2. Body Weight and Insulin Sensitivity Negative Correlation Insulin resistance may have evolved to prevent excessive weight gain BMI by CountyType II Diabetes by County Abbasi et al, J. Am. Col. Card. 2002CDC, 2012 Chang et al Diabetes Care, 1994

3. How Does Insulin Resistance Lead to Type II Diabetes Food Circulating Nutrients (Glucose) Insulin Secretion Glucose Production Glucose Disposal Nutrient Storage Insulin Resistance

4. Not All Obese People Get Insulin Resistance or Type II Diabetes About a third of obese people are not insulin resistant or hyperlipidemic. They are known as Metabolically Healthy Obese people What mechanism underlies this is unclear

5. Weight Fluctuations in Bears

6. The Question at Hand Bears seem to be able to cycle between fat accumulation and release on regular intervals What are the effects on insulin sensitivity that are associated with these massive fluctuations in weights?

7. “Patient” Characteristics May October January

8. Insulin and Glucose Levels are Unchanged in “Obese” Bears Normally with elevated fat mass you would expect a big increase in insulin resistance These are therefore a model of massive weight gain without increased diabetes May October January

9. Changes in Insulin Sensitivity More obese in October, but far more insulin sensitive. May October January

10. Key Questions 1.Why are lean(-ish) mid-hibernating bears insulin resistant 2.Why are obese pre-hibernating bears insulin sensitive

11. Are These Changes Due to Inflammation? May October January

12. Relationship Between Lipolysis and Insulin Sensitivity Adipose Triglycerides Serum FFA Lipolysis Insulin Resistance Mitochondrial Stress Insulin Basic Monoamines Rate Limiting Steps in Lipolysis are HSL and CGI-58 Phosphorylation

13. Increased Lipolysis in Hibernating Bears May October January

14. WHY ARE OBESE, PRE-HIBERNATING BEARS INSULIN SENSITIVE?

15. Functionally Need to store a lot of weight without side effects of hyperglycemia Some signal must occur to mediate this transition But what is the mechanism underlying this? What tissue is the originator of this effect?

16. PI3K Dependent Insulin Signaling

17. PTEN Phosphorylation PTEN Phosphorylation On Serine 308 Insulin Sensitization Due to Elevated PIP3/Akt Signaling

18. Measuring Protein Phosphorylation Measured both total protein and phosphorylated protein, the ratio is presented here

19. PI3K Signaling Enhanced Adipose Gastroc Liver May October January

20. Insulin Responsiveness in WAT May October January Hibernating Bear WAT Modest Effects of Insulin Non-hibernating Bear WAT Dramatic Effects of Insulin

21. Cause or Effect?

22. Insulin Promotes Weight Gain You need insulin to promote lipid accumulation into fat tissue. Possibly PTEN mediated insulin sensitization of fat tissue is causing the weight gain but does not cause sensitization of other tissues. Where is the knockout grizzly????

23. Adipose PTEN as a Regulator of Insulin Sensitivity

24. Confounders and Questions? Big changes in energy usage rate in hibernating bears? Is it PTEN or PTEN phosphorylation that’s changing. What is the signal? What stimulates the lipid breakdown in the hibernating bears?

25. Conclusion