Regulation of appetite

By Shiyi Liang

Eating is an essential process in a human’s life, and appetite is a vital part of human eating behaviour. Appetite can be described as the thirst for food and is regulated by both the central nervous system (CNS) and peripheral signals. The arcuate nucleus of the hypothalamus receives and integrates signals from appetite-related hormones and neurotransmitters (Hainerová and Lebl, 2010). Appetite can be expressed in two ways: homeostatically and hedonically, mediated by biological need and the reward-related system, respectively.   

Different brain regions take part in appetite regulation, with the hypothalamus playing an important role. The arcuate nucleus (ARC), a part of the hypothalamus, contains different cell subsets which express various receptors. AGRP neurons express agouti-related peptide (AGRP), which is an endogenous melanocortin receptor antagonist. When stimulating AGRP neurons, the appetite increases. 

An experiment done in mice using designer drugs to increase the expression of AGRP showed an increase in body weight due to increased food intake (Krashes et al., 2011). The activation of AGRP neurons could source from the paraventricular hypothalamic nucleus (PVH), especially from neurons expressing thyrotropin-releasing hormone and pituitary adenylate cyclase-activating polypeptide (Krashes et al., 2014). A decrease in PVH afferent signals can lead to an inhibition of AGRP neurons and reduce hunger-driven feeding. Another subunit of cells in the ARC expresses prohormone pro-opiomelanocortin (POMC) and has an opposite effect as AGRP neurons, in which AGRP neurons inhibit this cell subset function. When POMC neurons are stimulated, food intake is reduced. Both AGRP neurons and POMC neurons are stimulated via glutamatergic afferent signals, and both are regulated by serotonin and noradrenaline (Heisler and Lam, 2017). 

The lateral hypothalamic area (LHA) in the brain is also a region that affects appetitive behaviour. Like ARC, there are two types of LHA neurons: GABAergic LHA neurons and glutamatergic LHA neurons, which act oppositely. GABAergic LHA neurons increase appetite while glutamatergic LHA neurons suppress appetite. Furthermore, the parabrachial nucleus contains neurons that reduce appetite by expressing calcitonin gene-related peptides and targets the central amygdala (Heisler and Lam, 2017). 

Furthermore, hormones are also able to regulate appetite. The central nervous system receives information from hormones and other factors to control energy intake and consumption. Leptin and ghrelin are two typical hormones that act on different neurological pathways. Leptin is secreted by adipose tissue, and ghrelin is secreted by the stomach. Exogenous leptin downregulates appetite, while exogenous ghrelin produces an opposite effect (Heisler and Lam, 2017). Signals from the whole process of ingestion, digestion, absorption reach the central nervous system and take part in energy homeostasis. The solitary tract/area postrema integrates signals from the digestive system, and sensory organs (tongue, eye, and nose) then transmits them to further sites in the central nervous system (Harrold, Dovey, Blundell, and Halford, 2012). 

Abnormal appetite control can happen in many cases. It leads to diseases and has an undesired effect on people’s lives. Reduced appetite is a common issue in older adults and is part of the anorexia of ageing. Anorexia could lead to a specific nutritional deficit and lower energy intake, leading to low body weight (Payette, Gray-Donald, Cyr and Boutier, 1995). Furthermore, insufficient nutrition intake could increase the risk of osteomalacia, osteoporosis, and muscle weakness (Pilgrim, Robinson, Sayer and Roberts, 2015). 

Hormonal changes are one of the physiological causes of loss in appetite in older adults. For instance, a higher cholecystokinin level during fasting is detected and leads to prolonged ghrelin release so that appetite is not upregulated punctually. (Malafarina, Uriz-Otano, Gil-Guerrero, and Iniesta, 2013). The change of leptin level was also measured in various age groups. An experiment tested the leptin level on two groups of subjects (elderly group and younger control group) before and every 30 minutes after having a standard meal. The result indicates a higher serum concentration of leptin in the elderly group (Di Francesco et al., 2006). There are some other causes of anorexia of ageing. The weakening of the digestive system, olfactory disorders and taste disorders can worsen appetite. Reduction in saliva causes less tastant to be dissolved in liquid, with less being detected by taste receptor cells. Low gastric and pancreatic secretions slow down the speed of digestion. Hence a longer time is required for gastric emptying (Nieuwenhuizen, Weenen, Rigby and Hetherington, 2010). 

Eating disorder is a disease associated with appetite disorder, like Binge eating disorder, with one of the main symptoms of consuming a large amount of food in a short period. It could lead to fluctuating body weight and obesity (Binge Eating Disorder, 2021). Appetite disorder is also found to link with obesity. In obese men, higher neuronal activity was found in the prefrontal cortex compared to lean men. The prefrontal cortex region controls the response to stimuli, which means it also responds to stimuli after meal consumption (Gautier et al., 2000). Drugs that are designed to suppress appetite are used to regulate body weight and reduce obesity. Orlistat and Sibutramine are two drugs approved for long-term use. They are both inhibitors of essential protein and enzymes in the human energy intake system. Lowered calorie intake and slight weight loss were noticed in obese patients given GLP-1 subcutaneously before the meal (Wadikar and Premavalli, 2012).

Appetite is regulated by different brain regions simultaneously, and most investigations were done on the role of the hypothalamus and lateral hypothalamic area. Hormones like leptin and ghrelin also assisted the control. More experiments need to be done to find out other solutions for appetite disorder and design drugs for relevant diseases.

References:

1. Hainerová, I. and Lebl, J., 2010. Mechanisms of Appetite Regulation. Journal of Pediatric Gastroenterology and Nutrition, 51(Suppl 3), pp.S123-S124. 
2. Krashes, M., Koda, S., Ye, C., Rogan, S., Adams, A., Cusher, D., Maratos-Flier, E., Roth, B. and Lowell, B., 2011. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. Journal of Clinical Investigation, 121(4), pp.1424-1428.
3. Krashes, M., Shah, B., Madara, J., Olson, D., Strochlic, D., Garfield, A., Vong, L., Pei, H., Watabe-Uchida, M., Uchida, N., Liberles, S. and Lowell, B., 2014. An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature, 507(7491), pp.238-242. 
4. Heisler, L. and Lam, D., 2017. An appetite for life: brain regulation of hunger and satiety. Current Opinion in Pharmacology, 37, pp.100-106. 
5. Harrold, J., Dovey, T., Blundell, J. and Halford, J., 2012. CNS regulation of appetite. Neuropharmacology, 63(1), pp.3-17. 
6. Payette, H., Gray-Donald, K., Cyr, R. and Boutier, V., 1995. Predictors of dietary intake in a functionally dependent elderly population in the community. American Journal of Public Health, 85(5), pp.677-683. 
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8. Malafarina, V., Uriz-Otano, F., Gil-Guerrero, L. and Iniesta, R., 2013. The anorexia of ageing: Physiopathology, prevalence, associated comorbidity and mortality. A systematic review. Maturitas, 74(4), pp.293-302. 
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10. Nieuwenhuizen, W., Weenen, H., Rigby, P. and Hetherington, M., 2010. Older adults and patients in need of nutritional support: Review of current treatment options and factors influencing nutritional intake. Clinical Nutrition, 29(2), pp.160-169. 
11. National Eating Disorders Association. 2021. Binge Eating Disorder. [online] Available at: <https://www.nationaleatingdisorders.org/learn/by-eating-disorder/bed&gt; [Accessed 21 February 2021].
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