Journal Club Slides for the article ""Grizzly Bears Exhibit Augmented Insulin Sensitivity while Obese Prior to a Reversible Insulin Resistance during Hibernation"." available at http://dx.doi.org/10.1016/j.cmet.2014.07.008

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