Behind The Medical Headlines

PONDERING OBESITY: THERAPEUTIC TARGETS IN BRAIN AND FAT

• Dr JR Seckl, Moncrieff-Arnott Professor of Molecular Medicine, Endocrinology Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland

Summary

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.

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.

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.

For the brain, previous rather simplistic notions of generalised hypothalamic appetitive and satiety ‘centres’, largely based upon studies of crude lesions in animal and humans, have been superseded by an increasingly sophisticated knowledge of specific neuronal subnuclei, their interconnections and the many biochemical signals that underpin a series of complex control systems. Driven by the recent technologies of human genetics, molecular biology, biochemical microanatomy, functional pathway tracing and the explosion of pharmacophores, a series of novel hormonal and neuronal pathways have been identified and are increasingly understood. A fine example lies in the biology of the arcuate nucleus in the hypothalamus. Gross lesions of the arcuate nucleus had little effect upon appetite and it was largely overlooked until it was recognised to be a major central nervous system site for receptors for the adipose hormone leptin to deliver its satiety signal to the brain. Subsequent careful study revealed the complexity of the arcuate nucleus which is a major primary relay for both ‘eating’ (orexigenic) and ‘stop eating’ (anorexigenic) signals; total lesions produce a balanced effect on both paths, but each is a major physiological player.

Recent work suggests an expanding number of key signalling molecules from the periphery. These include leptin, which indicates satiety and sufficient bodily ‘energy abundance’ (i.e. adipose mass) for reproduction and other purposes. In contrast, the peptide ghrelin, derived predominantly from the stomach, is released prior to eating and is a potent stimulus to increased consumption of calories, acting upon a separate group of neurons in the arcuate nucleus. Indeed, ghrelin levels rise following dieting and weight loss perhaps explaining rebound weight gain, and loss of ghrelin with barostatic gastric surgery (for morbid obesity) may underpin successful weight control. Other peripheral peptides released from the gastrointestinal tract in relation to food consumption, notably peptide YY3-36, are also promising, not only reducing food intake in normal controls but also, crucially, in obese subjects. Within the arcuate nucleus neurons a series of neurotransmitters such as alpha-melanocyte stimulating hormone (a-MSH) and neuropeptide Y transduce the peripheral hormonal signals of leptin, ghrelin and others into further neuronal components of the intra-and extra-hypothalamic circuitry, altering appetite. A small, but important group of obese children have been identified who harbour mutations of the genes encoding some of the inputs, notably of leptin, of the key hypothalamic transmitters and their receptors, perhaps most commonly of the hypothalamic receptor for the anorexic agent a-MSH. However, these pathways are complex in the extreme and the transmitters and receptors involved are not restricted to appetitive pathways so other effects of drugs modifying such systems are anticipated. The efficacy of such approaches in long-term therapy is also unclear; the history of appetite modulators is not a happy one. Moreover, the bare biology does not necessarily indicate therapeutic effectiveness. A case in point is leptin which shows paradoxically increased levels in obesity, reflecting a state of leptin resistance. Whilst the potential biological value of such resistance to allow our ancestors fully to exploit episodic caloric excess may be speculated upon, this does rather obviate any therapeutic utility for the majority of obese patients. Nonetheless, drugs developed to modify appetite selectively, exploiting mimics for endogenous signals, are a substantial hope for the future. The ethical complexities of medicalising a fundamental human behaviour such as appetite remains a thorny problem for the fluoxetine and sildenafil generation.

An additional prospect is provided by our emerging understanding that adipose tissue is not as dull and inert as previously opined. Adipocytes, in addition to their recognised role in regulating energy balance directly by insulin-modulated uptake of glucose and lipids, produce a range of important hormonal signals which indirectly modulate insulin resistance (resistin, tumour necrosis factor alpha), insulin sensitisation (adiponectin), inflammation (interleukins), appetite (leptin), blood pressure control and angiogenesis (angiotensinogen) and more. Here the future therapeutic aim may be less to control appetite than to dissociate obesity from its adverse metabolic consequences. Thus recent interest has concentrated upon adiponectin, the major protein product of adipose tissue. Adiponectin levels not only correlate directly with insulin sensitivity, but low plasma levels also predict the onset of insulin resistance/type 2 diabetes. Treatment of rodents with this peptide improves insulin sensitivity, reduces weight and triglyceride levels. Polymorphisms in the adiponectin gene segregate with weight and it clearly represents an important line for future understanding.

Another recent highlight reflects a possible solution to the longstanding endocrine conundrum of the close morphological and metabolic similarities between the rare Cushing’s syndrome of glucocorticoid excess and simple obesity with or without the Metabolic Syndrome. Raised plasma cortisol levels cause the phenotypic changes in Cushing’s syndrome and enhance appetite. In contrast, cortisol levels are modestly if at all elevated in patients with the Metabolic Syndrome and are reduced in simple obesity. A likely resolution to this paradox has emerged recently in the guise of tissue metabolism of glucocorticoids by the hitherto arcane enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD-1). This catalyses the conversion of otherwise inert cortisone to physiologically active cortisol in specific tissues including adipose and liver. Recent evidence has shown an adipose-selective 2-3-fold increase in 11ß-HSD-1 in rodent models and human populations with obesity. It has been hypothesised that, by locally increasing glucocorticoid action, this might produce a localised ‘Cushing’s syndrome of adipose tissue’. To address causation, transgenic mice overexpressing 11ß-HSD-1 only in adipose tissue have been generated. These mice have elevated glucocorticoid levels only in fat, whilst systemic levels are unaltered. The transgenic mice show visceral obesity, hyperglycaemia, insulin resistance, dyslipidaemia and hypertension, thus fully modelling the metabolic syndrome. In contrast, 11ß-HSD-1 knock-out mice, made to explore the therapeutic potential of inhibitors, show improved glucose tolerance and lower plasma triglyceride levels driven by increased insulin sensitivity. The 11ß-HSD-1 knock-out mice can apparently ‘have their cake and eat it’, since when fed a high-fat ‘cafeteria’ diet the knock-out mice gain less weight despite eating more. The biology appears conserved, at least in part, since administration of the 11ß-HSD inhibitor carbenoxolone to humans also increases insulin sensitivity. The pharmaceutical industry is producing inhibitors, the first are entering early clinical phase studies.

Thus the emerging understanding of fat and brain has illuminated novel approaches to obesity. Today’s bleak news from epidemiology may be assuaged by the hope that the future will see drugs to modify appetite selectively and to reduce the severity and impact of metabolic consequences in the already stout.

References

1. Reaven, G. Metabolic syndrome - Pathophysiology and implications for management of cardiovascular disease. Circulation 2002; 106(3):286-8.
2. Zigman JM, Elmquist JK. Minireview: from anorexia to obesity - the yin and yang of body weight control. Endocrinology 2003; 144:3749-56.
3. O’Rahilly S, Farooqi IS, Yeo GSH et al. Minireview: Human obesity - Lessons from monogenic disorders. Endocrinology 2003; 144:3757-64.
4. Seckl JR, Walker BR. 11ß-hydroxysteroid dehydrogenase type 1: a tissue-specific amplifier of glucocorticoid action. Endocrinology 2001; 142:1371-6.
5. Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, Ghatei MA, Bloom SR. Inhibition of food intake in obese subjects by peptide YY3-36. New Engl J Med 2003; 349:941-8.