An interesting thought that has emerged in obesity research, still in its infancy in scientific enquiry, is the concept of weight set point. Set point theory proposes there are mechanisms for homeostasis of body weight to a predetermined set weight for each individual. It is common knowledge that our body weight is regulated by a myriad of factors, integrated by the central nervous system [Check previous Blog for theories of obesity]. However, how does the brain actuate its homeostatic potential? Set point theory says regulation is achieved by regulating energy intake and energy expenditure and increasing one or the other when our weight deviates from the set point. It was suggested in the famous Minnesota Starvation Experiment in which subjects were starved until only 34% of their fat mass remained; when they were re-fed afterwards, their fat mass increased to 145% the original mass (Keys et al, 1950) [1]. Generally, this overshooting of fat mass is known as the catch-up fat phenomenon and suggests a mechanism that compensates for weight loss. It is speculated that the catch-up fat phenomenon was favoured evolutionarily and that this physiological response to starvation-refeeding includes reduced biosynthesis, suppressed thermogenesis, and increase in fat mass above basal level.
Moreover, energy expenditure correlates with body mass – less energy is needed to support a lighter body at rest, which may explain the difficulty of maintaining weight loss after prolonged dieting. Regardless, set point theory alone does not explain the variation in body weight with socioeconomic factors and the environment. These trends may be accommodated by an extension of the model as a set range instead of a set point, and regulation only occurs when our weight falls outside of the weight range. Among direct and indirect mechanisms to influence weight change, research on controlling appetite has been especially prominent. Though the complete pathways are not known, there is growing knowledge on what common hormones do and how their release is induced, founded on decades of scientific literature. This article will explore some common and well-established hormones that regulate appetite.
Neurohormonal regulation of obesity
Broadly speaking, hormones that influence appetite can be divided into short-term controls and long-term controls, leading to changes in susceptibility to obesity. Short-term control hormonal systems that affect appetite include cholecystokinin (CCK), incretin hormones, ghrelin and peptide YY (PYY), while long-term control is uniquely leptin. Besides affecting appetite, these hormones also alter digestion but we focus on their actions in modulating appetite. The importance of appetite-regulatory hormones can be inferred from weight loss associated with bariatric bypass surgery. Bariatric bypass surgeries involve making changes to the digestive system to induce weight loss, mostly through restricting food intake and altering hormone release. For instance, Webb et al (2017) found that blood concentration of a hormone (GLP-1, more details to follow) increased sharply after bariatric surgery; GLP-1 is known to suppress appetite and its effects were consistent with post-operation outcomes of appetite and weight loss [2]. Logically, it suggests that hormones play a role in appetite and obesity.
Short-term control hormones initiate and terminate eating. CCK was the first hormone shown to influence food intake through the nervous system. By acting on the vagal nerve, it signals satiety and inhibits eating. As its release is induced by protein and fat digestion products in the duodenum, CCK is one of the reasons why we feel full after eating a high fat and protein meal, compared to a meal of carbohydrates of the same caloric amount. CCK-stimulated vagal signals feed into a brain area called the nucleus tractus solitaris, which is a major brain region for appetite control (D'Agostino et al, 2016) [3]. Moreover, disabling the gene for CCK receptor in rats – known as Otsuka Long-Evans Tokushima Fatty rats – leads to incessant and abnormally strong eating behaviour, likely due to unsuppressed sensation of hunger, and thus obesity (Kawano, 1994) [4].
Besides CCK, incretin hormone GLP-1, ghrelin and PYY influence appetite by acting on arcuate pro-opiomelanocortin (POMC) neurons and neurons that express PYY receptors. These hormones are released in response to the presence/absence of macronutrient digestion products at different points along the digestive system, e.g., GLP-1 is released when carbohydrate and fat are detected orally and ghrelin by food content in the stomach, and its level rises before meals and falls after meals. Stimulation of the POMC pathway leads to the sensation of satiety while hormones binding to PYY receptors on neurons stimulate hunger. GLP-1 stimulates POMC neurons but inhibits PYY neurons to enhance satiety; ghrelin inhibits POMC neurons and enhances appetite; PYY has a relatively prolonged effect on the hypothalamus and decreases appetite by inhibiting PYY neurons. In fact, the function of these hormones can be understood in context too – GLP-1 analogues (e.g., liraglutide, exenatide), drugs that share chemical similarities with GLP-1, are also known to cause appetite and weight loss. If you wish to put the scientific jargon aside, the takeaway should be that GLP-1, ghrelin and PYY are major hormones known to play a role in eating behaviour through POMC and PYY pathways.
Leptin is a hormone that has been indicated as a long-term control of energy homeostasis. Leptin’s role in signaling energy homeostasis was first suggested by an accidental gene mutation in Jackson’s lab mice in 1949. The mutation was identified in the leptin gene. The mutated mice were obese and ate excessively. Now, we know much more about leptin. Leptin has short-term and long-term actions. It stimulates POMC neurons to enhance satiety and also inhibits insulin release; on the long-run, leptin signals energy balance. For instance, plasma leptin level was found to correlate highly with the percentage of body fat (Ostlund, 1996) [5]. It seems that leptin is unique, at least as far as we know, in long-term energy signalling – in humans, leptin deficiency results in severe obesity by enabling the brain to sense body fat storage (Farooqi, 2014) [6]; no other genetic mutation in disordered adipocytes has been reproducibly shown to cause obesity.
Summary
Regulation of appetite and metabolism is an integrated system and hormones acting on our brain heavily influence our body composition, whether through regulating food intake or metabolism. The brain is acted on by both long-term (leptin) and short-term (CCK, GLP-1, ghrelin, PYY) meal-related energy homeostatic signals. Our diets definitely influence our weight, body composition and appetite, but be that as it may, no matter how “optimal” our diet composition is – with the perfect proportion of each macronutrient, assuming such a thing exists for each individual – meaningful weight change requires modulating energy intake as well as energy expenditure. A healthy diet with proper hormonal balance disposes us to appropriate appetite while unhealthy diets, like those of high fats, may dispose us to obesity by making it more difficult to eat only as much as we need. We ought not to let ongoing research in dietary composition become a reason to procrastinate and skip leg day – time to squat and eat well if you want to build muscle and lose weight!
References
Keys A. The Biology of Human Starvation. Minneapolis, MN: University of Minnesota; 1950.
Webb, D. L., Abrahamsson, N., Sundbom, M., & Hellström, P. M. (2017). Bariatric surgery - time to replace with GLP-1?. Scandinavian journal of gastroenterology, 52(6-7), 635–640. https://doi.org/10.1080/00365521.2017.1293154
D'Agostino, G., Lyons, D. J., Cristiano, C., Burke, L. K., Madara, J. C., Campbell, J. N., Garcia, A. P., Land, B. B., Lowell, B. B., Dileone, R. J., & Heisler, L. K. (2016). Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit. eLife, 5, e12225. https://doi.org/10.7554/eLife.12225
Kawano, K., Hirashima, T., Mori, S., & Natori, T. (1994). OLETF (Otsuka Long-Evans Tokushima Fatty) rat: a new NIDDM rat strain. Diabetes research and clinical practice, 24 Suppl, S317–S320. https://doi.org/10.1016/0168-8227(94)90269-0
Ostlund, R. E., Jr, Yang, J. W., Klein, S., & Gingerich, R. (1996). Relation between plasma leptin concentration and body fat, gender, diet, age, and metabolic covariates. The Journal of clinical endocrinology and metabolism, 81(11), 3909–3913. https://doi.org/10.1210/jcem.81.11.8923837
Farooqi I. S. (2014). Defining the neural basis of appetite and obesity: from genes to behaviour. Clinical medicine (London, England), 14(3), 286–289. https://doi.org/10.7861/clinmedicine.14-3-286