Washington DC, USA

1. Washington DC, USA 29-31 May 2012

2. Outline • Adipogenesis and insulin resistance • Metabolism and mechanism • Metabolism and cancer cells • Sirtuins and disease • Dietary factors in metabolic disease

3. Obesity, Diabetes and Cancer Insulin Resistance Insulin-like Growth Factor (IGF)

4. Outline • Adipogenesis and insulin resistance • Metabolism and mechanism • Metabolism and cancer cells • Sirtuins and disease • Dietary factors in metabolic disease

5. Irisin and the therapeutic effects of exercise – Bruce M. Spiegelman • Brown Adipose Tissue (BAT) is one of the two types of fat found in mammals • It is especially abundant in newborns and hibernating mammals • BAT maintains body heat by allowing protons to run back along the gradient and burn excess heat instead of ATP – this can occur through the uncoupling protein (UCP) • Strategies to increase brown fat in vivo are therefore being intensively explored to combat obesity

6. Brown fat and exercise • In adults brown fat is found in the upper chest, neck and along the spine • Recent research has shown that brown fat is not related to white fat but actually evolves from a muscle lineage  beije fat! • There are recent reports that exercise causes a mild increase in the expression of a thermogenic gene program in WAT (i.e., “browning” of white fat)

7. PGC1-α and exercise • PGC1-α is induced in muscle by exercise and stimulates many of the best-known beneficial effects of exercise • Mice with transgenically increased PGC1-α in muscle are resistant to age-related obesity and diabetes • Searching for proteins that can mediate the browning of adipose tissue they found a membrane protein called Fndc5 White fat in mice with transgenically increased pgc1-α in muscle gotqualities of brown fat

8. Irisin - a new protein • Fndc5 is proteolysed to give rise to a new secreted protein of 122 amino acids that was named Irisin • Irisin is produced from Fndc5 in the muscle and works on white adipose tissue to make it brown • There is 100% conservation between mouse and human Irisin • Irisin is secreted during exercise • Over-expression of Irisin results with an increase in UCP and improvement in glucose homeostasis • Irisin receptor hasn’t been identified yet. Once identified, small chemical compounds could be developed that target this receptor, thus providing a drug platform to turn white fat beige and reduce obesity in the clinic Bostrom et al., Nature 2012

9. Take Home Message Make Yourself Brown

10. Outline • Adipogenesis and insulin resistance • Metabolism and mechanism • Metabolism and cancer cells • Sirtuins and disease • Dietary factors in metabolic disease

11. Finding a mechanism from metabolicsignatures to disease – Christopher Newgard • Fatty acids (FA) and FA-derived metabolites have long been implicated in the development of insulin resistance and type 2 diabetes • They measured a few hundreds of metabolites in plasma samples from obese (BMI 37) and insulin-resistant versus lean (BMI 23) and insulin-sensitive subjects • Surprisingly, the component most correlated with insulin resistance (R=0.6) is Branched-Chain Amino Acids (BCAAs; Val, Leu and Ile)and BCAA-related metabolites

12. BCAAs are metabolic fuels

13. The relationship between BCAAs and metabolic disease • Rats were given 4 different diets: • HF • HF+BCAA • Standard Chow (SC) • SC+BCAA • HF+BCAA-fed rats consumed less fat and had lower weight, however, they were still insulin resistance • Despite the lower rate of food intake of HF+BCAA-fed rats, they accumulate acylcarnitine species in muscle to the same extent as HF-fed rats • Accumulation of acylcarnitines has been associated as an index of incomplete fatty acid oxidation in mitochondria

14. Suggested mechanisms The catabolic intermediates propionylCoA and succinylCoAreduce the efficiency of oxidation of fatty acids and glucose, leading to accumulation of incompletely oxidized substrates, mitochondrial stress, impaired insulin action, and ultimately to perturbation of glucose homeostasis Christopher Newgard, Cell Metabolism 2012

15. Take Home Message Don’t Get Fat Make Yourself Brown

16. Outline • Adipogenesis and insulin resistance • Metabolism and mechanism • Metabolism and cancer cells • Sirtuins and disease • Dietary factors in metabolic disease

17. Beyond insulin: Rethinking cellular metabolism – Craig Thompson

18. Glucose/Glutamine utilization mechanism (1) • If we remove glutamine from the media  cell death due to the cell’s inability to execute anaplerosis • If we remove IL-3 (growth factor) from the media the cell is unable to use its glutamine  cell death • If we remove glucose from the media but leave IL-3, there’s still no use in glutamine  cell death What is happening? The expectation is that the cell will use more glutamine to compensate for the lack of glucose

19. Glucose/Glutamine utilization mechanism (2) • In the absence of glucose, the α-chain IL-3R is missing and the receptor is inactive • Is the missing component is glycosylation? • Glutamine + IL3 + O-GlcNAc cell growth IL-3 Glutamine Cell Growth Jak/Stat ROS mTOR TCA Glucose BCAA

20. How to write a grant? “I require 10,000 marks”

21. Take Home Message Don’t Get Cancer Don’t Get Fat Make Yourself Brown

22. Outline • Adipogenesis and insulin resistance • Metabolism and mechanism • Metabolism and cancer cells • Sirtuins and disease • Dietary factors in metabolic disease

23. Sirtuins, Diet and Health – Leonard Guarente • The mammalian sirtuins SIRT1-7 are involved in changes in stress resistance and metabolism • Sirtuins are triggered by Calorie Restriction, which not only extends lifespan, but protects against many diseases of aging • Mice were separated into 4 groups: • LF + WT • HF + WT • LF + SIRT1 KO • HF + SIRT1 KO • Caspase1 cleavages SIRT1 • HF induce cleavage of caspase1 Clustered together – 80% similarity in gene expression  Gained weight

24. Sirtuins and the circadian clock (1) • Mammals have developed an endogenous circadian clock located in the suprachiasmatic nuclei of the anterior hypothalamus that responds to the environmental light-dark cycle • The circadian clock has been reported to regulate metabolism and energy homeostasis in the liver and other peripheral tissues

25. Sirtuins and the circadian clock (2) • Actogram - each horizontal line represents one day. Black vertical bars plotted side-by-side represent the activity, or number of wheel revolutions • This way of representation often facilitates the identification of existing rhythms • Actogram of old mice looks as the one of young + SIRT1 KO • Jet leg experiment: • Young adjust and old don’t • Old look like young + SIRT1 KO • Old + SIRT1 over-expression manage to adjust

26. Sirtuins and the circadian clock (3) • Immunohistochmistry showed a reduction of SIRT1 in aging • SIRT1 and PGC1-α enforce each other binding to the BMAL1 promotor • Lifespan experiment in 76 mice  Lifespan is not correlated with metabolic rate. Instead, lifespan was found to correlate with the innate circadian clock (τ)

27. Take Home Message Stay Young Don’t Get Fat Don’t Get Cancer Make Yourself Brown

28. Outline • Adipogenesis and insulin resistance • Metabolism and mechanism • Metabolism and cancer cells • Sirtuins and disease • Dietary factors in metabolic disease – some anecdotes

29. Does fructose play a role in metabolic disorders – Luc Tappy • There is evidence that high fructose diets can lead to development of obesity, insulin resistance and dyslipidemia in rodents models • Glucose and Fructose metabolism is quite different • Fructose is a precursor for de novolipogenesis • Fructose causes dyslipidemia

30. Take Home Message Don’t Eat Fruits Stay Young Don’t Get Fat Don’t Get Cancer Make Yourself Brown

31. Carbohydrates – the source of all evil • Jeff Volk presented evidences that low-carbohydrate diet is much more efficient than low-fat diet • It results in global improvement in traditional and emerging markers associated with metabolic syndrome • Eric Westmansuggested no carbohydrate diet • Our entire metabolism can be relied on ketone bodies for energy production • What about the brain??? “You will suffer from a short-term loss of memory but after a week or two you’ll be fine” ?!

32. Take Home Message Don’t Eat Carbs Don’t Eat Fruits Stay Young Don’t Get Fat Don’t Get Cancer Make Yourself Brown

33. Thank You