Mice with a Targeted Deletion of the Type 2 Deiodinase Are Insulin Resistant and Susceptible to Diet Induced Obesity

Autor: Cyril Chou, John W. Harney, Aditi Kumar, P R Larsen, Elena Gianetti, Thuy Van-Tran, Ting Chen, Cristina Aguayo-Mazzucato, Waile Ramadan Md, Elaine P. Lunsford, Mirra Chung, Ann Marie Zavacki, Jorge Enrique Silva, Susan Bonner-Weir, Alessandro Marsili
Rok vydání: 2011
Předmět:
Male
Anatomy and Physiology
Mouse
medicine.medical_treatment
lcsh:Medicine
Adipose tissue
DIO2
Mice
0302 clinical medicine
Brown adipose tissue
lcsh:Science
Mice
Knockout
Thyroid
2. Zero hunger
0303 health sciences
Glucose tolerance test
Hormone Synthesis
Multidisciplinary
medicine.diagnostic_test
Reverse Transcriptase Polymerase Chain Reaction
Muscles
Animal Models
medicine.anatomical_structure
Adipose Tissue
Liver
Medicine
Research Article
medicine.medical_specialty
Deiodinase
Endocrine System
030209 endocrinology & metabolism
Biology
Iodide Peroxidase
Endocrine Subsystems
03 medical and health sciences
Model Organisms
Insulin resistance
Internal medicine
medicine
Animals
Obesity
Nutrition
030304 developmental biology
Endocrine Physiology
Gene Expression Profiling
Insulin
lcsh:R
Prohormones
Glucose Tolerance Test
medicine.disease
Hormones
Diet
Mice
Inbred C57BL
Endocrinology
Iodothyronine deiodinase
biology.protein
lcsh:Q
Insulin Resistance
Zdroj: PLoS ONE, Vol 6, Iss 6, p e20832 (2011)
PLoS ONE
ISSN: 1932-6203
Popis: 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. Methodology/Principal Findings After 6-weeks of HFD feeding D2KO mice gained 5.6% more body weight and had 28% more adipose tissue. Oxygen consumption (V02) 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/Significance 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.
Databáze: OpenAIRE
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