Vincent Lowe 994907981 BIO407
Is Obesity a Disease ? <ul><li>Obesity = Energy Balance </li></ul><ul><li>+ imbalance = fat storage </li></ul><ul><li>- im...
Does Obesity have a Genetic Basis ? <ul><li>1977 NHLBI twin study  </li></ul><ul><ul><li>80% correlation of BMI in MZ </li...
<ul><li>A little background information </li></ul>
What does it mean to be Obese ? <ul><li>Body Mass Index </li></ul><ul><ul><li>Cheap and efficient </li></ul></ul><ul><ul><...
Leptin <ul><li>Protein signaling hormone in fat tissue  </li></ul><ul><li>Stimulates hypothalamus to increase or decrease ...
Insulin <ul><li>Protein signaling hormone secreted from pancreas  </li></ul><ul><li>Glucose balance and glycogen conversio...
The Brain & Behaviour <ul><li>Control of the homostatic levels via Leptin + insulin </li></ul><ul><li>2 types of tissues <...
<ul><li>Results & Discussion </li></ul>
Creating the TG and TGKO mice
 
Obesity & Hyperlipidemia <ul><li>KO mice had large increase in body weight , almost 1.5X compared to WT </li></ul><ul><li>...
Adipocyte Differentiation  <ul><li>KO mice store more fat tissues </li></ul><ul><li>KO adipocytes less differentiated  </l...
Energy Imbalance and Metabolism <ul><li>KO mice had increased consumption as well as increased metabolism </li></ul><ul><l...
Insulin and Glucose intolerance <ul><li>Glucose Tolerance test </li></ul><ul><li>Insulin Tolerance test </li></ul><ul><li>...
Leptin Resistance <ul><li>KO had radically affected Leptin and insulin system  </li></ul><ul><li>Leptin Tolerance test </l...
Protection from induced HFD obesity  <ul><li>WT had  greater body weight than the TG/TG mice on both Chow and HFD conditio...
<ul><li>Conclusions </li></ul>
Relevance & Human twin studies <ul><li>Jamshidi Et al. </li></ul><ul><ul><li>Sh2b gene is associated with serum leptin and...
Relevance & Human twin studies
Places to expand on further research  <ul><li>Neuronal expression is important , but what is the exact role of Pheripheral...
Critiques <ul><li>Sex differences </li></ul><ul><li>Scope of paper very board  </li></ul><ul><li>Non representative popula...
<ul><li>Questions ? Comments ? </li></ul>
SH2B, and SH2 adaptor family <ul><li>SH2B is an adaptor protein </li></ul><ul><li>One of 3 in the Src homology 2 family  <...
Possible pharmaceutical action fdfd
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Obesity

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neuronal expression of sh2b in regulating energy balance

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  • Obesity

    1. 1. Vincent Lowe 994907981 BIO407
    2. 2. Is Obesity a Disease ? <ul><li>Obesity = Energy Balance </li></ul><ul><li>+ imbalance = fat storage </li></ul><ul><li>- imbalance = fat loss </li></ul><ul><li>Risks associated with obesity </li></ul><ul><li>Type 2 diabetes </li></ul><ul><li>Cardiovascular diseases </li></ul><ul><li>Lowered immune function </li></ul><ul><li>Non Hodgkin's lymphoma </li></ul><ul><li>Hypertension </li></ul><ul><li>Social Costs </li></ul><ul><li>Absenteeism </li></ul><ul><li>Strain on medical system </li></ul>But is it a Disease ?
    3. 3. Does Obesity have a Genetic Basis ? <ul><li>1977 NHLBI twin study </li></ul><ul><ul><li>80% correlation of BMI in MZ </li></ul></ul><ul><ul><li>60% in DZ and 30% from shared environment </li></ul></ul><ul><li>Thrifty Gene Hypothesis </li></ul><ul><ul><li>Food sources were inconsistent and varied </li></ul></ul><ul><ul><li>Evolutionary beneficial to eat more </li></ul></ul><ul><li>International journal of Obesity </li></ul><ul><ul><li>23 genes responsible for single gene mutations causing 176 obesity cases </li></ul></ul><ul><ul><li>244 genes seen in animal models </li></ul></ul><ul><ul><li>400+ genes awaiting further reasearch using positional and qualitative gene analysis </li></ul></ul>
    4. 4. <ul><li>A little background information </li></ul>
    5. 5. What does it mean to be Obese ? <ul><li>Body Mass Index </li></ul><ul><ul><li>Cheap and efficient </li></ul></ul><ul><ul><li>Overweight if <25 and >29.9 </li></ul></ul><ul><ul><li>Obese if <30 </li></ul></ul><ul><ul><li>Does not account for muscle % and bone mass </li></ul></ul><ul><li>Duel Energy X-ray Analysis </li></ul><ul><ul><li>Differential imaging to determine different tissues like fat and bone </li></ul></ul><ul><li>Formal Terms </li></ul><ul><ul><li>Hyperlipidemia , hyperphagia … </li></ul></ul>
    6. 6. Leptin <ul><li>Protein signaling hormone in fat tissue </li></ul><ul><li>Stimulates hypothalamus to increase or decrease appetite </li></ul><ul><li>Inhibits </li></ul><ul><ul><li>Neuropeptide Y (NPY) </li></ul></ul><ul><ul><li>Agouti related peptide (Agrp) </li></ul></ul><ul><li>Stimulates </li></ul><ul><ul><li>Pre-opiomelanocortin (POMC) </li></ul></ul><ul><ul><li>A-melanocyte stimulating hormone ( α- MSH) </li></ul></ul><ul><li>Errors in communication </li></ul>
    7. 7. Insulin <ul><li>Protein signaling hormone secreted from pancreas </li></ul><ul><li>Glucose balance and glycogen conversion </li></ul><ul><li>Insulin cycle </li></ul><ul><ul><li>Blood glucose rises </li></ul></ul><ul><ul><li>Insulin secretion </li></ul></ul><ul><ul><li>Stimulations production of glycogen synthase </li></ul></ul><ul><ul><li>Blood glucose drops and homeostasis is returned </li></ul></ul><ul><li>Errors in communication </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Insulin resistance and hyperglycemia </li></ul></ul>
    8. 8. The Brain & Behaviour <ul><li>Control of the homostatic levels via Leptin + insulin </li></ul><ul><li>2 types of tissues </li></ul><ul><ul><li>Neuronal tissue </li></ul></ul><ul><ul><li>Arcuate nucleus , Lateral Hypothalamus & ventromedial hypothalamus </li></ul></ul><ul><ul><li>Hunger / Full loop </li></ul></ul><ul><ul><li>Peripheral Tissue </li></ul></ul><ul><ul><li>Current state of energy reserves and homeostatic levels </li></ul></ul><ul><ul><li>Adipose tissue , liver , pancreases , stomach ,ect. </li></ul></ul><ul><li>Working in conjunction to control motivation and behavior </li></ul>
    9. 9. <ul><li>Results & Discussion </li></ul>
    10. 10. Creating the TG and TGKO mice
    11. 12. Obesity & Hyperlipidemia <ul><li>KO mice had large increase in body weight , almost 1.5X compared to WT </li></ul><ul><li>KO also had high FFA & TG levels </li></ul><ul><li>KO mice had large fatty livers </li></ul><ul><li>Tgko mice had similar weight , TG & FFA levels to WT </li></ul>
    12. 13. Adipocyte Differentiation <ul><li>KO mice store more fat tissues </li></ul><ul><li>KO adipocytes less differentiated </li></ul><ul><li>and larger size </li></ul><ul><li>KO mice had reduced differentiated preadipocytes </li></ul><ul><li>TGKO had less fat and smaller fat cells than WT </li></ul><ul><li>3T3-L1 preadipocytes , require Sh2b protein from day 6 onward to create fat cells </li></ul>
    13. 14. Energy Imbalance and Metabolism <ul><li>KO mice had increased consumption as well as increased metabolism </li></ul><ul><li>KO mice ate more food than WT and TGKO , however net positive balance still present </li></ul><ul><li>WT , TG and TGKO mice had similar metabolilic rates </li></ul><ul><li>TGKO rescue worked and neuronal SH2b is sufficient to return metabolism and appetite </li></ul>
    14. 15. Insulin and Glucose intolerance <ul><li>Glucose Tolerance test </li></ul><ul><li>Insulin Tolerance test </li></ul><ul><li>KO mice had 2x blood glucose level </li></ul><ul><li>26X plasma insulin level </li></ul><ul><li>Decreased reduction of blood glucose and longer onset to return to homeostasis </li></ul><ul><li>TGKO had similar results to wild type </li></ul><ul><ul><li>No peripheral sh2b in pancreas </li></ul></ul><ul><li>Reduction of efficiency of insulin system </li></ul>
    15. 16. Leptin Resistance <ul><li>KO had radically affected Leptin and insulin system </li></ul><ul><li>Leptin Tolerance test </li></ul><ul><li>Immunoblotting and immunoprecitating of hypothalamus for both phosphoralated and active stat3 </li></ul><ul><li>tgKO showed almost exactly the same levels of expression as WT </li></ul><ul><li>Real time PCR of AGRP ,NPY and POMC </li></ul><ul><li>POMC levels were similar in all groups </li></ul><ul><li>NPY and AgRP were expressed higher in the KO , and moderately inTGKO </li></ul><ul><li>KO group , would be more hungry leading to hyperphagia </li></ul>
    16. 17. Protection from induced HFD obesity <ul><li>WT had greater body weight than the TG/TG mice on both Chow and HFD conditions </li></ul><ul><li>Leptin systems of TG/TG were more effective than the wild type </li></ul><ul><li>TG/TG had thinner and leaner body composition than the wild type </li></ul><ul><li>Leptin Resistance & obesity induced from a high fat diet is dose dependent on the neuronal SH2b levels </li></ul>
    17. 18. <ul><li>Conclusions </li></ul>
    18. 19. Relevance & Human twin studies <ul><li>Jamshidi Et al. </li></ul><ul><ul><li>Sh2b gene is associated with serum leptin and body fat in normal female twins </li></ul></ul><ul><ul><li>N=2500 </li></ul></ul><ul><ul><li>Correlation study with leptin , total fat , waist circumference and body weight </li></ul></ul><ul><li>3 genotype variations </li></ul><ul><ul><li>Alanine Homozygous – major type </li></ul></ul><ul><ul><li>Threonie homozygous – minor type </li></ul></ul><ul><ul><li>Alanine , threonine heterozygous - common type </li></ul></ul>
    19. 20. Relevance & Human twin studies
    20. 21. Places to expand on further research <ul><li>Neuronal expression is important , but what is the exact role of Pheripheral tissue expression </li></ul><ul><li>Isolation of SH2B functions to look at specific roles to enhance purposed mechanism </li></ul><ul><li>The role of Leptin in tgKO and the resulting elevation of agrp </li></ul>
    21. 22. Critiques <ul><li>Sex differences </li></ul><ul><li>Scope of paper very board </li></ul><ul><li>Non representative population </li></ul><ul><li>Correlation does not equal causation </li></ul>
    22. 23. <ul><li>Questions ? Comments ? </li></ul>
    23. 24. SH2B, and SH2 adaptor family <ul><li>SH2B is an adaptor protein </li></ul><ul><li>One of 3 in the Src homology 2 family </li></ul><ul><li>4 similar but different isoforms </li></ul><ul><ul><li>SH2B1 is the one of interest in this study </li></ul></ul><ul><li>Bind and Phosphoralate protein , cytoplasmic and receptor kinases </li></ul><ul><li>Previous experiements yeilded broad obesity findings </li></ul><ul><li>A focused view of the relationship of leptin and insulin </li></ul>
    24. 25. Possible pharmaceutical action fdfd

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