Knockout mice lacking steroidogenic factor 1 are a novel genetic model of hypothalamic obesity.
Knockout (KO) mice lacking steroidogenic factor 1 (SF-1) exhibit a phenotype that includes adrenal and gonadal agenesis, impaired gonadotropin expression, and abnormalities of the ventromedial hypothalamic nucleus (VMH). Studies in rodents with lesions of the ventromedial hypothalamus have implicated the VMH in body weight regulation, suggesting that SF-1 KO mice may provide a genetic model of obesity. To prevent death, SF-1 KO mice were rescued with corticosteroid injections, followed by syngeneic adrenal transplants from wild-type (WT) littermates. Corticosterone and ACTH levels in WT and SF-1 KO mice were indistinguishable, documenting restoration of hypothalamic-pituitary-adrenal function. Although weights at earlier ages did not differ significantly from WT littermates, SF-1 KO mice were significantly heavier by 8 wk of age and eventually weighed almost twice as much as WT controls. Obesity in SF-1 KO mice predominantly resulted from decreased activity rather than increased food intake. Leptin was increased markedly, insulin was modestly elevated, and glucose was indistinguishable from WT mice. Although sex steroids in rodents affect weight, ovariectomy did not abolish the weight difference between WT and SF-1 KO mice. These SF-1 KO mice are a genetic model of late-onset obesity that may help elucidate the role of the VMH in weight regulation.
Majdic
Gregor
G
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Young
Morag
M
Gomez-Sanchez
Elise
E
Anderson
Paul
P
Szczepaniak
Lidia S
LS
Dobbins
Robert L
RL
McGarry
J Denis
JD
Parker
Keith L
KL
D000305:Adrenal Cortex Hormones / Q000097:blood; D000311:Adrenal Glands / Q000637:transplantation; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D004195:Disease Models, Animal; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; D007027:Hypothalamic Diseases / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics*; D010052:Ovariectomy; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone / Q000235:genetics* / Q000502:physiology*; D054339:Steroidogenic Factor 1; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*; D014697:Ventromedial Hypothalamic Nucleus / Q000502:physiology
D000305:Adrenal Cortex Hormones; D004268:DNA-Binding Proteins; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C515058:steroidogenic factor 1, mouse