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
Insulin
Resistance
Obesity
Insulin-like
Growth Factor
(IGF)
Aging
Diabetes
Cancer
Outline
 Adipogenesis
and insulin resistance
 Metabolism and mechanism
 Metabolism and cancer cells
 Sirtuins and disease
 Dietary factors in metabolic disease
Irisin and the therapeutic effects of
exercise – Bruce M. Spiegelman
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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)
White Adipose Tissue
Brown Adipose Tissue
No UCP
UCP
Small number of mitochondria Large number of mitochondria
Pro-inflammatory

Anti-inflammatory
Strategies to increase brown fat in vivo are therefore
being intensively explored to combat obesity
Brown fat and exercise
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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
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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
White fat in mice with
transgenically increased pgc1-α in
muscle got qualities of brown fat

Searching for proteins that can mediate the browning of
adipose tissue they found a membrane protein called
Fndc5
Irisin - a new protein

Fndc5 is proteolysed to give rise to a new secreted protein of 122 amino acids
that was named Irisin
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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.
identified, small chemical compounds
could be developed that target this receptor,
providing a drug platform to turn white fat beige and
reduce obesity in the clinic
Once
thus
Bostrom et al., Nature 2012
Take Home Message
Make 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 metabolic
signatures to disease – Christopher Newgard
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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:
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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 mechanisms
The catabolic intermediates
propionyl CoA and succinyl CoA reduce 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
Take Home Message
Don’t Get Fat
Make Yourself Brown
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)
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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)
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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
Glucose
TCA
BCAA
How to write a grant?
“I require
10,000 marks”
Take Home Message
Don’t Get Cancer
Don’t Get Fat
Make Yourself Brown
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
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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:
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LF + WT
HF + WT
Clustered together – 80%
similarity in gene expression
LF + SIRT1 KO
HF + SIRT1 KO  Gained weight
Caspase1 cleavages SIRT1
HF induce cleavage of caspase1
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 lightdark 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)
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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:
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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)
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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
Stay Young
Don’t Get Fat
Don’t Get Cancer
Make Yourself Brown
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
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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
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Take Home Message
Don’t Eat Fruits
Stay Young
Don’t Get Fat
Don’t Get Cancer
Make Yourself Brown
Carbohydrates – the source of all evil
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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 shortterm loss of memory but after a week or two you’ll be
fine” ?!
Take Home Message
Don’t Eat Carbs
Don’t Eat Fruits
Stay Young
Don’t Get Fat
Don’t Get Cancer
Make Yourself Brown