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Analysis of Metabolism Research


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Involvement of Vitamin D Receptor In Energy Metabolism: Regulation of Uncoupling Proteins

Today, obesity is a rising epidemic that leads to serious health problems. Obesity can be defined as a medical condition in which excess fat has accumulated. To help understand this epidemic, Wong et. al researched the role of vitamin D in energy metabolism. They created vitamin D receptor-null mutant mice (VDR-null) and compared the metabolic phenotypes with those of wild type mice. On a high-fat diet, VDR-null mice had less body fat and lower plasma triglycerides and cholesterol than wild-type mice. To understand why plasma lipids were increased, Wong et. al looked at brown fat and found the expression of uncoupling proteins (UCPs) was higher in VDR-null mice. Upregulation of UCPs, which alters ATP production by separating oxidative phosphorylation from ATP production, suggests higher energy expenditure and could help explain the lower plasma lipid levels. This research shows vitamin D does play a role in energy metabolism and could be useful in creating new ways to minimize body fat. Now, we may better understand how it may be possible to increase energy expenditure, helping to reduce the prevalence and incidence of obesity.

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Analysis of Metabolism Research

  1. 1. Kari E. Wong, Frances L. Szeto, Wenshuo Zhang, Honggang Ye, JuanKong, Zhongyi Zhang, Xiao Jian Sun, and Yan Chun Li 22 January 2009 Presented by: Cheryl Gregory Linh Pho
  2. 2. IntroductionMaterials & MethodsResults◦ Graphs & DiagramsConclusionFurther Research
  3. 3. What is the definition of obesity? ◦ The Excess of Body Fat What is the prevalence of obesity in the United States? ◦ In 2008, the obesity prevalence increased to 30% What are the associated health problems? ◦ Gangreen ◦ Type II Diabetes ◦ Cancer ◦ Cardiovascular Disease ◦ Hypertension
  4. 4. Energy Metabolism: the use of fuels to create energy to beused for work. D- Vitamin D-Receptor (VDR) knockout mice used to show 1alpha,25- D-Vitamin D, 1alpha,25-dihydroxyvitamin D-3, involvement inenergy metabolism VDR-null mice had decreased adiposity and lower plasmalipid levels VDR-null mice had increased Uncoupling Protein expression UCPs separate the process of oxidative phosphorylation from ATP production Overall, VDR knockout mice had higher energy expenditure
  5. 5. Animal Treatment◦ Created Vitamin D Receptor (VDR) knockout mice◦ Placed the mice on two diets: High Fat & High Calcium High Fat (HF) Mice were place on HCa for 4 months, then switch to HF diet Mice were weighed and monitored weekly End, animals were killed: plasma and adipose tissue were harvested High Calcium (HCa) To normalize the plasma calcium level Used as a control
  6. 6. Assessed Plasma Parameters Using Test Kits◦ Used to determine levels of: Triglycerides Cholesterol Adipokine Thyroid Stimulating Hormone
  7. 7. Observed the Histology◦ Cultured White Adipose Tissue (WAT) Storage depot of the body Stores excess energy in triglyceride form Releases signals indicating the body’s energy state◦ Cultured Brown Adipose Tissue (BAT) Regulates thermogenesis Expresses uncoupling protein Separate oxidative phosphorylation from ATP production◦ Adipose tissues were: Processed and Stained
  8. 8. Assayed Fatty Acid B-oxidation◦ Isolated white adipose tissue from male mice◦ Measure the B-oxidation using tritiated palmitateAnalyzed Northern Blot of total RNA◦ Show the total cellular RNA extractionPerformed RT-PCR◦ Strands of DNA extracted from the mice◦ To analyze protein and hormone mRNA levels
  9. 9. Weight Difference•VDR (-/-) mice weighed sig. less than WT on both high-Ca++ andhigh-fat diet•Gender difference: Male mice more protected against weight gain MALE FEMALE•VDR-null mice had a decrease in adiposity •Lower # of adipocytes •Smaller size
  10. 10. ADIPOSE DIFFERENCE C. White Adipose Tissue•VDR-null mice on the high-fatdiet had smaller adipocytes & lessBAT•The BAT accumulated fewer lipids& had better cell morphology•VDR-null had less adipose tiss. inall fat depots•More dramatic difference betweenmales D. Brown Adipose Tissue
  11. 11. ENZYME LEVELSMALE MICE ONLYFatty acid synthase higher in VDR-null mice on HCa diet butdiff. not as big on HF dietMalonyl-CoA Dehydrogenase and Stearoyl CoA-Desaturase-1were not significantly differentLPL lower in mutant mice on HF dietPPAR-gamma higher in mutant mice on HCa diet
  12. 12. Fatty Acid SynthaseLipoprotein LipasePPAR - Gamma
  13. 13. ADIPOKINE LEVELSLeptin: lower in VDR-null mice on HCa diet and much lower inHF dietAdiponectin: On the HF diet, mRNA expression was reduced inWT miceResistin: no difference between mice on HCa or HF
  14. 14. PLASMA LIPID LEVELS Triglyceride Female: No difference in plasma triglycerides, cholesterol, free-fatty acids on both diets Male: VDR-null mice had lower triglycerides and cholesterol on both diets (NOT DUE TO: food intake, increased physical activity, decreased intestinal absorption, or increased thyroid stimulating hormone levels) Top Image: Bottom Image:
  15. 15. B-Oxidation•Carnitine palmitolytransferase II (CPTII) protein is responsible fortransporting fatty acids into the mitochondrial matrix• CPTII expression higher in the WAT of VDR-null mice CPTII mRNA increased too•Increased rate of B-oxidation in adipocytes helps explain increased levelof lipids in VDR-null mice•Suggests more fatty acids are oxidized, which leads to higher basalenergy expenditure
  16. 16. UNCOUPLING PROTEINS UCP expression in BAT was increased in VDR-null mice, the difference washigher when mice where on the HF diet The expression of the B-adrenergic receptor 3 was unchanged B/c AdrB3 is known to directly regulate UCPs Suggests Vit D directly regulates UCPs Double Check: treated VDR-null and WT mice with 1,25(OH)2D3 As expected, found no effect on VDR-null cells VDR transcript was missing in VDR-null mice Vit D directly targets fat
  17. 17. High Calcium Diet High Fat Diet
  18. 18. VDR-Knockout Phenotype:◦ Lower fat mass & lower plasma lipid levelsVit D-Receptor is involved in EnergyMetabolism◦ VDR-null mice had higher energy expenditure as shown by the indirect calorimetric measurementPossible Mechanism for this involvement:◦ Vit D directly downregulates UCP expression in BATThis Alteration of E Metabolism explains:◦ The lower adiposity and lower plasma lipid profile
  19. 19. Studies should look at VDR in other body tissues tofurther understand its role in total body energymetabolism.Also, look at the difference btwn in vivo and in vitroBy better understanding total body energymetabolism, we may be one step closer to helpingunderstand and treat obesity.May eventually, lead to a way to alter energymetabolism
  20. 20., Kari. E. “Involvement of the vitamin D receptor in energy metabolism: regulation of uncoupling proteins.” Division of Biological Sciences. Dept.of Medicine Metabolism and Nutrition. Chicago, Illinois. 22 Jan.
  21. 21. Question & Answer