Which hormone is produced by adipose tissue and causes decreased appetite and increased metabolic rate?

Introduction

Projections suggest that, by 2030, obesity prevalence may reach over 45% of the entire US population, and 48% in the United Kingdom. Behind this lies a progressive rise in body fat of individuals with age, that is, the disease process of obesity, as recognized by the American Medical Association. By age 65, almost 40% of UK adults are now obese, and only 15% of men and 28% of women have a ‘normal’ body mass index [BMI] of 18.5–25 kg m−2.

Rapidly growing obesity research is now shedding light on the complex and interrelated biological and psychosocial underpinnings of appetite regulation and eating behaviour. The changing food environment and food culture have a major role in the recent rise in obesity: with ready availability of attractive high-calorie foods, often in excessive portion sizes, and sedentary lifestyles all now regarded as normal. However, a body of evidence supports a continuing role for the gut–brain axis in regulation of food intake and the maintenance of body weight., , , Thus, a complex array of signals from peripheral and central nervous systems, possibly under epigenetic programming, interacts with psychological and social factors to determine energy balance and body weight homeostasis.

A great deal of research has been applied to the search for genetic factors behind obesity. Although many single gene variants have been discovered, their individual and indeed cumulative effect sizes are rather small, and they do not appear to account for the dramatic epidemic rise of obesity internationally. Most appear to be associated with alterations in appetite/food intake, rather than metabolic effects on energy balance. It is possible that the rapidly growing study of epigenetics will reveal more mechanisms.

It is difficult to disentangle altered physiological factors that are possibly contributory, from the multiple biological consequences of weight gain and obesity. The underlying processes do not emerge only when people reach an arbitrary BMI or waist cutoff for ‘obesity’, but exert causal influences from the earliest stages as body fat content begins to rise. The combined effects of physiological factors are usually only sufficient to generate weight gains of 0.5–1 kg year−1, which implies energy imbalances of around 10–20 kcal day−1, on average. This amount [protein>carbohydrate] of the ingested meal., Fat intake is the strongest stimulant of PYY secretion, whereas carbohydrate intake has a limited effect in obese or non-obese individuals.,

Several studies have documented the obesity-related attenuation of postprandial responses in PYY levels., , For example, in one study, the PYY response in obese subjects was significantly lower than in normal-weight controls after each of six test meals of increasing caloric content []. This attenuated response corresponded with significantly lower subjective ratings of fullness in obese subjects, beginning 30 min after the meal and persisting for 3 h. Zwirska-Korczala et al. also observed blunted postprandial PYY responses in obese and morbidly obese women compared with lean control subjects. Racial differences in PYY responses were examined in another study of obese and lean women. Significantly lower postprandial PYY levels were noted in obese black women compared with lean black women, lean white women or obese white women; unfortunately, given the known racial differences in body compositions, these authors did not report body fat content or any relationship between PYY levels and body composition.

Figure 2

PYY responses 90 min after each of six test meals of increasing caloric content in 20 obese and 20 normal-weight subjects. *P90% of total ghrelin] has been considered as a non-functional peptide. Ghrelin concentration peaks in response to fasting and anticipation of the coming meal, and thus initiates and promotes eating []. Concentrations in normal-weight individuals exhibit a preprandial peak with a decline after eating. Working in opposition to satiety hormones, ghrelin increases the rate of gastric emptying and increases hunger. However, some recent data do not favour a role of peripheral ghrelin in the regulation of food intake., First, ghrelin infusion at both physiological and supraphysiological doses was found to have no effect on appetite or spontaneous meal request. In addition, it has been reported that food restriction-induced increases in appetite were not influenced by changes in plasma acylated ghrelin concentrations. At the same time over the past few years, effects of unacylated ghrelin on insulin sensitivity, metabolism, muscle regeneration and β-cell protection have been reported., Regardless of the current debate about the primary function of ghrelin, research investigating the role of this hormone in appetite regulation deserves discussion.

Fasting and postprandial plasma ghrelin levels were reported to be lower in obese than in normal-weight individuals []. Little change from fasting levels was noted in obese subjects in other studies., , , , , One of these studies demonstrated a 30% reduction from preprandial ghrelin levels in lean women, beginning 30 min after a test meal, but no significant changes were noted in either obese or severely obese women. There may be nutrient-specific effects on ghrelin levels. Yang et al. found greater postprandial suppression of ghrelin in obese and lean subjects following a high-carbohydrate meal [88% carbohydrate, 8% protein and 4% fat] than after a high-fat meal [25% carbohydrate, 4% protein and 71% fat]. However, compared with lean subjects, obese subjects demonstrated less suppression of ghrelin following either meal.

Figure 3

Ghrelin responses to a test meal in 10 normal-weight and 13 severely obese women. Ghrelin levels were significantly higher. *[P⩽0.05] in normal-weight women at baseline [P=0.001] and at 15 [P=0.001], 60 [P=0.032] and 120 [P=0.044] min postprandially. Reproduced with permission.

Full size image

Thus, observations of the relationship between obesity and failure to suppress ghrelin levels after a meal are consistent across studies. The flattened hormone profiles around traditional mealtimes may be a factor in the continuous ‘grazing’ pattern reported in obese subjects.,

Diet-induced weight loss in obese subjects was accompanied by alterations in ghrelin levels in several studies. Compared with baseline measures, plasma ghrelin was increased by 17% in overweight and obese women who reduced their body weight by 4.5% at the completion of a 10-week weight loss intervention programme that included an energy-restricted diet of 40% carbohydrates, 30% fat and 30% protein. It should be noted that these results were obtained at the end of the acute intervention, and thus participants were presumably still in a state of negative energy balance, which may have confounded the results. In two other studies, short-term diet-induced weight loss in obese subjects resulted in an exaggerated pattern of postprandial changes in ghrelin levels compared with the pre-weight loss setting, with significantly greater levels persisting over weight maintenance/stabilization periods of 6 and 12 months., Repeated weight loss and regain may result in long-term alterations in ghrelin signalling. Among 159 weight-stable obese or overweight women, a history of intentional weight loss over the preceding 20 years, defined as episodes of intentionally losing at least 10 pounds, and frequency of intentional weight cycling were associated with higher fasting levels of ghrelin, in analyses adjusted for age, BMI and physical activity. This evidence raises the intriguing possibility that, as well as weight loss, weight cycling may promote an appetite-stimulating hormonal profile, further hindering weight maintenance. However, reaching this conclusion hinges on effective adjustment of the data for confounders, of which the most important is body composition; relatively small differences in body composition may introduce errors, and BMI is not sufficiently specific to avoid these errors.

The role of ghrelin in the control of appetite has been examined extensively in exercise studies. A recent meta-analysis reported that in normal-weight individuals, acute exercise suppresses acylated ghrelin levels, in line with a transient suppression of hunger in the hours immediately after exercise. However, chronic exercise resulting in significant weight loss was found to enhance fasting concentrations of total and acylated ghrelin in obese and overweight individuals. At the same time, increased suppression of postprandial acylated ghrelin was observed in one of the studies. This is in line with the observation that although medium-term exercise-induced weight loss increases both fasting hunger and hunger across the day, it also improves meal-induced satiety.

In contrast to the above results, a study conducted in a group of morbidly obese men and women showed that fasting and meal related circulating ghrelin levels remained unchanged despite 5% weight loss induced by a 3-week integrated body weight reduction programme with exercise training. No impact of aerobic training on circulating acylated ghrelin levels was found in a study conducted on overweight and obese men and overweight children. Differences in fat mass loss, volume and duration of exercise interventions, and inclusion of different genders are likely to be factors contributing to the discrepancy. In addition, changes in ghrelin concentration with exercise may be also dependent on extent and direction of change in levels of other potential appetite regulators, such as a leptin, insulin and probably PYY.,

Effect of corticosteroids on gut peptides

Elevated corticosteroid status provides a useful model for some types of obesity. Weight gain varies widely in human clinical studies, depending on dose/circulating concentration and on individual factors. Alterations in the hypothalamic–pituitary–adrenal axis have been demonstrated in obesity. Weight gain is a feature of Cushings syndrome and a common side effect of glucocorticoid therapy. A systematic review has suggested an average weight gain of 2 kg, but the stringent inclusion criteria of that review resulted in only one RCT paper being included. It is surprising that weight change with corticosteroids, which can often be large, has not been better documented. Therapeutic doses of glucocorticoids were shown to increase food intake in healthy male volunteers [N=10]. Vicennati et al. reported weight gain and the development of obesity in women [N=14] after a significant stressful event; these changes were manifested via a hyperactive adrenal cortex. In another study, stress-related cortical secretion was positively correlated with BMI, waist-to-hip ratio and sagittal recumbent trunk diameter in a population of 51-year-old men [N=284]. In a study examining the effects of methodology on gut hormone levels in 10 normal-weight men, the temporal plasma PYY concentration profile was altered by study-induced stress, and the PYY area under the curve was positively correlated with the cortisol area under the curve. In 33 young adults, serum ghrelin exhibited a strong inverse association with serum cortisol during 12–84 h of fasting [r=−0.79; P