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158

I S S U E S E V E N

H O R I Z O N 2 0 2 0 P R O J E C T S : P O R TA L

www.horizon2020projects.com

P R O F I L E

M E TA B O L I C D I S E A S E S

The fat in the fire

IN

1975 a group of scientists, led by the author, at

Beecham Pharmaceuticals decided to search for

compounds that would increase energy expenditure

as a treatment for obesity. The premise for this approach was that

it was clear from the earlier work of the pioneering nutritionist

Elsie Widdowson that one could identify pairs of individuals doing

similar jobs and eating the same amount of food, but they were of

very different body weight and fatness. So there was something in

the lean individual that allowed them to dissipate the excess

energy. As a result, the Beecham group built an experimental

system in which they could measure the energy expenditure of

mice over a 24-hour period, and hence seek compounds that

would stimulate energy expenditure.

BMI

In the mid-1970s the rate of obesity (BMI >30) was 16% in the

US and, whilst lower in Europe, it was beginning to cause concern,

such that the UK Department of Health and the Medical Research

Council set up a working group to examine the problem. They

concluded: “We are unanimous in our belief that obesity is a

hazard to health and a detriment to wellbeing. It is common

enough to constitute one of the most important medical and

public health problems of our time, whether we judge importance

by a shorter expectation of life, increased morbidity, or cost to the

community in terms of both money and anxiety. It is difficult to

document the importance of obesity statistically; it receives only

one line in the International Classification of Diseases. This may

be compared with ‘congenital disorders of lipid metabolism’,

which receives 22 lines.

Today the rate of obesity in adults in the US is 34% in men and

36% in women. Rates across Europe vary, with the UK towards the

top at 24% in men and 26% in women.

The possibility of treatment

The drive to seek agents to stimulate metabolic rate contrasted

with drug treatments at that time, which involved short term

treatment for no more than 12 weeks, with drugs to suppress

appetite and food intake. The 12-week limit was partly because

the drugs available were amphetamine-based, but also due to the

beliefs that obesity was the result of gluttony and sloth (and so

stopping the gluttony should completely reverse the obesity

syndrome) and that patients should be able to stay at their

reduced weight. This approach contrasted, for example, with the

treatment of high blood pressure, where drugs would continue to

be taken to maintain the reduced blood pressure within the

normal range.

The team at Beecham was able to identify a class of new drugs

that stimulated energy expenditure in obese mice and rats. Not

only did these drugs slim down the laboratory rodents, they were

also highly effective in the treatment of the concomitant Type 2

diabetes. The drugs were believed to act at a

β

-adrenoceptor.

However, at the time the only

β

-adrenoceptors identified were

β

1

and

β

2-adrenoceptors, and these compounds were clearly acting

at a different receptor – referred to as atypical but ultimately

shown to be a

β

3-adrenoceptor.

At the same time as this work was proceeding, Michael Stock and

Nancy Rothwell (now Dame Nancy) were trying to understand how

rats were able to resist weight gain when fed a so-called ‘cafeteria

diet’ composed of typical snacks eaten by Man. Both groups

simultaneously realised that the energy dissipation was probably

due to the ability of brown adipose tissue (previously known to be

present in hibernating animals) to burn metabolic fuels and,

instead of generating adenosine triphosphate, give off heat. In

Cambridge Philip James and Paul Trayhurn, working with a

spontaneous obese mouse as a result of a mutation, also showed

that this mouse had virtually inactive brown adipose tissue.

The work of the Beecham team was followed by several

pharmaceutical companies, including Lilly, Roche, ICI (now

AstraZeneca), Merck and American Cyanamid (now Pfizer).

The Buckingham Institute of Translational Medicine speculates on the role of

brown fat in fighting metabolic disease