Food, food and more food. The bottom line is, we are eating our ‘weigh’ into an obesity crisis. Particularly in the Western world, where ultra-processed and highly palatable foods are becoming the norm. Food is no longer just a source for survival but a source of pleasure, fueling a battle between homeostatic hunger and hedonic hunger. With around 650 million people affected by obesity, largely caused by the over consumption of food, we have to ask, what makes us want to eat? The answer is appetite.

Appetite is the body’s desire to satisfy bodily needs and its regulation driven by a complex interplay of peptides, hormones and the body’s neuronal circuitry. It is largely controlled by the hypothalamus, where there are two opposing circuits: one to stimulate appetite and the other suppresses it, both influenced by peripheral hormones that feedback on energy intake and expenditure. Orexigenic peptides increase appetite, while anorexigenic peptides decrease it. 

With the rise of obesity-related diseases, this blog aims to understand the role of appetite-regulating peptides in homeostatic hunger as well as hedonic hunger and to promote peptides as a possible solution to end the current obesity epidemic.

How are Peptides Involved in Appetite Regulation? 

To regulate gut motility, secretion, and absorption, appetite hormones are secreted by cells within the digestive system. When plasma levels of the orexigenic peptide ghrelin rise, feelings of hunger increase and so does food intake. After eating, levels of this appetite-stimulating hormone dissipate. Conversely, leptin induces feelings of satiety and increases after eating. Ghrelin and leptin act as antagonists on different hypothalamus nuclei to maintain energy homeostasis.

Figure 1: The role of leptin and ghrelin in hunger (left) and satiety (right)

Ghrelin was the first appetite stimulator to be identified and since then, many other appetite peptides have been uncovered. For example those that induce satiety like glucagon-like peptide-1 (GLP-1), neuromedin U, amylin, leptin, neuropeptide Y, peptide YY, and cholecystokinin. Ongoing research suggests that many of these peptides have a promising future in clinical applications targeting obesity reduction. Since the only long-term treatment to significantly reduce a patient’s weight is gastrointestinal surgery, there is a need to understand more about the function of these appetite-regulating peptides. Below we will briefly outline the role of a selection of appetite peptides and how they could be used to treat obesity.

Glucagon-like Peptide-1 (GLP-1)

Figure 2: A brief summary of GLP-1’s role in appetite
GLP-1 functions to suppress appetite, reduce the rate of digestion and increase glucose-stimulated insulin release. It is produced in the gut and the nucleus tractus solitarrri (NTS) of the brain stem. In the gut, GLP-1 acts on vagal afferents leading to the brainstem and it is further released into the general circulation and the pancreas. Most GLP-1 circulating in the blood, is degraded by dipeptidyl peptidase 4 (DPP-4) before it reaches the brain. As GLP-1 suppresses appetite, it is of clinical interest to increase the duration and endogenous levels of GLP-4. Therefore DPP-4 inhibitors such as linagliptin and sitagliptin have been produced and are being used to treat type 2 diabetes.

There are also many GLP-1 receptor agonists that have been approved to treat type 2 diabetes and obesity and include exendin-4, semaglutide, dulaglutide and liraglutide. GLP-1 receptor agonists serve to decrease food intake, increase satiety and delay gastric emptying. They also activate insulin release and inhibit glucagon secretion. A success story is semaglutide, which when given to patients once a week, resulted in a ’15-17%’ weight loss. One disadvantage of the current GLP-1 receptor agonist treatments however is that they are injected and therefore invasive. In response, oral GLP-1 receptor agonists are in development alongside combination therapies such as Tirzepatide, a combination of GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonists. Tirzepatide has been approved for type 2 diabetes management and is currently being assessed for use in obesity treatment. 

Another interesting avenue of GLP-1 is its possible role in hedonic hunger in addition to homeostatic hunger. Regions of the brain associated with reward, motivation, emotion and memory, to which the NTS extends into, has GLP-1 receptors. This suggests GLP-1 to be an interesting candidate for research into food addiction.

Leptin

Produced in white adipocytes, leptin plasma concentration increases as body fat mass increases. As such leptin can be used as an adiposity biomarker. Leptin receptors are highly expressed in the hypothalamus of the brain and as already discussed, when hypothalamic leptin signaling is activated, food intake is reduced and energy expenditure is induced. It has also been found that when leptin is produced in the gastric epithelium, it acts locally to induce satiation signals.

In relation to obesity, some obese humans and rodents have exhibited a leptin deficiency, which can be treated through leptin administration. Contrary to this, the leptin plasma levels of most obese individuals are in fact high, reflecting a possible leptin resistance in such individuals. In these cases the administration of leptin is ineffective. A few possible causes of leptin resistance could be the saturation of leptin transporters at the blood brain barriers, preventing leptin transportation into the brain. Another reason is reduced leptin transport as a result of increased free fatty acids and plasma proinflammatory cytokines. It is evident that leptin resistance plays a role in obesity and provides another direction for obesity research.

Amylin

Figure 3: The role of amylin in appetite regulation

Amylin is another peptide with important functions in appetite regulation. In response to food intake, amylin is produced by beta cells in the pancreas and acts to decrease appetite, feeding and overall reduces body weight. This appetite peptide also plays a key role in controlling glucose homeostasis. Currently the compound pramlintide, which acts on the amylin pathway has been approved by the FDA for use in type I diabetes patients. However due to Amylin’s short half-life in blood, salmon calcitonin is often used in research as it mimics amylin’s ability to reduce feeding and uses amylin’s receptor (AMYR).

Cholecystokinin (CCK)

CCK is a gut hormone that displays anorexigenic action, by transferring signals of satiety to the hypothalamus. It is secreted from enteroendocrine cells in the dueodenum and small intestines. It was found that the injection of CCK into humans and rats, caused a reduction in their meal size. This alludes to CCK being another important appetite regulator to be researched.

Ghrelin

Although ghrelin is an orexigenic peptide and increases food intake and weight gain, it still could prove to be an interesting subject in the fight against obesity and obesity related disease. Ghrelin is a ligand to the growth hormone secretagogue receptor (GHSR) and while it is primarily produced in the stomach, it can also be produced in the brain. Intriguingly past studies have alluded to a possible connection between ghrelin, hunger and addiction. Plasma levels of ghrelin are known to increase in the event of food restriction and in one study increased consumption of amphetamine and cocaine was observed in rats whose food was restricted. Moreover, GHSR-1A has been found to form complexes with dopamine receptors, ultimately regulating reward-related behaviors. There is mounting evidence to suggest that ghrelin and GHSR-1A play a part in addiction modulation and addiction -related behaviors.

Peptide YY (PYY) and Pancreatic Polypeptide PP

Plasma levels of anorexigenic peptides like PYY rise after food intake, leading to a feedback circuit to the hypothalamus to induce satiety. Various studies demonstrate that when PYY is administered to rodents, food intake is inhibited. Pancreatic polypeptide (PP) like PYY has anorectic effects, but it is thought that PP is involved in the long term control of appetite. PP is secreted from pancreatic islet PP cells after food intake and its levels are proportional to the amount of calories consumed. Interestingly PP levels last for 6 hours. In regard to those with obesity, PP plasma levels are reduced and it was found that food intake was reduced in mice who were administered PP.

Figure 4: Summary of the effect that different peptides have on appetite

Hedonic Hunger and its Role in the Obesity Crisis 

In our modern world a phenomenon known as hedonic hunger is becoming more prevalent. The availability of diverse and palatable foods has increased so that we now eat for pleasure rather than to maintain energy homeostasis. A good example of hedonic hunger is used in an article by Monteleone et al. (2012), where it is explained that during hedonic eating despite eating a meal that creates satiety, we often crave a dessert afterwards. 

Hedonic eating is controlled by the brain reward system in the midbrain, home to the mesolimbic and mesocortical dopamine pathways which are also involved in other addiction behaviors. It is thought that the consumption of tasty food stimulates the brain reward circuits, resulting in the release of endocannabinoids, opiates and dopamine. Dopamine that is released in the ventral tegmental area activates ‘neuronal pathways’ from the ventral tegmental area to the nucleus accumbens. Consequently hypothalamic hunger signals are stimulated while satiety mediators are inhibited. Metabolic signals play a role in regulating hedonic eating, for example Leptin suppresses the need to eat through acting on the ventral tegmental area on dopaminergic neurons. However it is possible for hedonic eating to continue despite these signals. In one study it was found that when food was eaten purely for pleasure there was an increase in ghrelin and endocannabinoid 2-arachidonoyl-glycerol levels.

It is thought that hedonic hunger is a huge factor contributing to individuals becoming overweight and obese. Research has shown that those with obesity have increased hedonic hunger compared to those who do no have obesity. The most effective treatment currently available to treat obesity is bariatric surgery which has shown to decrease a person’s hedonic appetite and reduce food addiction. Therefore hedonic hunger is another interesting appetite processes to target when developing obesity treatments.

The strain that the obesity epidemic has brought in Western countries is considerable. The prevalence of overweight people has created a threat to health services that incur high costs for treating weight-related conditions such as diabetes type II, hypertension, cardiovascular disease and metabolic-dysfunction associated steatotic liver disease. And with obesity on the rise scientists are looking to key appetite peptides to provide a therapeutic solution. Biosynth are excelling in the peptide field, offering a range of catalog peptides and custom peptide services. We have a whole host of appetite related peptides with the potential to end the obesity crisis. Contact us for more information.

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References 

Aukan, M. I., Finlayson, G. Martins, C. (2024). Hedonic hunger, eating behavior, and food reward and preferences 1 year after initial weight loss by diet or bariatric surgery. Obesity, 32(6), 1059-1070.

Coccurello, R., Maccarrone, M. (2018). Hedonic Eating and the “Delicious Circle”: From Lipid-Derived Mediators to Brain Dopamine and Back. Frontiers in Neuroscience, 12-2018.

Melson, E., Ashraf, U., Papamargaritis, D., Davies, M. J. (2024). What is the pipeline for future medications for obesity? International Journal of Obesity, (2024).

Monteleone, P., Piscitelli, F., Scognamiglio, P., Monteleone, A. M., Canestrelli, B., Di Marzo, V., Maj, M. (2012). Hedonic Eating Is Associated with Increased Peripheral Levels of Ghrelin and the Endocannabinoid 2-Arachidonoyl-Glycerol in Healthy Humans: A Pilot Study. The Journal of Clinical Endocrinology & Metabolism, 97(6), E917-E924.

Shevchouk, O, T., Tufvesson-Alm, M., Jerlhag, E. (2021). An Overview of Appetite-Regulatory Peptides in Addiction Processes; From Bench to Bed Side. Frontiers in Neuroscience, 15.

Yu, J. H., Kim, M. (2012). Molecular Mechanisms of Appetite Regulation. Pathophysiology, 36, 391-398.