Peripheral Considerations Regarding Hunger and Appetite Control

Table of Contents


In the prior few articles I discussed many of the brain considerations for hunger and appetite regulation, mentioning that there are a few brain centers (primarily certain hypothalamic nuclei, the nucleus tractus solitarius (“NTS”), and the area postrema (“AP”)) that are able to survey and assimilate peripheral signals from the rest of the body. I will discuss these peripheral signals in this article.

Note: Similar to how a lot of the brain research is done in rodents, cell culture, or other avenues, it is difficult to rigorously research the peripheral hormonal signals and other considerations that influence hunger. For example, we can measure hormones in the bloodstream before and after a meal, but that will not necessarily correlate with the concentration of a hormone at a specific site of action and will not indicate how they may work synergistically with other hormones. Additionally, some hormones, such as ghrelin and PYY, have multiple forms, and teasing apart all of the different influences of each type is challenging. Nonetheless, I will present findings that are consistent in much of the literature.

The following figure provides a good overview of the complexity of peripheral signaling from the GI tract. The key points to take away from this figure are that:

  • The gastrointestinal (“GI”) tract has enteroendocrine cells that can secrete many different hormones and these hormones can travel to the brain through the bloodstream or can act on receptors in vagal afferent nerves (which then coalesce into the vagus nerve that transmits these signals to the brain).
  • The stomach can additionally provide mechanical information based on gastric distension and pressure.
  • Ingested nutrients as well as compounds from other parts of the body, such as leptin (not shown in the figure) from adipose tissue, will also reach the brain via the bloodstream.
Reproduced from: Berthoud HR, Morrison CD, Ackroff K, Sclafani A. Learning of food preferences: mechanisms and implications for obesity & metabolic diseases. Int J Obes (Lond). 2021 Oct;45(10):2156-2168. doi: 10.1038/s41366-021-00894-3. Epub 2021 Jul 6. PMID: 34230576; PMCID: PMC8455326.

Hormones and other peripheral compounds

I will discuss the most pertinent hormones in greater detail and then include smaller blurbs on potentially other relevant compounds.


Ghrelin is often referred to as the “hunger hormone”. It is produced mainly in the stomach but also in the small intestine, hypothalamus, and pituitary. Its concentration is determined in part by your overall level of energy restriction and also based on conditioned circadian and orosensory cues; it generally peaks 3-4 times daily prior to meals and then gradually returns to baseline within an hour after eating. The cells that secrete ghrelin have receptors for various nutrients that can suppress ghrelin’s release (protein is the primary suppressant).

The ghrelin receptor is highly expressed in the arcuate nucleus of the hypothalamus (“ARH”) and ghrelin can activate AgRP/NPY neurons in the ARH. By stimulating AgRP/NPY neurons ghrelin will increase hunger. It also stimulates the orexin-producing neurons in the lateral hypothalamic area (“LHA”), inhibits the POMC/CART neurons in the ARH, increases gastric motility and gastric acid secretion, inhibits insulin secretion while promoting hepatic glucose production, increases fat storage in adipose tissue, and attenuates vagally mediated satiation signals (such as those from CCK (discussed below)). Ghrelin additionally may help resists emotionally stressful states of anxiety and depression; the fact that it also increases hunger may help explain why eating is a coping mechanism for many people with these mental health conditions.

Ghrelin is secreted in a non-acylated form that can impact energy expenditure, and this is the form that increases when fasting. It needs to be acylated to become active regarding hunger regulation (acylation is required for it to be able to cross the blood-brain barrier). This acylated form has a half-life of ~30 minutes. It can additionally activate mesolimbic reward circuitry, thus making rewarding aspects of food intake more prominent when hungry. However, prolonged fasting decreases the activity of the enzyme that acylates ghrelin and thus attenuates the acylated ghrelin peaks, which may correlate with decreased hunger as fasting duration lengthens.

Regarding obesity, people with obesity generally have lower levels of ghrelin at baseline, but potentially more importantly, they also have smaller decreases in ghrelin levels after eating a meal. Thus, people with obesity may have more hunger-stimulating and satiety-preventing effects of ghrelin even after eating a meal. Of note, though, this finding was with regular ghrelin, not necessarily acylated ghrelin. Certain types of gastric bypass surgery are found to decrease ghrelin levels and it is thought that this may also contribute to the weight-loss effects of these surgeries. Separately, a FTO gene variant associated with obesity leads to higher levels of ghrelin.

Note: Moderate or vigorous intensity exercise may temporarily decrease ghrelin levels in part due to decreased blood supply to the stomach but it is unclear what impact exercise has on ghrelin long-term. This may be one reason why many people find they are not very hungry during or after intense exercise sessions.

The following image demonstrates ghrelin’s signaling in the brain:

Here LDTg = laterodorsal tegmental area and PPTtg = pedunculopontine tegmental area; both of these areas are involved in reward signaling. The rest of the locations have been discussed previously in this series. Reproduced from: Howick K, Griffin BT, Cryan JF, Schellekens H. From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation. Int J Mol Sci. 2017 Jan 27;18(2):273. doi: 10.3390/ijms18020273. PMID: 28134808; PMCID: PMC5343809.


Insulin is a hormone produced by pancreatic β-cells that helps regulate blood glucose levels and has several other roles in the body. It additionally interacts with other hunger-regulating hormones such as GIP & GLP-1 (discussed below). After eating it can cross the blood-brain barrier to act on insulin receptors in the ARH that stimulate the POMC neurons, and insulin signaling leads to inhibition of the AgRP/NPY neurons. It can also help stimulate leptin secretion.

Regarding obesity, people with obesity may develop insulin resistance and this may prevent its action to promote satiety; thus people with insulin resistance tend to have decreased postprandial satiety and more poorly regulated meal-to-meal appetite control.


Leptin is a hormone secreted by adipose tissue (termed an “adipokine”) at a level proportional to total fat mass. It can act on several of the hypothalamic nuclei including the ARH, LHA, dorsomedial hypothalamus (“DMH”), and ventromedial hypothalamus (“VMH”). In the ARH this leads to stimulation of the POMC neurons (possibly indirectly by decreasing inhibitory tone from presynaptic GABAergic neurons) and leads to inhibition of the AgRP neurons (via both direct effects on these neurons as well as upstream effects) over the time scale of hours. It will decrease ghrelin’s orexigenic action. It can also act on POMC neurons in the NTS to augment signals from the vagus nerve; it increases the sensitivity of the vagal nerve afferents to gastric distension as well as CCK and GLP-1 (both are short-term satiety-inducing peptide signals discussed further below). Thus, leptin promotes satiety. It typically peaks at around midnight.

Leptin may additionally increase energy expenditure through interactions with amylin (discussed further below), and these interactions also support amylin’s action at the AP and ventral tegmental area (“VTA”) that will generally inhibit eating. People with congenital leptin deficiency also have increased activity in several components involved in hedonic eating regulation when presented with food cues implying leptin helps to suppress the hedonic drive to eat (likely through its action at the VTA). Leptin can also inhibit adrenal corticosteroid secretion and can selectively inhibit responses to sweet taste by binding to taste receptor cells.

Regarding obesity, people with obesity can develop leptin resistance, leading to a smaller effect in promoting satiety. There are many theorized mechanisms to explain the etiology of leptin resistance, but this is still a subject of debate. As seen in the image below, leptin signaling at a molecular level involves several components, and determining the primary underlying mechanism(s) generating leptin resistance is an active area of research as this would hopefully generate further drug targets to treat obesity.

If curious, you can access the article to read the caption. Reproduced from: Liu H, Du T, Li C, Yang G. STAT3 phosphorylation in central leptin resistance. Nutr Metab (Lond). 2021 Apr 13;18(1):39. doi: 10.1186/s12986-021-00569-w. PMID: 33849593; PMCID: PMC8045279.

Glucagon-like peptide 1 (“GLP-1”)

GLP-1 is a hormone with precursors secreted by L-cells in the distal ileum, colon, pancreas, and brain. It is then cleaved by different enzymes to make tissue-specific products. It is rapidly released after ingestion of carbohydrate and fat, at levels proportional to caloric intake, and its production is also stimulated by bile acids and neural activation. Thus, its levels are lowest after an overnight fast, and after eating it is secreted in a rapid phase within 10-15 minutes and a longer phase at 30-60 minutes. Its half-life is <2 minutes as it is degraded by the enzyme dipeptidyl peptidase-4.

It has receptors in several locations in the brain, including the ARH (where it can act on POMC neurons), PVN, NST, and AP. It can additionally innervate vagal afferent nerves and influence myenteric neurons to delay gastric emptying with an “ileal brake” (discussed below). It otherwise acts to promote satiety, potentiate glucose-dependent insulin release (the “incretin” effect), and inhibit glucagon release. Much of its anorexigenic effect seems to derive from its influence in the hedonic brain areas. GLP-1 may also help stimulate the release of serotonin in the GI tract, with serotonin then enhancing the effect of GLP-1 on vagal afferent nerves.

Regarding obesity, people with obesity have an attenuated GLP-1 postprandial response in some (though not all) studies, implying people with obesity may experience a smaller satiety-promoting effect from GLP-1 after eating.

Peptide Y (“PYY”)

PYY is a hormone secreted by L-cells in the ileum, colon, and rectum, peaking at 60 minutes post-ingestion but remaining elevated for up to 6 hours, primarily in response to lipid and secondarily to protein ingestion. Other stimulating factors include bile acids, gastric acids, and CCK (discussed below). It seems to be co-secreted with GLP-1 and oxyntomodulin (discussed below) and has complementary effects. Its active form (PYY3-36, as opposed to the initially secreted form of PYY1-36) binds to the NPY Y2 receptors to inhibit AgRP/NPY neurons and it also stimulates POMC neurons to have an overall effect of inducing satiety. It functions in the ileal break system (discussed below). It additionally transmits satiety signals via vagal afferent nerves, promotes insulin secretion, and can increase colonic water & ion absorption. Various diseases characterized by decreased appetite are often associated with higher levels of PYY3-36.

Regarding obesity, in some (but not all) studies people with obesity have lower levels of PYY both when fasting and after consuming a meal, and when people lose weight via dieting PYY levels tend to decrease.

The following cartoon demonstrates how enteroendocrine cells, making up ~1% of intestinal cells, can secrete several different products that act directly on vagal afferent nerves. These products can also pass through the circulation to reach the brain in areas where the blood-brain barrier is not completely intact.

Reproduced from: Sun EWL, Martin AM, Young RL, Keating DJ. The Regulation of Peripheral Metabolism by Gut-Derived Hormones. Front Endocrinol (Lausanne). 2019 Jan 4;9:754. doi: 10.3389/fendo.2018.00754. PMID: 30662430; PMCID: PMC6328484.

Pancreatic polypeptide (“PP”)

PP is secreted primarily from the pancreas and in smaller amounts by the colon and rectum with plasma levels dependent on caloric intake, gastric distension, blood glucose concentration, and circulating hormones. It can act on NPY Y4 or Y5 receptors in the hypothalamus, NTS, and AP to inhibit AgRP/NPY neurons, increase satiety, and it can also function to delay gastric emptying, decrease gallbladder motility, and decrease pancreatic exocrine secretion.

Regarding obesity, people with obesity generally have lower levels of PP.

Cholecystokinin (“CCK”)

CCK is a hormone released by I-cells of the duodenum and jejunum in the postprandial phase, and it is also secreted in the CNS. It is stimulated primarily by fat and protein as opposed to carbohydrate ingestion. It gradually increases in concentration in the first 10-30 minutes after beginning a meal and remains elevated for up to 5 hours as the food transitions to the duodenum, but it only has a half-life of 1-2 minutes. It can act on vagal afferent nerves, POMC neurons in the NTS, the ARH, and other brain regions, with additive or potentially synergistic effects with leptin due to colocalization of their receptors on vagal afferent fibers. It generally increases satiety and additionally:

  • facilitates nutrient absorption by delaying gastric emptying
  • stimulates overall gut motility, gallbladder contraction, and pancreatic enzyme secretion
  • increases insulin secretion
  • acts on taste receptor cells to influence bitter taste

Regarding obesity, people with obesity who undergo weight loss and subsequent weight loss maintenance have continually decreased levels of postprandial CCK secretion relative to their levels prior to weight loss.

Several of the above hormones, as well as various hunger/appetite ratings, were recently evaluated in a systematic review and meta-analysis comparing people with and without obesity.(Aukan, 2022) I have included a table showing their primary findings below. In summary, people with obesity had decreased levels of total ghrelin before and after eating and they also had decreased levels of total PYY as well as hunger after eating. However, due to the high heterogeneity with many of the analyses due to varying protocols, as well as the always-present question of whether these changes cause obesity or are a consequence of obesity, it’s hard to draw firm conclusions form this literature base; we need to wait for more studies.

Negative values mean lower values were found in obesity. Reproduced from: Aukan MI, Coutinho S, Pedersen SA, Simpson MR, Martins C. Differences in gastrointestinal hormones and appetite ratings between individuals with and without obesity-A systematic review and meta-analysis. Obes Rev. 2022 Nov 23:e13531. doi: 10.1111/obr.13531. Epub ahead of print. PMID: 36416279.

Note: The levels of several hunger-related hormones change with dietary weight loss. Even after a year of weight loss maintenance there may still be increased levels of ghrelin and decreased levels of leptin, insulin, PYY, and CCK. This is not necessarily a bad thing; for example, if leptin and insulin decrease due to decreased leptin and insulin resistance this will likely prove beneficial from a health standpoint without significantly increasing hunger.

However, with bariatric surgery things are different:

  • This can lead to increases in PYY and GLP-1 postprandially as well as decreases in ghrelin, with larger changes seen in those who are more successful with weight loss. This all may contribute to the general decrease in hunger levels seen after bariatric surgery despite substantial weight loss.
  • Bariatric surgery can change taste and food preferences, alter the neural response to food cues, and decrease sweet taste palatability.
  • In studies of mice, weight loss induced by bariatric surgery does not increase the activity of AgRP neurons, and thus the body weight may move to a new, lower settling point.

Thus, if we could ever find pharmacologic methods to replicate some of the physiologic implications of bariatric surgery that could go a long way in helping to treat obesity on a broader scale.


Glucagon is a hormone with precursors secreted by pancreatic α-cells. It stimulates glucose production via upregulating gluconeogenesis in the liver. It also acts on the vagus nerve, reaches the brain, and can contribute to delayed gastric emptying, increased satiety, and increased lipolysis.

Oxyntomodulin (“OXM”)

OXM is a separate product from the proglucagon gene and it is secreted by L-cells in the distal ileum and colon, at levels proportional to the caloric content of a meal. It activates both GLP-1 and glucagon receptors leading to inhibition of gastric emptying and gastric acid secretion as well as decreased pancreatic enzyme secretion. Collectively, this promotes satiety & contributes to fullness. OXM can additionally inhibit ghrelin secretion, lead to increased energy expenditure, and impact brain areas involved in reward.

Glucose-dependent insulinotropic peptide (“GIP”, formerly known as gastric inhibitory polypeptide)

GIP is an incretin hormone secreted by K-cells of the duodenum and proximal jejunum. It has receptors in the hypothalamus, NTS, pancreas, and on adipocytes. It is secreted in response to glucose- & fat-rich meals, increasing over 10-15 minutes and returning to baseline after 180 minutes, with a half-life of 5-7 minutes. In the fasted state it can enhance glucagon release but after food intake it stimulates insulin production, increases satiety, and also influences brain reward areas.

Apolipoprotein A-IV

Apolipoprotein A-IV is secreted by the small intestine in amounts proportional to dietary lipid intake. Its secretion is downregulated by leptin and it interacts positively with CCK circuits.

Bombesin-like peptides

Bombesin-like peptides include two anorectic compounds (gastrin-releasing peptide and neuromedin beta) that can increase thermogenesis, decrease appetite, and inhibit gastric emptying.


Secretin controls gastric acidification and motility, and it can also increase thermogenesis and impact appetite-control signaling in the hypothalamus.

Vasoactive intestinal peptide & adenylate cyclase activating polypeptide 1

These play roles in the central control of food intake; more research is needed to determine their mechanisms of action.

Calcitonin-Related Peptides

These are primarily secreted in the pancreas and in the brain and consist of amylin (islet amyloid polypeptide), adrenomedullin, calcitonin, and calcitonin gene-related peptide (“CGRP”).

  • Amylin: this is released by β-cells of the pancreas and has multiple roles in hunger regulation. It acts in the AP, on POMC neurons in the ARH, and in the VMH to collectively inhibit food intake. It can aid in potentiating the action of CCK while increasing sensitivity to leptin. Additionally, amylin functions to increase energy expenditure. It also decreases gastric emptying, postprandial glucagon secretion, and blood glucose levels. Basal levels of amylin increase with obesity but with weight loss this decreases.
  • Adrenomedullin: this has roles in growth, endocrine regulation, neurotransmission, and antimicrobial activity, so any impact on appetite is likely indirect.
  • Calcitonin & CGRP both have functional roles in appetite regulation, with calcitonin being orexigenic and CGRP being anorexigenic.

Apelin (“APLN”)

This is an adipokine primarily produced by adipocytes but also produced by the gastric mucosa and Kupffer cells in the liver. It rises in response to elevated blood glucose and helps lower the glucose concentration. It is increased with obesity possibly to delay or compensate for insulin resistance.

Fibroblast Growth Factor 21 (“FGF21”)

This compound is secreted in the liver upon sugar ingestion and inhibits appetite. It is upregulated in obesity potentially to help protect the liver from excess nutrients. However, it is also upregulated with dietary protein deficiency, in which case it likely would not negatively influence appetite and may help drive greater food intake to make up for the deficiency in protein. Thus, its overall role in appetite regulation is unclear.


This is an anorectic peptide that can directly activate the vagus nerve and influence hypothalamic signaling to inhibit AgRP/NPY neurons and activate the melanocortin system. It additionally enhances glucose-induced insulin secretion.


This compound stimulates β-cell function to improve insulin sensitivity and additionally has roles in improving fatty acid oxidation, increasing energy consumption, and decreasing snacking.


This compound is secreted between meals to stimulate peristaltic waves in line with migrating motor complex (“MMC”) contractions. It may also induce feelings of hunger via vagal nerve activation. Typically its peak provokes entry into MMC phase 3 (maximum mechanical & electrical activity causing active peristalsis for 5-10 minutes), but people with obesity have a lack of a clear peak and thus impaired gastric motility.


This adipokine has antiinflammatory and antiatherogenic properties, improves insulin sensitivity, and enhances AMPK activity in the ARH; it will inhibit AgRP neurons while stimulating POMC neurons. It is present in lower concentrations in individuals with obesity which may help the body adapt to increased energy intake (by decreasing appetite), but this has negative consequences regarding insulin resistance and hypertension.


This adipokine is secreted upon fasting, triggers glycogenolysis in the liver, and may directly activate AgRP neurons. It is generally upregulated in obesity.

Acyl-coenzyme A binding protein (“ACBP” or  “diazepam binding inhibitor (DBI)”)

This is a protein that is expressed in the cytoplasm of nucleated cells and affects multiple aspects of cellular metabolism. It can be relocated to the extracellular space and sense nutrient scarcity; it then triggers an increase in appetite. It is overexpressed in obesity and thus may represent a feedforward mechanism that leads to a further increase in obesity.


This is produced by L-cells and has roles in increasing glucose-dependent insulin secretion while decreasing gut motility, gastric acid secretion, and gastric emptying. It also can influence brain reward regions.


This is produced from enteroendocrine N-cells & CNS neurons. It increases gastric emptying and decreases food intake.


This hormone targets POMC neurons in the ARH and indirectly represses the activation of AgRP/NPY, leading to decreased hunger. It also promotes subcutaneous fat deposition at the expense of visceral fat.

Bile acids

Bile acids stimulate L-cell secretion of GLP-1 and PYY and additionally influence gut microbiota composition; it is unclear what influence this has overall on hunger levels.

Short-chain fatty acids (“SCFA”)

SCFA are generally produced in the colon from the gut microbiome when the bacteria ferment and metabolize fermentable dietary fiber. Besides imparting general health benefits, SCFAs can stimulate GLP-1 and PYY secretion.

Additional peripheral considerations

Besides specific metabolic/hunger/satiety/nutrition-related hormones and related endogenously produced compounds, there are other physiologic and dietary components that contribute to hunger and satiety as well.


During fasting there is a cyclic pattern of motility and secretion via the migrating motor complex; this has 3 phases and contributes to sensations of an empty stomach associated with increased hunger. With food consumption the stomach is able to expand up to 15x in volume before intragastric pressure increases; this increase is detected by mechanosensing vagal nerve afferents and relayed to the NTS as a satiation signal. This then leads to efferent motor signals to increase peristaltic contractions and gastric emptying. The gastric emptying rate is influenced by the volume, caloric density, and osmolality of the gastric contents as well as by feedback from the various signals release by the GI tract during digestion (ie, the “ileal brake” mechanism discussed below). As examples, CCK and GLP-1 can directly stimulate the inhibitory circuit to slow gastric emptying while leptin can increase activation of the CCK1 receptors.

Note: Variations in gastric emptying account for ~35% of the variations in postprandial blood glucose in healthy humans. Additionally, hyperglycemia typically inhibits gastric emptying while hypoglycemia typically accelerates gastric emptying. Protein and fat intake can slow gastric emptying, as can soluble, viscous, gel-forming fiber, relative to simple carbohydrate intake.

Additionally, liquid forms of foods will pass more quickly through the stomach than pureed and solid forms. The gastric emptying rate of liquids follows an exponential curve proportional to the volume of consumed liquid, while the gastric emptying rate of solids follows a linear rate (after a lag period) independent of food volume.(Dhillon, 2016) Liquid versions of foods are generally considered less satiating than pureed and solid versions, possibly due to this reason but also likely due to the expectation that they will be less filling. However, soup seems more satiating than a solid equivalent, potentially due to an additional effect of quenching thirst.

Ileal break

The “ileal brake” describes a process where when nutrients (primarily protein and fat) reach the ileum in the distal part of the small intestine this induces a feedback response to the proximal GI tract. Due to activation of enteroendocrine cells and mucosal nerve afferents this ultimately decreases intestinal motility and inhibits further gastric emptying. This is primarily regulated by GLP-1 and CCK from the proximal gut and PYY from the distal gut. The intensity of the ileal brake is dependent upon the caloric load, food composition, and gastric emptying rate.

Resting metabolic rate (“RMR”)

A higher RMR is generally associated with greater daily energy intake.(Blundell, 2015) The primary contributor to your RMR is your total level of fat-free mass, and people with obesity have higher levels of fat-free mass. Thus, this higher amount of lean body tissue that is associated with excess adiposity in obesity drives an increased need for calorie consumption, contributing to greater hunger levels overall.

If curious, you can see approximate values and thus the relative contribution of different organs to your RMR in the following table:

table showing contribution of different organs to resting metabolic rate
Residual includes intestines, pancreas, thyroid, etc. This example sums to 1685 kcal for a 71 kg person. Of note, as these are approximate values that change with age, gender, and body weight, these numbers are not directly applicable to any one specific person. References are included in Lesson 1 of the Nutrition and Weight Management Course.

Note: With weight loss the body will try to “fight” this in several ways, one of which is to make metabolically active tissue work more efficiently (likely via alterations of sympathetic nervous system activity). This will lead to less heat loss and thus less energy waste when actively losing weight. This also occurs with regular exercise where the body learns to work more efficiently, leading to a smaller caloric expenditure for the same amount of work as your general fitness or weight loss increases.

I have not read anything to indicate that metabolic efficiency is directly linked to hunger levels, but as this is one way energy intake and energy expenditure could be linked together it would not surprise me if there is an association.

Lean body mass

It seems that in addition to passively stimulating hunger via an increase in metabolism when lean body mass increases, when undergoing weight loss and losing lean body mass this seems to actively stimulate hunger. The signals that lead to this increase in hunger are currently unknown, though several putative candidates exist and largely consist of various myokines (signaling molecules from skeletal muscle). I discuss data evaluating this in the following YouTube video.

Fat mass

While higher fat-free mass contributes to an increased RMR and thus increased caloric intake, when lean individuals begin to gain greater levels of fat mass this generally has a tonic inhibitory effect on energy intake (likely due to increased leptin), leading to decreased hunger levels.(Blundell, 2015) However, the strength of this inhibition weakens as people develop insulin and leptin resistance, and at some point this tonic inhibition seems to disappear. At this point the increased fat mass then contributes to a higher RMR and caloric inake via the associated increase in lean body mass.


The three primary macronutrients are protein, carbohydrates, and fat, all of which can contribute to satiety when consumed in different ways.


Protein seems to be the most satiating macronutrient. When protein is ingested this can slow down gastric emptying, increase thermogenesis, stimulate an increase in secretion of various satiety hormones mentioned above (ie, CCK, GIP, GLP-1, PYY), suppress ghrelin, and influence POMC neurons to stimulate thermogenesis. Of interest, there is a putative “deficit” signal for dietary protein (FGF21), but not for carbohydrate and fat, that may contribute to greater food intake when protein consumption is low to help make up for the deficit in protein intake.

Note: The “protein leverage hypothesis”, suggests that part of the drive of the obesity epidemic stems from the notion that as people eat more highly palatable foods, which generally contain less protein, they will experience a greater drive to eat overall to help make up for the protein deficit. Leptin can also be considered a deficit signal (for total caloric intake) but is not specific to any one macronutrient.


Carbohydrates are less satiating than protein but more satiating than fat (when normalized by calorie content). Carbohydrate intake, including fiber, can increase gastric secretions as well as the release of CCK and GLP-1, suppress ghrelin, and stimulate the sympathetic nervous system to increase thermogenesis. The source of carbohydrate is likely significant; many people will find simple sugars in isolation to not be very satiating, while whole grains may be considerably more satiating.


Fat intake seems less satiating than protein and carbohydrate intake when normalized for calorie content. Dietary fat can delay gastric emptying and stimulate the release of various satiety hormones (ie, CCK, GLP-1, PYY), but their high palatability may lead to increased consumption via hedonic stimulation. This higher palatability is particularly seen with snacks that combine fats and carbohydrates, which can more easily trigger hedonic eating that overrides homeostatic considerations. Alternatively, healthier fat sources such as olive oil, whole-fat dairy, and nuts, may prove more satiating.

Stress and cortisol

Some people typically eat less when in stressful situations while some people eat more (“stress eating”), with the intensity of the stressor likely impacting the desire for food consumption. Cortisol, the “stress” hormone, can reduce the brain’s sensitivity to leptin and insulin and enhance the release or activity of both ghrelin and NPY, which will stimulate increased hunger and food consumption; this may ultimately induce an increase in the reward sensitivity of food and the hedonic drive to eat.(Kuckuck, 2022)


While the mechanisms are still being worked out, it seems that poor sleep can negatively impact hunger and appetite regulation by impacting the function of several of the peripheral hormone signals.

Reproduced from: Liu S, Wang X, Zheng Q, Gao L, Sun Q. Sleep Deprivation and Central Appetite Regulation. Nutrients. 2022 Dec 7;14(24):5196. doi: 10.3390/nu14245196. PMID: 36558355; PMCID: PMC9783730.

Note: One topic I did not discuss above or in any of the prior articles is that of pregnancy. There are several differences in various aspects of hunger and appetite regulation during pregnancy, and much work remains to be done to better characterize the underlying physiology.(Clarke, 2021) In brief, changes include:

  • increased food intake throughout pregnancy
  • increases in leptin and insulin levels as well as increases in leptin and insulin resistance
  • increases in AgRP/NPY neuron output
  • nutrient sensors in the tongue are altered potentially to preference protein intake
  • the intestines enlarge and GI satiety hormone production increases
  • there are changes in estrogen, progesterone, prolactin, and growth hormone

All of these changes are likely not solely to influence food intake (ie, if hunger and food intake increases what is the purpose of increasing GI satiety hormone release). We will need more research to better characterize what changes occur that actually influence food intake directly. This knowledge may then help guide efforts to assist pregnant individuals in gaining gestational weight within the guidelines for a healthy pregnancy.


There are many peripheral considerations that impact hunger and appetite, either directly or indirectly. All of the gastrointestinal hormones seem to play a role to some degree, with ghrelin, insulin, PYY, CCK, GLP-1, and PP being the more relevant considerations. Leptin has a large impact, and stress responses mediated by cortisol can also influence eating habits significantly. Beyond the hormones, nutrients and metabolites themselves can influence satiety, mechanical considerations from food intake play an acute role, and total levels of fat-free mass and fat mass can impact overall metabolism and influence caloric consumption over the long-term in various ways. Importantly, these signals all influence the brain in some way, feeding into the homeostatic and hedonic regulation mechanisms discussed earlier in this series.

With all of basic physiologic aspects of hunger regulation now covered, in the next and last article of this series I will discuss the practical points that can be deduced from this knowledge.

Click here to proceed to article 6 of this series, or jump around with the drop-down menu below.


  1. Aukan MI, Coutinho S, Pedersen SA, Simpson MR, Martins C. Differences in gastrointestinal hormones and appetite ratings between individuals with and without obesity-A systematic review and meta-analysis. Obes Rev. 2022 Nov 23:e13531. doi: 10.1111/obr.13531. Epub ahead of print. PMID: 36416279.
  2. Blundell JE, Finlayson G, Gibbons C, Caudwell P, Hopkins M. The biology of appetite control: Do resting metabolic rate and fat-free mass drive energy intake? Physiol Behav. 2015 Dec 1;152(Pt B):473-8. doi: 10.1016/j.physbeh.2015.05.031. Epub 2015 May 31. PMID: 26037633.
  3. Clarke GS, Gatford KL, Young RL, Grattan DR, Ladyman SR, Page AJ. Maternal adaptations to food intake across pregnancy: Central and peripheral mechanisms. Obesity (Silver Spring). 2021 Nov;29(11):1813-1824. doi: 10.1002/oby.23224. Epub 2021 Oct 8. PMID: 34623766.
  4. Dhillon, J., Running, C. A., Tucker, R. M., & Mattes, R. D. Effects of food form on appetite and energy balance. Food Quality and Preference. 2016;48(Part B), 368–375. doi:10.1016/j.foodqual.2015.03.009
  5. Kuckuck S, van der Valk ES, Scheurink AJW, van der Voorn B, Iyer AM, Visser JA, Delhanty PJD, van den Berg SAA, van Rossum EFC. Glucocorticoids, stress and eating: The mediating role of appetite-regulating hormones. Obes Rev. 2022 Dec 8:e13539. doi: 10.1111/obr.13539. Epub ahead of print. PMID: 36480471.
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