Steve Bloom
Division of Investigative Science, Imperial College London at Hammersmith, London, UK

https://doi.org/10.36866/pn.59.27

World-wide, over 150,000 people a month die prematurely from obesity. This massive number of unnecessary deaths rivals those directly caused by the catastrophic Boxing Day tsunami. Unlike the tsunami, it happens regularly and predictably, month after month, year after year. We have no medicines that are effective in treating obesity. Advice to stop eating and take more exercise has been dished out by doctors for the last 100 years – the only effect has been accelerating adiposity.

Modern man is a survivor of many famines. Malthus proposed that with no dominant predator, the numbers of a species would increase until the food ran out. Man is the top predator and his numbers have therefore been limited by food availability for aeons. Restrained eaters would sometimes starve to death. Only the greediest survived. This genetic legacy makes us voracious overeaters. In a modern world dripping with highly nutritious and easily available fast food which never runs out, only by the exercise of enormous will power do some of us keep our waist lines from expanding. This calorie rich environment combined with the lack of need for exercise is hog heaven for overeaters, and makes the current obesity epidemic seemingly inevitable. Faced with previous disease epidemics and natural catastrophes, man has successfully applied science as a remedy. We now need to apply science to reset man’s inappropriate appetite, and to succeed we must understand how appetite is controlled. Physiologists to the rescue!

The first real breakthrough was the discovery of the appetite inhibiting fat hormone leptin. It was also the first big disappointment. Leptin has turned out to be only a reassurance factor, released from fat to tell the brain that you aren’t starving to death. Thus if you loose your fat in a famine you have no leptin to reassure the brain. You can think only of food, all growth stops, menstrual cycles stop, and the immune system shuts down. Injecting leptin instantly restores all of these functions, without the need for any extra food. In contrast, giving fat people leptin doesn’t reduce their appetite at all because the obese already have lots of leptin.

But we can limit our hunger. Everyone feels less hungry after lunch. Why? It isn’t the bulk. Just compare the effect on your appetite of eating two big chocolate bars or a pile of boiled cabbage – only the former assuages appetite. It isn’t the rise in circulating nutriments because intravenous infusions of nutriments don’t stop you feeling hungry. Actually it is likely that the loss of appetite after a meal is due to specific neural or hormonal gut signals to the brain. Eating releases a number of gut hormones, including oxyntomodulin, glucagon-like peptide 1 (GLP1), peptide YY (PYY3-36) and pancreatic polypeptide (Batterham et al. 2003; Dakin et al. 2004; Holst, 2004; Wynn et al. 2005). These hormones have been found to inhibit appetite. They also inhibit release of the ‘hunger hormone’ ghrelin. Ghrelin is a peptide hormone released from the endocrine cells of the stomach when you’re hungry and ghrelin release is reduced after a meal (Wren et al. 2001). Thus gut hormones produce a co-ordinated satiety response.

These circulating peptide hormones penetrate the CNS in specific regions such as the area postrema and arcuate nucleus, where they affect the neuronal circuitry that regulates how hungry you feel. The central dogma of CNS appetite control is that the hypothalamic arcuate nucleus receives and coordinates signals giving information about the acute and chronic state of energy balance (Fig. 1). This nucleus contains two important types of neurone. One type stimulates appetite by releasing the neurotransmitters neuropeptide Y (NPY) and agouti­related protein (AgRP). The ‘hunger hormone’, ghrelin, stimulates this neurone, while leptin and the ‘satiety gut hormones’, PYY, GLP1 and oxyntomodulin, inhibit it. The second type of neurone inhibits energy expenditure and appetite via the release of the alpha melanocyte stimulating hormone (alpha MSH), and ‘cocaine and amphetamine related transcript’ (CART). These hunger reducing neurones are inhibited by ghrelin but stimulated by leptin and the satiety gut hormones. Both the appetite-stimulating and appetite- inhibiting arcuate neurones project to another area of the hypothalamus, the paraventricular nucleus (PVN). The PVN is the ‘motor nucleus’ of the appetite system and is responsible for actually making you feel hungry or full and for burning off excess energy. If these gut hormones normally act on the brain to inhibit hunger after a meal, can giving them to the obese before meals make them lose appetite, eat less and thus lose weight? It has already been shown that artificial administration of these hormones to hungry volunteers inhibits hunger and decreases meal size. This specific physiological effect offers an exciting new way to regulate hunger and may lead to an effective way of treating obesity (Fig. 2). We can only hope that bigger and longer clinical trials show the inhibition of appetite by gut hormones to be both powerful and sustained. The benefits of such anti­obesity agents are potentially immense.

References

Batterham RL, Cohen MA, Ellis SM, le Roux CW, Withers DJ, Frost GS, Ghatei MA & Bloom SR (2003). Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med 349, 941-948

Dakin CL, Small CJ, Batterham RL, Neary NM, Cohen MA, Patterson M, Ghatei MA & Bloom SR (2004). Peripheral oxyntomodulin reduces food intake and body weight gain in rats. Endocrinology 145, 2687-2695

Holst JJ (2004). On the physiology of GIP and GLP-1. Horm Metab Res 36, 747-754

Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatei MA & Bloom SR (2001). Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 86, 5992-5995

Wynne K, Stanley S, McGowan BMC & Bloom SR (2005). Appetite control. Endocrinology 184, 291-318

See also the related article in our last issue (Trayhurn P (2005). Obesity – why all the noise? Physiology News 58, 15.