PONDERING OBESITY: THERAPEUTIC TARGETS IN BRAIN AND FAT
Two recent areas of research into obesity have caused considerable scientific and popular interest; the role of the brain in controlling appetite and metabolism, and the emerging biology of adipose tissue. These two fields have converged with recognition that the fat and other metabolic tissues send potent signals to the brain and vice versa. Prof Jonathan Seckl reviews the emerging evidence.
- Human metabolism has evolved to allow individuals to survive episodic starvation.
- In affluent, and increasingly in developing, countries freely available calorie-rich food and a lack of exercise are producing an epidemic of obesity.
- Obesity is caused by an excess of calorie intake over energy expenditure. Obesity, especially abdominal obesity, can be associated with a ‘metabolic syndrome’ of resistance to the action of insulin, diabetes type II, high blood cholesterol and high blood pressure which predispose to cardiovascular disease.
- Knowledge of appetite control by the brain and the nature of the metabolism of fat tissue may provide new methods of treatment in the future.
- Improved knowledge of the nerve connections and hormone receptors in the brain shows that the arcuate nucleus has centres for signalling the need to ‘eat’ or ‘not eat’, and it is also a major receptor site for the hormone leptin from fat tissue.
- Hormones are important in appetite regulation. Leptin, made by fat tissue, suppresses appetite; ghrelin, made by the stomach, increases appetite; both act on the arcuate nucleus. Neurotransmitters within the brain may also moderate appetite. Drugs related to these hormones and neurotransmitters are capable of controlling appetite and are a hope for the future in obesity treatment.
- Fat tissue has emerged as metabolically active in energy control. Hormones produced by fat tissue control appetite, increase insulin resistance and effect blood pressure control. Drug treatment based on this knowledge might prevent the ill-effects of the ‘metabollic syndrome’ of obesity.
- Cortisol can produce a syndrome similar to that of obesity, and investigation of the ways in which fat tissue metabolises cortisol may give another avenue for treatment of obesity.
Declaration of interests: No conflict of interests declared
I am resolved to grow fat and look young till forty, and then slip out of the world with the first wrinkle.
John Dryden, The Maiden Queen, 1668
The archetypal seventeenth century view of obesity as a convenient disguise for ageing reflects an era when the average life expectancy was less than half the eight decades or more enjoyed in contemporary western society. Hundreds of millions of years of vertebrate evolution and most of human history has produced efficient metabolic adaptations to episodic starvation. Dryden’s heroine not only exemplified the optimum Enlightenment complexion but also was likely to be resistant to the inevitable episodic famine and endemic contagion. Today, obesity itself has reached epidemic proportions for the world’s affluent nations and, increasingly, for developing countries as well. Excess fat contributes to much early morbidity and mortality bringing a contemporary irony to Dryden’s verse. Indeed, it has been suggested that the recent welcome downturn in cardiovascular mortality in developed countries will soon be countered by an upsurge in cardiovascular disorders driven by the epidemic of obesity and its attendant risks of diabetes, dyslipidaemia and hypertension.
The primary cause of obesity is a chronic imbalance between calorie intake and energy expenditure. Underlying variable vulnerabilities within individuals modulate the likelihood of the development of adiposity and its many complications, notably the Metabolic Syndrome (Reaven’s Syndrome X; the Insulin Resistance Syndrome), which describes a constellation of cardiovascular risk factors, specifically insulin resistance, type 2 diabetes, dyslipidemia and hypertension. The relative risk of morbidity in the Metabolic Syndrome is increased by the co-occurrence of obesity, particularly visceral (abdominal) obesity. The Metabolic Syndrome is also rapidly increasing in prevalence and is a worldwide burden upon health care delivery. Understanding the pathogenesis and potential treatments for visceral obesity and its cardiometabolic associations is a high priority.
In terms of treatment, millennia of professional and social exhortations to ‘eat less’ are undermined by the primal nature of the drive to eat and the body’s physiological adjustments when obesity is chronic. These mean that dieting is misperceived by the brain and periphery as ‘starvation’ engendering potent physiological countermeasures to defend the status quo, however overweight the subject may be. Drug treatments for obesity have also had at best a very chequered history; from thyroxin to amphetamines, most have fallen by the wayside from toxicity or inefficacy. New thinking is desperately required.