Which option is best described as a hormone that induces feelings of satiety or fullness when eating?

If there was a hormone in your body whose chief job was to make you feel hungry, most of us probably wouldn't be too keen on it. (I don't know about you, but having a healthy appetite has never been a problem for me.) But if there was a hormone that decreased our appetites, we'd order buckets of it!

Well, let me introduce you to some hormones that do just those things: the "hunger hormones," leptin and ghrelin.

Leptin is a hormone, made by fat cells, that decreases your appetite. Ghrelin is a hormone that increases appetite, and also plays a role in body weight.

Levels of leptin -- the appetite suppressor -- are lower when you're thin and higher when you're fat. But many obese people have built up a resistance to the appetite-suppressing effects of leptin, says obesity expert Mary Dallman, PhD, from University of California at San Francisco.

Here's what we know so far about the "hunger hormones" and what we can do to help control our appetites.

What We Know About Ghrelin

Ghrelin, the appetite increaser, is released primarily in the stomach and is thought to signal hunger to the brain. You'd expect the body to increase ghrelin if a person is undereating and decrease it if they are overeating. Sure enough, ghrelin levels have been found to increase in children with anorexia nervosa and decrease in children who are obese.

German researchers have suggested that ghrelin levels play a big role in determining how quickly hunger comes back after we eat. Normally, ghrelin levels go up dramatically before you eat; this signals hunger. They then go down for about three hours after the meal.

But some researchers believe that ghrelin is not as important in determining appetite as once thought. They think that its role in regulating body weight may actually be a more complex process.

What We Know About Leptin

Of the two hormones, leptin -- the appetite suppressor -- appears to be the bigger player in our bodies' energy balance. Some researchers think that leptin helps regulate ghrelin.

Leptin helps signal the brain that the body has enough energy stores such as body fat. But many obese people don't respond to leptin's signals even though they have higher levels of leptin.

In general, the more fat you have, the more leptin is in your blood. But the level varies depending on many factors, including when you last ate and your sleep patterns.

A study showed that rats that were given doses of leptin ended up eating less, but this effect lasted only about two weeks. It seems that the rats developed a resistance to leptin's appetite-cutting effects.

How to Control Hunger Hormones

Are there ways to control our "hunger hormones," and thus rein in our appetites? Possibly -- by avoiding high-fat foods.

When we eat, messages go out to various parts of our bodies to tell us we've had enough. But when we eat fatty meals, this system doesn't work as well, says Dallman. Eating fat tends to lead to eating more calories, gaining weight, and storing fat, Dallman says. Researchers have seen some of these effects after only three days of a high-fat diet.

But researchers have shown that either a diet rich in either "good" carbohydrates (like whole grains) or a diet high in protein suppresses ghrelin more effectively than a diet high in fat.

Something that might help (and certainly won't hurt) is to get enough sleep! In a study of 12 young men, sleep deprivation was associated with an increase in ghrelin levels, appetite, and hunger compared with when they slept 10 hours a night.

All in all, this adds to the huge amount of evidence showing that avoiding a high-fat diet is one of the keys to maintaining a healthy weight.

The Stomach and the Regulation of Food Intake, Hunger, and Satiety

Hunger is a basic human drive, a stressful condition that is eliminated or reduced by the ingestion of food. Hunger is also described as an uncomfortable “emptiness” of the stomach. The ingestion of food elicits relaxation of the stomach musculature (receptive relaxation) and accommodation of the physical volume of the meal; as these gastric neuromuscular events occur, hunger disappears and the comfortable, postprandial sensations of stomach fullness are experienced.

The volume of food ingested suppresses hunger and stimulates the sense of fullness more than the calorie content of the meal.80,81 Infusion of nutrients into the stomach induces a greater intensity of fullness or satiety compared with infusion of the same nutrients into the duodenum. The suppression of hunger is greater when nutrients are taken by mouth, indicating that CNS, oropharyngeal, and gastric neuromuscular factors are integrated to produce the comforts of normal postprandial stomach fullness.82

Healthy individuals usually eat until they are reasonably full. The physiologic attributes of postprandial fullness are notcompletely known, but the physical stretch on the stomach walls (and changes in intragastric pressure) induced by ingestion of food and the secretion of gastric juice are in part responsible.80,81 Subjects experience a dramatic change from the sensation of stomach emptiness at baseline to the sensation of stomach fullness after ingesting water over a 5-minute period. The average volume of water ingested to achieve fullness is 600 mL; in contrast, patients with functional dyspepsia (FD) ingest, on average, only 350 mL to feel full, indicating a disturbance in stomach wall relaxation and/or wall tension.52 Similarly, fullness and satiety can be achieved by ingesting a nutrient drink until achieving maximum tolerated satiety.83 The presence of acid or nutrients in the duodenum or an elevated blood glucose level decreases the stomach wall tension.84,85

The ingestion of a solid meal initially elicits fundic relaxation, and little emptying of the food occurs during the lag phase.Sensations of fullness continue during the lag phase when the food is being triturated. Once the linear phase of gastric emptying begins, there is a progressive perception of decreasing stomach fullness and increasing stomach emptiness over time. Four or 5 hours after a solid meal, the stomach is indeed empty and the healthy individual feels hungry once again.

The physiologic mechanisms of hunger and satiety (and stomach emptiness and fullness) are under intense investigation. In the fasting state plasma motilin levels increase during the phase 3 of the MMC, but correlations between the sensation of hunger and increases of motilin or onset of phase 3 have not been described. As discussed inChapters 4 and7, ghrelin is a 28–amino acid peptide secreted from endocrine cells of the oxyntic glands in the gastric fundus.86 Ghrelin levels also increase in the plasma during fasting (hunger) and stimulate food intake, probably acting via vagal afferent nerves.87 Orexins or appetite-stimulating peptides are synthesized by neurons in the lateral hypothalamus, promote food intake, and stimulate gastric contractility (in the rat) by actions on the dorsal motor nucleus of the vagus with projections to the gastric fundus and corpus.88 After ingestion of food, ghrelin levels decrease89 and are profoundly suppressed after gastric bypass surgery.90 Ghrelin also has promotility effects on the stomach and is being evaluated for the treatment of gastroparesis.91,92

Satiety Signals

Satiety signals can be thought of as occurring in a sequence. In addition to sensory-specific satiety, which involves reduced activity in cortical areas that represent the pleasantness of food, further temporally overlapping signals include gastric distension, duodenal chemosensory signals, glucose utilization, and hormonal (including leptin) signals. Many of these signals are likely to have influences, in some cases via the lateral hypothalamus, on the orbitofrontal cortex, and by modulating sensory activity there, to set the current pleasantness and reward value of food. Investigation of hunger and satiety signals has been a major and difficult issue for many years, but whatever the details of these signals, they must influence processing in brain areas such as the orbitofrontal cortex. The outputs of the orbitofrontal cortex then reach brain regions such as the striatum, cingulate cortex, and dorsolateral prefrontal cortex, where behavioral responses to food may be elicited, because these structures produce behavior which makes the orbitofrontal cortex reward neurons fire, as they represent a goal for behavior. At the same time, outputs from the orbitofrontal cortex and amygdala, in part via the hypothalamus, may provide for appropriate autonomic and endocrine responses to food to be produced, including the release of hormones such as insulin.

Satiety

Serotonin has long been a focus of attention for its possible role in disrupted satiety. There is substantial evidence that altered 5-hydroxytryptamine (5-HT, serotonin) functioning contributes to dysregulated appetite, mood, and impulse control in EDs and that such alteration persists after recovery from AN and BN, possibly reflecting premorbid vulnerability.25, 26 There also is evidence that CCK levels are altered in ED populations. Findings for AN are inconsistent. Although there is some evidence that young women with AN have high levels of pre- and postprandial CCK that may impede treatment progress by contributing to postprandial nausea and vomiting,27, 28 other reports have shown decreased CCK compared with controls.29 In patients with BN, there is consistent evidence for an impaired satiety response, characterized by a blunted postprandial CCK response as well as delayed gastric emptying.30-32 In contrast, individuals with BED and obesity do not differ in postprandial CCK responses from those with obesity but no BED.33 The relationships between CCK, binge eating, and BMI warrant further clarification.

Peptide tyrosine (PYY), the intestinally derived anorexigen that elicits satiety, appears to be dysregulated in individuals with AN and BN, but not in those with BED. Young women with AN have higher levels of PYY compared with controls, perhaps contributing to reduced food intake.34, 35 In individuals with BN, expected elevations in PYY after meals are blunted,36, 37 possibly playing a role in impaired satiety. A recent report found no differences between BED and non-BED groups in fasting levels and postprandial changes in PYY.38 Women with BN have been found to secrete abnormally low levels of the GI satiety peptides glucagon-like peptide 1 and pancreatic polypeptide, which is thought to be a consequence of the adaptation to large meals in the form of enlarged gastric capacity and reduced muscle tone in the gastric wall. Attenuated secretion of these GI satiety polypeptides may play a role in maintaining bulimic behavior.39

Satiety Signals

Satiety signals can be thought of as occurring in a sequence. In addition to sensory-specific satiety, which involves reduced activity in cortical areas that represent the pleasantness of food, further temporally overlapping signals include gastric distension, duodenal chemosensory signals, glucose utilization, and hormonal (including leptin) signals (Rolls, 2014). Many of these signals are likely to have influences, in some cases via the lateral hypothalamus, on the orbitofrontal cortex, and by modulating sensory activity there, to set the current pleasantness and reward value of food (Rolls, 2014, 2016b). Investigation of hunger and satiety signals has been a major and difficult issue for many years, but whatever the details of these signals, they must influence processing in brain areas such as the orbitofrontal cortex. The outputs of the orbitofrontal cortex then reach brain regions such as the striatum, cingulate cortex, and dorsolateral prefrontal cortex, where behavioral responses to food may be elicited, because these structures produce behavior which makes the orbitofrontal cortex reward neurons fire, as they represent a goal for behavior. At the same time, outputs from the orbitofrontal cortex and amygdala, in part via the hypothalamus, may provide for appropriate autonomic and endocrine responses to food to be produced, including the release of hormones such as insulin (Rolls, 2014: p. 5199; Rolls, 2016b).

Upper Gut Symptoms: Anorexia, Nausea, Vomiting, Satiety

Gastroduodenal GVHD in long-term survivors is called persistent, recurrent, or late acute GVHD because symptoms, endoscopic appearance, and histology are identical whether they occur before day 100 or years after transplant.350 Long-term use of oral topical glucocorticoids can be effective in patients with protracted upper gut GVHD.351 However, adrenal suppression and the symptoms of adrenal insufficiency (e.g., anorexia, nausea) from prolonged glucocorticoid exposure may mimic those of upper gut GVHD. Focal intestinal strictures can be seen as sequelae of gut GVHD. Herpesviruses (HSV, CMV, VZV) may cause nausea, vomiting, and satiety in survivors if prophylactic antiviral medications and viral surveillance have been discontinued. When upper gut symptoms appear along with abdominal distention and elevated serum ALT levels, visceral VZV infection should be suspected and confirmed with PCR for VZV DNA in blood.283,352 Gastroparesis may develop after HCT and typically responds to prokinetic agents.353

B Models for studying satiation- and satiety-related effects

The behavioral satiety sequence (Halford, Wanninayake, & Blundell, 1998) describes a repertoire of behaviors in rodents that occurs in an orderly progression during a feeding episode of between 30 and 60 min. When food is first presented, feeding (manipulating or chewing food) immediately becomes the dominant behavior, which then gradually gives way to a period of activity (rearing, sniffing, locomotion) followed by grooming, rest, and sleep. The satiety sequence is absent during sham feeding (Young et al., 1974), but is advanced in time with a more rapid transition to rest, by prefeeding a small amount of food prior to the test meal (Cooper & Francis, 1993; Kitchener & Dourish, 1994). The critical measure of augmentation of satiety processes therefore is that a compound or manipulation should reduce food intake and hasten the transition through the sequence, while keeping the overall pattern of behavior intact. An early example of the application of the satiety sequence is the pioneering work of Smith and Gibbs who first described the gastrointestinal peptide cholecystokinin (CCK) as a satiety factor on the basis that it curtailed sham feeding and elicited the complete satiety sequence (Antin et al., 1975).

Microstructural analyses of meal patterns (review Clifton, 2000) typically involve apparatus that allows each rat to access 45 mg food pellets from a food magazine in such a way that each pellet removed can be time-logged precisely. To ensure an accurate record of intake the cage environment must be adjusted to prevent hoarding, so that each pellet is eaten before another can be taken. In addition, water intake is monitored in fine detail by logging each tongue contact with a drinking spout and delivering water through activation of a pump. In general, rodents can be housed in this meal pattern apparatus for several weeks at a time allowing for continuous records of feeding and drinking responses to be collected before, during, and after drug treatment. Consequently, analysis of feeding records can provide measures of latency to feed, meal size and duration, meal frequency, rate of eating, with similar data for drinking records. From these various intermeal and intrameal parameters it is possible to tease out any satiety-enhancing consequences of an experimental manipulation. Thus, a decrease in meal size without a delay in beginning the meal is a behavioral correlate of within-meal satiation (the process which terminates a meal), while an increase in intermeal interval suggests enhanced postingestive satiety. Simansky (1996) suggested that drug-induced alterations of feeding rate require careful interpretation as slowing of feeding rate could indicate nonspecific motor effects. However, there is evidence, in both humans (Rogers & Blundell, 1979) and rats (Clifton, 2000), to demonstrate that the rate of eating decreases toward the end of a meal as satiation becomes advanced.

Microstructural approaches in rodents can also be used over a much shorter time scale by analyzing patterns of licking for a palatable solution. The behavior is highly structured with bouts of licking separated by short pauses. An increase in palatability of the solution by, for example, increasing the concentration of glucose, will increase the number of licks in individual bouts, whereas a change in hunger will either increase or decrease the number of bouts (Davis:1993va; Davis & Smith, 1992). The technique has been widely applied to the psychopharmacology of appetite, including serotonergic agents.

Human eating behavior can also be studied experimentally, but as Gibbons et al. (2014) point out, techniques vary along a continuum which stretches from those that are “naturalistic” and carried out in everyday settings to those that are laboratory based and can achieve greater precision, but at the potential expense of ecological validity. Microstructural analyses of meal eating in the laboratory can be accomplished using hidden balances and are often combined with repeated measurement of “hunger,” “satiation,” and related measures using visual analogue scales as the meal progresses (Gibbons et al., 2014; Yeomans & Chambers, 2011). In recent years the wide popularity of smartphones has led to an increase in the use of ecological momentary assessment (EMA) tools to examine a range of trait and state influences on eating outside of the laboratory (for reviews of EMA see Shiffman, Stone, & Hufford, 2008; Smith et al., 2018). While this has been useful in determining how affective states underpin overeating and binge eating to date, this method has not been used in combination with serotonergic drug treatments.

Neurochemical correlates of human eating behavior, sometimes in combination with brain imaging, can be studied using appropriate drug probes although the choice of serotonergic agents is quite restricted (see Section 5.5).

Overview of Studies Investigating the Role of the Mediterranean Diet in OSAHS

Based on the satiety properties of the Mediterranean diet, this dietary pattern would result in greater weight loss and, hence, greater improvement in OSAHS compared with a general weight reduction diet. Moreover, a diet rich in antioxidants like the Mediterranean diet could favorably affect lipid peroxidation in OSAHS patients (Figure 4).

To examine these hypotheses, a recent study conducted at the University of Crete in Greece examined the effect of the Mediterranean diet compared with that of a prudent diet on 40 obese adults with moderate-to-severe OSAHS who were treated with CPAP while receiving counseling to increase their physical activity [25]. Another study from the same research group investigated the effect of the Mediterranean diet compared to the prudent diet on lipid peroxidation, estimated using the thiobarbituric acid-reacting substances (TBARS) method, in 21 obese patients with OSAHS who were under CPAP treatment [26]. In both studies, the intervention lasted for 6 months. Additionally, compliance with CPAP therapy was monitored.

A series of consecutive patients, who were diagnosed with OSAHS by overnight attended polysomnography during a 1-year period, were evaluated and the study population was selected based on the following criteria. Inclusion criteria were: (1) age 18 to 65 years; (2) BMI > 30 kg/m2; and (3) apnoea-hypopnoea index (AHI) > 15 events/h. Exclusion criteria were: (1) diseases such as cardiac ischaemic disease, diabetes mellitus, thyroid disorders, psychotic disease and malignancies, and alcoholism; (2) upper airway surgery; (3) pregnancy; (4) diet for weight reduction in the last 6 months or medications affecting weight; (5) eating habits close to the Mediterranean diet at the entry phase; and (6) treatment with sleeping pills. Being smokers during the selection period was an additional exclusion criterion in the case of examining the effect of the Mediterranean diet on lipid peroxidation. After the visit to the study physicians and confirmation that the patients fulfilled the inclusion/exclusion criteria, the subjects were allocated randomly to two study groups. Two groups of patients with moderate-to-severe OSAHS were formed. In both groups, the patients received CPAP therapy and lifestyle intervention including a program of increasing physical activity, mainly involving walking for 30 min daily. At the same time, the two groups were advised to follow a low-calorie diet, one a prudent diet and the other a Mediterranean diet. In all patients, a specific motivation program and education in reducing calorie intake were offered, aiming to restrict the daily energy to 1200–1500 kcal for females and 1500–1800 kcal for males. The general guidelines to the participants in the Mediterranean diet group were consumption of six servings per day of nonrefined cereals, five or more servings per week of potatoes, five servings per day of various vegetables (two of them as salad), four servings per day of various fresh fruits, three or more servings per week of legumes, three servings per week of fish (at least one serving of oily fish), one serving per day of nuts, three servings per week of poultry without skin, three servings per week of red meat, and seven glasses each week of red wine. The recommended intake of fruits, vegetables, legumes, nonrefined cereals, and fish was three times higher in the Mediterranean diet group than in the prudent diet group, whereas the red meat intake in the former group was one-third of that in the latter. The moderate daily consumption of nuts and alcohol (red wine) was only recommended in the Mediterranean diet group. In both groups, the moderate consumption of olive oil was recommended because, based on the local conditions, almost all the people living on the island of Crete produce and consume this type of oil. Patients in both groups were also advised to eliminate or limit the consumption of cream, butter, margarine, carbonated and/or sugared beverages, commercial bakery products (e.g., sweet desserts, cakes, biscuits/cookies, puddings, and custard), potato fries, and processed meats (e.g., burgers and sausages), and to consume two servings per day of low-fat dairy products (Table 1).

Table 1. Recommended Consumption of Several Food Groups According to Intervention Group

2.1 Gastric Distension

Several signals appear to stimulate satiety after a meal. One results from gastric distension, detected by stretch receptors on the walls of the stomach; the greater the distension, the greater the inhibition of eating (McHugh and Moran 1985). This afferent signal projects to the caudal brainstem via the gastric branch of the vagus nerve; as expected, animals eat unusually large meals when the gastric vagus is cut or its projection sites in the brain are destroyed. Experiments in rats have revealed that an intestinal hormone secreted during the meal, CCK, potentiates the gastric vagal signal and produces a heightened sensation of satiety related to gastric distension. This signal is related to the volume of the gastric contents, not its nutrient contents, because there are no known detectors of calories in the stomach. Drugs that acutely block CCK receptors increase food intake during a meal, as if the animal were less aware of gastric distension signals (Smith and Gibbs 1992).

Abstract

Leptin is an adipokine signaling satiety and increased energy expenditure, mainly acting in the hypothalamus. Leptin has also been shown to participate to the control of reproductive processes, from pubertal development to male and female reproduction, modulating hypothalamic, pituitary and gonadal functions. Interestingly, impaired circulating leptin levels and signaling have been reported in PCOS, anorexia nervosa and obesity, suggesting a role for this adipokine also in the reproductive impairment often associated with these diseases. Leptin may thus be regarded as a hormone connecting modulation of energy expenditure/food intake and reproductive function.

Cholecystokinin

Cholecystokinin (CCK) is another satiety-inducing neuropeptide secreted by the gastrointestinal tract. CCK regulates motor functions in the gastrointestinal tract such as gastric emptying and gut motility and is thought to transmit satiety signals via the vagal pathway (Peters et al., 2006).

The results of studies of CCK in AN are inconsistent. Some studies found elevated basal plasma CCK levels and/or increased postmeal secretion of CCK (Harty et al., 1991; Tamai et al., 1993; Tomasik et al., 2004). Other studies found normal or decreased levels of CCK in AN subjects (Brambilla et al., 1995a; Baranowska et al., 2000).

Basal levels of CCK were found to be decreased in BN subjects during the acute stage of the disorder (Lydiard et al., 1993; Brambilla et al., 1995b). Most studies suggest that meal-induced CCK release is diminished in symptomatic BN subjects in comparison to controls (Devlin et al., 1997; Keel et al., 2007) but returns to normal following treatment (Geracioti and Liddle, 1988). It has been suggested that a blunted CCK response to a meal may be one underlying factor for disturbances of postingestive satiety found in bulimic patients.