Washington DC, USA

29-31 May 2012

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

Obesity, Diabetes and Cancer

Cancer

Diabetes

Obesity

Insulin Resistanc

eInsulin-like

Growth Factor (IGF)Agin

g

Obesity

Cancer

Diabetes

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

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

Irisin and the therapeutic effects of exercise – Bruce M. Spiegelman

Brown Adipose Tissue White Adipose TissueUCP No UCP

Large number of mitochondria

Small number of mitochondria

Anti-inflammatory Pro-inflammatory

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)

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 got qualities of brown fat

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

Take Home MessageMake Yourself Brown

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

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

BCAAs are metabolic fuels

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

Suggested mechanismsThe catabolic intermediates

propionyl CoA and succinyl CoA reduce the efficiency ofoxidation 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

Take Home Message

Make Yourself Brown

Don’t Get Fat

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

Beyond insulin: Rethinking cellular metabolism – Craig Thompson

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

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

Glucose

Jak/Stat

Glutamine

TCAROS

BCAA

mTOR

Cell Growth

How to write a grant?

“I require 10,000 marks”

Take Home Message

Make Yourself BrownDon’t Get Fat

Don’t Get Cancer

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

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

Gained weight

Clustered together – 80% similarity in gene expression

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

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

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)

Take Home Message

Make Yourself BrownDon’t Get Fat Don’t Get Cancer

Stay Young

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

anecdotes

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 novo lipogenesis Fructose causes dyslipidemia

Take Home Message

Don’t Get Fat

Stay Young

Don’t Get Cancer Make Yourself Brown

Don’t Eat Fruits

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 Westman suggested 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” ?!

Take Home Message

Don’t Get Fat Don’t Get Cancer Make Yourself Brown

Don’t Eat Fruits

Don’t Eat Carbs

Stay Young

Thank You