D007328:Insulin; D020738:Leptin; D008070:Lipopolysaccharides; D011993:Recombinant Fusion Proteins; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus