title: Mice with a targeted deletion of the type 2 deiodinase are insulin resistant and susceptible to diet induced obesity.
abstract: BACKGROUND
  The type 2 iodothyronine deiodinase (D2) converts the pro-hormone thyroxine into T3 within target tissues. D2 is essential for a full thermogenic response of brown adipose tissue (BAT), and mice with a disrupted Dio2 gene (D2KO) have an impaired response to cold. BAT is also activated by overfeeding.
  
  
  RESULTS
  After 6-weeks of HFD feeding D2KO mice gained 5.6% more body weight and had 28% more adipose tissue. Oxygen consumption (V0(2)) was not different between genotypes, but D2KO mice had an increased respiratory exchange ratio (RER), suggesting preferential use of carbohydrates. Consistent with this, serum free fatty acids and β-hydroxybutyrate were lower in D2KO mice on a HFD, while hepatic triglycerides were increased and glycogen content decreased. Neither genotype showed glucose intolerance, but D2KO mice had significantly higher insulin levels during GTT independent of diet. Accordingly, during ITT testing D2KO mice had a significantly reduced glucose uptake, consistent with insulin resistance. Gene expression levels in liver, muscle, and brown and white adipose tissue showed no differences that could account for the increased weight gain in D2KO mice. However, D2KO mice have higher PEPCK mRNA in liver suggesting increased gluconeogenesis, which could also contribute to their apparent insulin resistance.
  
  
  CONCLUSIONS
  We conclude that the loss of the Dio2 gene has significant metabolic consequences. D2KO mice gain more weight on a HFD, suggesting a role for D2 in protection from diet-induced obesity. Further, D2KO mice appear to have a greater reliance on carbohydrates as a fuel source, and limited ability to mobilize and to burn fat. This results in increased fat storage in adipose tissue, hepatic steatosis, and depletion of liver glycogen in spite of increased gluconeogenesis. D2KO mice are also less responsive to insulin, independent of diet-induced obesity.
authors.affiliation: Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Marsili
authors.forename: Cristina
authors.initials: C
authors.lastname: Aguayo-Mazzucato
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.forename: Aditi
authors.initials: A
authors.lastname: Kumar
authors.forename: Mirra
authors.initials: M
authors.lastname: Chung
authors.forename: Elaine P
authors.initials: EP
authors.lastname: Lunsford
authors.forename: John W
authors.initials: JW
authors.lastname: Harney
authors.forename: Thuy
authors.initials: T
authors.lastname: Van-Tran
authors.forename: Elena
authors.initials: E
authors.lastname: Gianetti
authors.forename: Waile
authors.initials: W
authors.lastname: Ramadan
authors.forename: Cyril
authors.initials: C
authors.lastname: Chou
authors.forename: Susan
authors.initials: S
authors.lastname: Bonner-Weir
authors.forename: Philip Reed
authors.initials: PR
authors.lastname: Larsen
authors.forename: Jorge Enrique
authors.initials: JE
authors.lastname: Silva
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Zavacki
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D004032:Diet; D020869:Gene Expression Profiling; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009132:Muscles / Q000378:metabolism; D009765:Obesity / Q000209:etiology* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D007453:Iodide Peroxidase; D000097564:Iodothyronine Deiodinase Type II