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

I S S U E S E V E N

159

P R O F I L E

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

Mike Cawthorne

Professor of Metabolic Diseases

Clore Laboratory

University of Buckingham

te l :

+44 (0)1280 820309

mike.cawthorne@buckingham.ac.uk www.buckingham.ac.uk/bitm/

Unfortunately, none of the compounds developed, although they

were very effective in rodents in treating obesity and Type 2

diabetes, were sufficiently efficacious in Man to merit serious

clinical development.Why did the compounds fail? The first issue

was they were developed in a pre-genomic era without the benefit

of cell lines expressing the human genes. The compounds were

both less efficacious at the human

β

3-adrenoceptor than at the

rodent receptor, but were also much less selective from

β

1

(increase in heart rate) and

β

2-adrenoceptor (muscle tremor)

side effects. Indeed, this was probably the first occasion when

species differences in the structure of the receptor between rats

and mice and Man was sufficient to make the compounds

useless as therapeutics.

Brown adipose tissue

The problem of species specificity could be overcome by new

chemistry, but from the early 1980s until about 2009, the

prevailing view was that brown adipose tissue, although present in

human neonates and infants, did not occur in significant amounts

in adult Man. This certainly influenced pharmaceutical

management to close these research programmes.

Evidence that brown adipose tissue did exist in adult Man came

from the cancer biologists. The use of positron emission

tomography combined with computed tomography to measure

and localise the uptake of 18F-fluorodeoxyglucose into tissues

was used to identify tumours. They found high uptake of this tracer

into what appeared to be symmetrical tumours running close to

the major blood vessels close to the spine. Surgical intervention

showed they were not tumours but brown adipose tissue.

These studies have led to a resurgence of interest in brown

adipose tissue as a target for thermogenic anti-obesity drugs, and

this has been further spurred by the discovery of a lineage of

‘beige’ or ‘brite’ fat cells in white adipose tissue deposits. These

beige cells develop following exposure to cold, high intensity

exercise and by treatment with some drugs, particularly the

thiazolidinedione insulin sensitiser agents such as rosiglitazone.

Unfortunately, the amount of functional brown fat in obese

subjects is less than in lean, and it also seems to be lost with

ageing. Therefore, in considering a treatment it is necessary not

only to be able to activate the brown fat (and the beige cells), but

also to increase the number of brown fat cells and the overall

thermogenic capacity of individuals.

β

3-adrenoceptor

If brown adipose tissue plays a significant role in adult humans,

should

β

3-adrenoceptor agonists be reconsidered for the

treatment of both obesity and Type 2 diabetes? In rodents, dogs

and rhesus monkeys, earlier studies showed that

β

3-

adrenoceptor agonists not only activate thermogenesis but, when

given repeatedly, they increase the capacity of brown fat to

respond to acute activation. There is no reason to suspect the

same would not happen in humans, because the

β

3-

adrenoceptor is certainly present in human brown fat. Moreover, in

pheochromocytoma, an adrenal medulla neuroendocrine tumour,

over-secretion of noradrenaline and adrenaline (which are the

natural agonists for the

β

3-adrenoceptor) causes a marked

increase in brown fat mass, and this is associated with a

reduction in the body fat mass.

The

β

3-adrenoceptor is also expressed in the smooth muscle of

the bladder, and a

β

3-adrenoceptor agonist, mirabegron, has

been developed for this disorder which affects some 33 million

people in the US. The company marketing mirabegron has clearly

decided that overactive bladder treatment is a much safer focus.

However, in a recent study it was shown (at a dose four times that

used for the bladder indication) to increase metabolic rate by

13% in an acute study. If this level of thermogenesis could be

sustained, then one could expect a fat weight loss of 5kg in the

first year of treatment.

Will the pharma industry follow-up on this? Despite the huge

market and unmet clinical need I suspect not.Why? Obesity is

associated with major co-morbidities, including Type 2 diabetes,

cardiovascular disease and some cancers. Thus, downstream

some patients taking any drug will inevitably develop one of these

conditions and class actions will develop in the US, with the

lawyers knowing that pharma will pay up rather than face a long

battle to defend a potentially innocent drug.

Alternative approaches

Are there other approaches, such as nutraceuticals – substances

present in edible plants that will stimulate metabolic rate? Work

so far has demonstrated effects by some materials such as

capsinoids and oolong tea. However, the benefits of these have

proved to be small, and a more comprehensive search is needed

to possibly find edible vegetable matter that not only stimulates

energy expenditure but also suppresses appetite, since any

benefit of an agent that increases energy expenditure just like

exercise can be overcome by additional food consumption. The

author’s laboratory has identified a number of promising agents.

Professor Mike Cawthorne leads the Buckingham Institute of

Translational Medicine based at the Clore Laboratory, University of

Buckingham, which has research interests in treatments for Type 2

diabetes, obesity and metabolic disease. Its staff members

include Jon Arch, Paul Trayhurn and John Clapham, who

collectively have the largest and longest experience of brown fat

research worldwide.