Pharmacokinetics, safety, and endocrine and appetite effects of ghrelin total ghrelin, with elimination half life (t(1/2)) of and min respectively. Slight alterations of blood glucose and insulin levels after the injection were observed. Peripheral mechanisms in appetite regulation include the motor functions of the stomach, The relevance of these factors is demonstrated by the effects of sleeve gastrectomy on . Gut endocrine cells may also detect microbiota, as they also express toll-like . Adiposity- and Glycemia-related Hormones. The hypothalamus acts as the control center for hunger and satiety. These mice are also obese, insulin resistant, hyperglycemic, and have increased body length . It is mainly produced by the endocrine cells of the gastric mucosa of Ghrelin has multiple effects, including stimulation of GH, ACTH.
effects (including effects and appetite) Endocrine glycemic
The anorexic response of leptin is attenuated by administration of an MC4R antagonist, demonstrating that the melanocortin pathway is perhaps an important downstream mediator of leptin signalling Seeley et al. Mice lacking leptin signalling in POMC neurons are mildly obese and hyperlepti-naemic, but less so than mice with a complete deletion of the leptin receptor Balthasar et al.
This suggests that POMC are important, but not essential, for leptin signalling in vitro. Chronic hypothalamic over-expression of the leptin gene, using a recombinant adeno-associated virus vector, has demonstrated distinct actions of leptin in different hypothalamic nuclei. Leptin over-expression in the ARC, PVN and VMH results in a reduction of food intake and energy expenditure, whereas leptin over-expression in the medial preoptic area results in reduced energy expenditure alone Bagnasco et al.
Peripheral administration of leptin also results in neuronal activation within the NTS Elmquist et al. Thus leptin appears to exert its effect on appetite via both the hypothalamus and brainstem. Although a small subset of obese human subjects have a relative leptin deficiency, the majority of obese animals and humans have a proportionally high circulating leptin Maffei et al.
Indeed, recombinant leptin administered subcutaneously to obese human subjects has only shown a modest effect on body weight Heymsfield et al. Administration of peripheral leptin to rodents with diet-induced obesity fails to result in a reduction in food intake, although these rodents retain the capacity to respond to icv leptin Van Heek et al.
Exogenous leptin in mice is transported across the blood—brain barrier less rapidly in obese animals Banks et al. Leptin resistance may be the result of a signalling defect in leptin-responsive hypothalamic neurons, as well as impaired transport into the brain. Resistance to the effects of leptin has been shown to develop in NPY neurons following chronic central leptin exposure Sahu Furthermore, the magnitude of hypothalamic STAT3 activation in response to icv leptin is reduced in rodents with diet-induced obesity El Haschimi et al.
SOCS-3 acts as a negative regulator of leptin signalling. Therefore, increased or excessive SOCS-3 expression may be an important mechanism for obesity-related leptin resistance.
Consistent with this, neuron-specific conditional SOCSknockout mice are resistant to diet-induced obesity Mori et al. Mice with heterozygous SOCS-3 deficiency are also resistant to obesity and demonstrate both enhanced weight loss and increased hypothalamic leptin receptor signalling in response to exogenous leptin administration Howard et al.
Although as yet untested, SOCS-3 suppression may be a potential target for the treatment of leptin-resistant obesity. Leptin resistance seems to occur as a result of obesity, but a lack of sensitivity to circulating leptin may also contribute to the aetiology of obesity.
Furthermore, it may be that the high-fat diet itself induces leptin resistance prior to any change in body composition, as rodents on a high-fat diet rapidly demonstrate an attenuated response to leptin administration before they gain weight Lin et al. Although leptin deficiency has profound effects on body weight, the effect of high leptin levels seen in obesity are much less potent at restoring body weight.
Thus, leptin may be primarily important in periods of starvation, and have a lesser role in times of plenty. Insulin is a major metabolic hormone produced by the pancreas and the first adiposity signal to be described Schwartz et al. Like leptin, levels of plasma insulin vary directly with changes in adiposity Bagdade et al. Levels of insulin are determined to a great extent by peripheral insulin sensitivity, and this is related to total body fat stores and fat distribution, with visceral fat being a key determinant of insulin sensitivity Porte et al.
However, unlike leptin, insulin secretion increases rapidly after a meal, whereas leptin levels are relatively insensitive to meal ingestion Polonsky et al. Insulin penetrates the blood—brain barrier via a saturable, receptor-mediated process, at levels which are proportional to the circulating insulin Baura et al.
Recent findings suggest that little or no insulin is produced in the brain itself Woods et al. Once insulin enters the brain, it acts as an anorexigenic signal, decreasing intake and body weight. An infusion of insulin into the lateral cerebral ventricles in primates Woods et al. Thus, the VMH and PVN seem therefore to play an important part in the ability of centrally administered insulin to reduce food intake. Male mice with neuron-specific deletion of the insulin receptor in the CNS are obese and dyslipidaemic with increased peripheral levels of insulin Bruning et al.
Reduction of insulin receptor proteins in the medial ARC, by administration of an antisense RNA directed against the insulin receptor precursor protein, results in hyperphagia and increased fat mass Obici et al. Treatment of mice with orally available insulin mimetics decreases the weight gain produced by a high-fat diet as well as adiposity and insulin resistance Air et al.
If insulin elicits changes in feeding behaviour at the level of the hypothalamus, then levels of circulating insulin should reflect the effect of centrally administered insulin. Studies of systemic insulin administration have been complicated by the fact that increasing circulating insulin causes hypoglycaemia which in itself potently stimulates food intake. Thus peripheral and central data are consistent with the insulin system acting as an endogenous controller of appetite.
The insulin receptor exists as two splice variants resulting in subtype A, with higher affinity for insulin and more widespread expression, and subtype B with lower affinity and expression in classical insulin-responsive tissues such as fat, muscle and liver. The phenotype of IRSknockout mice does not show differences in food intake or body weight Araki et al. There is also evidence to suggest that insulin and leptin, along with other cytokines, share common intracellular signalling pathways via IRS and the enzyme phoshoinositide 3-kinase, resulting in downstream signal transduction Niswender et al.
Insulin receptors are widely distributed in the brain, with highest concentrations found in the olfactory bulbs and the hypothalamus Marks et al.
Within the hypothalamus, there is particularly high expression of insulin receptors in the ARC; they are also present in the DMH, PVN, and suprachiasmatic and periventricular regions Corp et al. This is consistent with the hypothesis that peripheral insulin acts on hypothalamic nuclei to control energy homeostasis.
The mechanisms by which insulin acts as an adiposity signal remain to be fully elucidated. Earlier studies pointed to hypothalamic NPY as a potential mediator of the regulatory effects of insulin. NPY expression is increased in insulin-deficient, streptozocin-induced diabetic rats and this effect is reversed with insulin therapy Williams et al.
Administration of insulin into the third ventricle of fasted rats increases POMC mRNA expression and the reduction of food intake caused by i. Taken together, these experiments suggest that both the NPY and melanocortin systems are important downstream targets for the effects of insulin on food intake and body weight. Adiponectin is a complement-like protein, secreted from adipose tissue, which is postulated to regulate energy homeostasis Scherer et al.
The plasma concentration of adiponectin is inversely correlated with adiposity in rodents, primates and humans Hu et al. Adiponectin is significantly increased after food restriction in rodents Berg et al. Peripheral administration of adiponectin to rodents has been shown to attenuate body-weight gain, by increased oxygen consumption, without affecting food intake Berg et al. The effect of peripheral adiponectin on energy expenditure seems to be mediated by the hypothalamus, since adiponectin induced expression of the early gene c- fos in the PVN, and may involve the melanocortin system Qi et al.
It is perhaps counterintuitive for a factor that increases energy expenditure to increase following weight loss; however, reduced adiponectin could perhaps contribute to the pathogenesis of obesity. Studies show that plasma adiponectin levels correlate negatively with insulin resistance Hotta et al.
Adiponectin-knockout mice demonstrate severe diet-induced insulin resistance Maeda et al. Thus adiponectin, as well as increasing energy expenditure, may also provide protection against insulin resistance and atherogenesis. In addition to leptin and adiponectin, adipose tissue produces a number of factors which may influence adiposity.
Resistin is an adipocyte-derived peptide which appears to act on adipose tissue to decrease insulin resistance. Circulating resistin levels are increased in rodent models of obesity Steppan et al. Although resistin may be a mechanism through which obesity contributes to the development of diabetes Steppan et al.
Ghrelin is an orexigenic factor released primarily from the oxyntic cells of the stomach, but also from duodenum, ileum, caecum and colon Date et al. It is a amino-acid peptide with an acyl side chain, n -octanoic acid, which is essential for its actions on appetite Kojima et al. In humans on a fixed feeding schedule, circulating ghrelin levels are high during a period of fasting, fall after eating Ariyasu et al.
Ghrelin levels fall in response to the ingestion of food or glucose, but not following ingestion of water, suggesting that gastric distension is not a regulator Tschop et al. In rats, ghrelin shows a bimodal peak, which occurs at the end of the light and dark periods Murakami et al. In humans, ghrelin levels vary diurnally in phase with leptin, which is high in the morning and low at night Cummings et al.
An increase in circulating ghrelin levels may occur as a consequence of the anticipation of food, or may have a physiological role in initiating feeding.
Administration of ghrelin, either centrally or peripherally, increases food intake and body weight and decreases fat utilization in rodents Tschop et al. Furthermore, central infusion of anti-ghrelin antibodies in rodents inhibits the normal feeding response after a period of fasting, suggesting that ghrelin is an endogenous regulator of food intake Nakazato et al.
The severe hyperphagia seen in Prader—Willi syndrome is associated with elevated ghrelin levels Cummings et al. However, one study has failed to show a correlation between the ghrelin level and the spontaneous initiation of a meal in humans Callahan et al. Thus ghrelin secretion may be a conditioned response which occurs to prepare the metabolism for an influx of calories. Whatever the precise physiological role of ghrelin, it appears not to be an essential regulator of food intake, as ghrelin-null animals do not have significantly altered body weight or food intake on a normal diet Sun et al.
Plasma ghrelin levels are inversely correlated with body mass index. Anorexic individuals have high circulating ghrelin which falls to normal levels after weight gain Otto et al. Obese subjects have a suppression of plasma ghrelin levels which normalize after diet-induced weight loss Cummings et al.
Unlike lean individuals, obese subjects do not demonstrate the same rapid post-prandial drop in ghrelin levels English et al. Variations within the ghrelin gene may contribute to early-onset obesity Korbonits et al. Ghrelin is the endogenous agonist of the growth hormone secretagogue receptor GHS-R , and stimulates growth hormone GH release via its actions on the type 1a receptor in the hypothalamus Kojima et al.
However, the orexigenic action of ghrelin is independent of its effects on GH Tschop et al. Ghrelin administration does not increase food intake in mice lacking GHS-R type 1a, suggesting that the orexigenic effects may be mediated by this receptor; however, these mice have normal appetite and body composition Chen et al.
This lack of a phenotype suggests that ghrelin receptor antagonists may not be an effective therapy for obesity. GHS-R type 1a is found in the hypothalamus, pituitary myocardium, stomach, small intestine, pancreas, colon, adipose tissue, liver, kidney, placenta and peripheral T-cells Date et al.
Some studies have also described ghrelin analogues which show dissociation between the feeding effects and stimulation of GH, suggesting that GHS-R type 1a may not be the only receptor mediating the effects of ghrelin on food intake Torsello et al.
Ghrelin is thought to exert its orexigenic action via the ARC of the hypothalamus. Studies of knockout mice demonstrate that both NPY and AgRP signalling mediate the effect of ghrelin, although neither neuropeptide is obligatory Chen et al. GHS-R are also found on the vagus nerve Date et al. The central ghrelin neurons also terminate on orexin-containing neurons within the LHA Toshinai et al.
The feeding response to centrally administered ghrelin is attenuated after administration of anti-orexin antibody and in orexin-null mice Toshinai et al. They all share significant sequence homology and contain several tyrosine residues Conlon PYY is secreted predominantly from the distal gastrointestinal tract, particularly the ileum, colon and rectum Adrian et al. The L-cells of the intestine release PYY in proportion to the amount of calories ingested at a meal. Post-prandially, the circulating PYY levels rise rapidly to a plateau after 1—2 h and remain elevated for up to 6 h Adrian et al.
However, PYY release occurs before the nutrients reach the cells in the distal tract, thus release may be mediated via a neural reflex as well as direct contact with nutrients Fu-Cheng et al. The levels of PYY are also influenced by meal composition: Other signals, such as gastric acid, CCK and luminal bile salts, insulin-like growth factor 1, bombesin and calcitonin-gene-related peptide increase PPY levels, whereas gastric distension has no effect, and levels are reduced by GLP-1 Pedersen-Bjergaard et al.
Circulating PYY exists in two major forms: Administration of PYY causes a delay in gastric emptying, a delay in secretions from the pancreas and stomach, and increases the absorption of fluids and electrolytes from the ileum after a meal Allen et al. Peripheral administration of PYY 3—36 to rodents has been shown to inhibit food intake, reduce weight gain Batterham et al. The effect on appetite may be dependent on a minimization of environmental stress, which in itself can result in a decrease in food intake Halatchev et al.
The reduction in calories is accompanied by a reduction in subjective hunger without an alteration in gastric emptying. This effect persists for up to 12 h after the infusion is terminated, despite circulating PYY 3—36 returning to basal levels Batterham et al. Thus, PYY 3—36 may be physiologically important as a post-prandial satiety signal. Obese human subjects have a relatively low circulating PYY and a relative deficiency of post-prandial secretion Batterham et al.
Obese patients treated by jejunoileal bypass surgery Naslund et al. Thus long-term administration of PYY 3—36 could be an effective obesity therapy. After chronic peripheral administration of PYY 3—36 , rodents do indeed demonstrate reduced weight gain Batterham et al.
PP is produced by cells at the periphery of the islets of the endocrine pancreas, and to a lesser extent in the exocrine pancreas, colon and rectum Larsson et al. The release of PP occurs in proportion to the number of calories ingested, and levels remain elevated for up to 6 h post-prandially Adrian et al.
The release of PP is biphasic, with the contribution of the smaller first phase increasing with consecutive meals, although the total release remains proportional to the caloric load Track et al. The circulating levels of PP are increased by gastric distension, ghrelin, motilin and secretin Christofides et al. There is also a background diurnal rhythm, with circulating PP low in the early hours of the morning and highest in the evening Track et al.
The levels of PP have been found to reflect long-term energy stores, with lower levels Lassmann et al. However, conflicting studies have found no difference between lean and obese subjects Wisen et al. Peripheral administration of PP reduces food intake, body weight and energy expenditure, and ameliorates insulin resistance and dyslipidaemia in rodent models of obesity Malaisse-Lagae et al. Transgenic mice that over-express PP also have a lean phenotype with reduced food intake Ueno et al.
Unlike rodents, humans do not seem to have altered gastric emptying in response to PP Adrian et al. Further investigation of the administration of PP to obese subjects may indicate whether it could be an effective therapy for obesity.
PP does appear to be an efficacious treatment for hyperphagia secondary to Prader—Willi syndrome. These patients have blunted basal and post-prandial PP responses which may contribute to their hyperphagia and obesity Zipf et al. The PP-fold family bind to Y 1 —Y 5 receptors, which are seven-transmembrane-domain, G-protein-coupled receptors Larhammar PP binds with greatest affinity to Y 4 and Y 5 receptors Larhammar It is thought that the effect of peripheral PYY 3—36 on appetite may be mediated by the arcuate Y 2 receptor, a pre-synaptic inhibitory receptor expressed on NPY neurons Broberger et al.
The anorectic effect of PYY 3—36 is abolished in Y 2 receptor-knockout mice and reduced by a selective Y 2 agonist Batterham et al. Immunohistochemical studies have demonstrated that peripherally administered PYY 3—36 induces c- fos expression Batterham et al. The peripheral administration of PYY 3—36 has also been shown to decrease ghrelin levels Batterham et al.
PYY administered into the third, lateral or fourth cerebral ventricles Clark et al. This orexigenic effect is reduced in both Y 1 and Y 5 receptor-knockout mice Kanatani et al. Circulating PP is unable to cross the blood—brain barrier, but may exert its anorectic effect on the ARC via the area postrema Whitcomb et al.
This effect may occur via the Y 5 receptor as there is no response in Y 5 receptor-knockout mice, although the anorectic effect is not reduced by Y 5 receptor antisense oligonucleotides Katsuura et al. PP may also exert some anorectic action via the vagal pathway to the brainstem, as vagotomy seems to reduce its efficacy Asakawa et al.
Like PYY 3—36 , PP is also able to reduce gastric ghrelin mRNA expression, and this has been postulated to mediate its efficacy in the treatment of hyperphagia secondary to Prader—Willi syndrome Asakawa et al. Thus PP sends anorectic signals via brainstem pathways, hypothalamic neuropeptides and by modulating expression of other gut hormones such as ghrelin.
In contrast to the peripheral effects, when administered centrally into the third ventricle PP causes increased food intake Clark et al. However, the mechanism of this orexigenic effect following central injection is unclear.
The proglucagon gene product is expressed in the L-cells of the small intestine, pancreas and central nervous system. The enzymes prohormone convertase 1 and 2 cleave proglucagon into different products depending on the tissue Holst Peripheral administration also inhibits food intake and activates c-Fos in the brainstem Tang-Christensen et al. Thus, GLP-1 may influence energy homeostasis via the brainstem pathways. In humans, intravenous administration of GLP-1 decreases food intake in both lean and obese individuals in a dose-dependent manner Verdich et al.
However, the effect is small when infusions achieve post-prandial circulating levels Flint et al. Some evidence suggests GLP-1 secretion is reduced in obese subjects Holst et al. Reduced secretion of GLP-1 could therefore contribute to the pathogenesis of obesity and replacement may restore satiety. In addition to its effect on appetite, GLP-1 is an incretin hormone Kreymann et al.
GLP-1 has been found to normalize blood glucose levels, in poorly controlled type 2 diabetes, during both a short-term intravenous infusion Nauck et al. Body weight was also reduced by 2 kg after the subcutaneous infusion Zander et al. However, resistant albumin-bound GLP-1, exendin-4 a naturally occurring peptide from the lizard Heloderma and inhibitors of the enzyme DPP-IV are all currently in development for the treatment of diabetes see the review by Holst Although GLP-1 may be useful in type 2 diabetic patients, it has been reported to cause hypoglycaemia in non-diabetic subjects Todd et al.
OXM is released from the L-cells of the small intestine in proportion to nutrient ingestion Ghatei et al. Administration of OXM centrally or peripherally acutely inhibits food intake in rodents Dakin et al. OXM may also increase energy expenditure, as OXM-treated animals lose more weight than pair-fed animals, an effect which is postulated to be mediated by the thyroid axis Dakin et al.
Anorexia occurs in human conditions associated with high OXM levels, such as tropical sprue Besterman et al. Thus OXM may be a physiological regulator of energy homeostasis. However, the circulating concentrations of OXM in obese subjects and its potential to decrease weight in humans remain unknown. Furthermore, the affinity of OXM for GLP-1 receptor is approximately two orders of magnitude less than that of GLP-1 yet they appear to be similarly efficacious at reducing food intake Fehmann et al.
There may thus be distinct receptors mediating the physiological effects of the two peripheral gut hormones. CCK is rapidly released locally and into the circulation in response to nutrients, and remains elevated for up to 5 h Liddle et al. CCK coordinates digestion by stimulating the release of enzymes from the pancreas and gall bladder, increasing intestinal motility and inhibiting gastric emptying Liddle et al.
Administration of CCK, to both humans and animals, has long been known to inhibit food intake by reducing meal size and duration Gibbs et al. Although CCK exerts its effect on food intake rapidly, its duration of action is brief.
It has a half-life of only 1—2 min, and it is not effective at reducing meal size if the peptide is administered more than 15 min before a meal Gibbs et al.
In animals, chronic pre-prandial administration of CCK does reduce food intake, but is seen to increase meal frequency, with no resulting effect on body weight West et al. Thus, the efficacy of CCK as a potential treatment for human obesity is in doubt. Peripherally, CCK A receptors are found in the pancreas, on vagal afferent and enteric neurons. CCK B receptors are also distributed widely in the brain, are present in the afferent vagus nerve, and are found within the stomach Moran et al.
The CCK A receptor subtype is thought to mediate the effect of the endogenous agonist on appetite Asin et al. Further-more, administration of a CCK A receptor antagonist increases calorie intake and reduces satiety Hewson et al. The vagal nerve projects to the NTS, which in turn relays information to the hypothalamus Schwartz et al. CCK may also act as a longer-term indicator of nutritional status: Chronic administration of both CCK antibodies and CCK A antagonists also results in weight gain in rodent models, although not with a significant increase in food intake McLaughlin et al.
The long-term effect of CCK on body weight may partially result from an interaction with signals of adiposity such as leptin, which enhance the satiating effect of CCK Matson et al. The brain integrates peripheral signals of nutrition in order to maintain a stable body weight. However, in some individuals, genetic and environmental factors interact to result in obesity.
Understanding of the complex system which regulates energy homeostasis is progressing rapidly, enabling new obesity therapies to emerge. Available pharmacological agents, such as sibutramine and orlistat, have limited efficacy and are restricted to 1 or 2 years of therapy respectively see review by Finer Currently, the only obesity treatment in clinical use that has shown significant long-term weight loss is gastrointestinal bypass surgery Frandsen et al. However, because of its complications, this procedure is restricted to patients with morbid obesity.
This suggests that therapies based on these hormones may be effective in the long term, without the need for surgical intervention. As mechanisms of disordered energy homeostasis are clarified, treatments based on peripheral hormones or central neuropeptide signals could be tailored to the individual; just as leptin deficiency is treated successfully with leptin replacement.
Therapeutic strategies may thus significantly impact on the enormous morbidity and mortality associated with obesity, as even modest weight loss can reduce the risk of diabetes, cancer and cardiovascular disease.
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Numerous studies provide evidence that supports the use of a high-protein diet to induce appetite suppression and decreased ad libitum energy intake. These effects were evident in the absence of ghrelin suppression. Similar to the results presented by Weigle et al. The likely mechanism of action of high-protein diets on appetite suppression and decreased caloric intake may be outside of the control of ghrelin.
As mentioned earlier, endogenous insulin secretion may result in the suppression of ghrelin [ 15 ]. In a recent study of healthy Pima Indians, higher plasma insulin responses were associated with a decrease in subsequent carbohydrate consumption and less weight gain [ 23 ]. These results further point to insulin as a regulator of calorie consumption.
It is unclear whether the glycemic index or glycemic load plays a direct role in the regulation of appetite and subsequent energy intake through tempered insulin responses as results from past studies have been conflicting [ 26 , 27 ].
It would appear to be most beneficial if the additional protein is ingested from solid food sources as food form also appears to play a role in feelings of satiety [ 30 , 31 ]. Future research should investigate the effects of large doses of insoluble fiber 33 to 41 grams in addition to a high-protein diet to determine if this combination could further attenuate appetite and energy intake.
Another factor associated with weight control that may not necessarily have a concomitant decrease in caloric intake is meal frequency. Caloric intake can be affected by caloric density in food, total energy consumption as well as meal frequency, but Solomon et al.
Additionally Stote et al. Though the general public would suggest that three meals a day are important [ 33 ] there have been few well-controlled studies that have compared meal frequency, with the same caloric consumption, and its effect on health outcomes and weight control. To date evidence suggests that less frequent meal consumption with a large bolus of calories at each meal can lead to increases in adipose tissue [ 34 ].
Conversely consuming the same amount of calories with more frequent and smaller meals does not seem to impact the deposition of fat [ 34 ]. Additionally Solomon et al. These hormonal effects may primarily be related to ghrelin and insulin and possibly cortisol [ 33 , 35 ]. Much of the research regarding weight control and hormones has focused principally on ghrelin, a hormone produced primarily in the gastrointestinal tract with larger amounts in the stomach [ 35 ]. Recent findings have suggested that ghrelin may play a role in the control of food intake and meal frequency as well as energy intake [ 36 ].
Specifically ghrelin in the plasma increases preprandially in fasting conditions and before meal initiation and will rapidly decrease nadir postprandially [ 37 ] and therefore is reported to play a role in appetite regulation, meal frequency, and hunger [ 36 ]. Other study authors have reported that ghrelin may play an important role in metabolic balance by decreasing fat utilization and increasing appetite and meal frequency [ 38 ].
The same authors report that this metabolic role has occurred in both healthy populations and in cancer patients suffering anorexia. Another hormone thought to regulate appetite is insulin. Postprandial insulin levels have been more controlled with more frequent meals, with meal skipping primarily skipping breakfast associated with higher levels of insulin [ 39 ], but most of the research regarding insulin and ghrelin has focused on the interaction of the two hormones and how each may affect each other in appetite control and meal initiation and frequency.
Postprandial suppression of ghrelin has been demonstrated to be partially dependent on the release of insulin [ 32 , 40 ] and can be subject to insulin sensitivity. Previous reports [ 41 ] have suggested that the administration of ghrelin in apparently healthy participants has an inverse relationship with insulin levels and causes an increase in plasma glucose concentrations. Other study findings [ 32 ] also suggest that insulin and ghrelin have an inverse relationship in fasting conditions as well as with low-frequency meal ingestion, causing poor control of insulin and decrease in glucose consumption [ 41 ], yet when meals are consumed more frequently with the same caloric consumption, the insulin-ghrelin relationship is less apparent.
Conversely, an increase in feeding frequency that is associated with an increase in caloric consumption may cause the insulin to exert less control on ghrelin causing an increase in preprandial ghrelin [ 42 ].
This can be especially true in Type II diabetics [ 32 ]. Postprandial ghrelin suppression and downregulation in insulin-resistant disease states such as diabetes and obesity and in syndromes such as metabolic syndrome is lesser than in apparently healthy populations [ 32 , 34 , 44 ].
A third hormone that may have an effect on appetite control, meal frequency, and regulation is cortisol. One study [ 36 ] reported that cortisol levels correlated negatively with ghrelin suggesting that cortisol may peak after ingestion of a meal and return to nadir some time after meal completion. Hypercortisolism in another study [ 45 ] suppressed ghrelin levels. Therefore a novel approach to weight control in the absence of direct caloric restriction could be in the control of ghrelin levels.
One study [ 46 ] concluded that a ghrelin mimetic increased appetite transiently and that the infusion of ghrelin countered the effect of anorexia in elderly persons. Similarly, other studies suggested a ghrelin mimetic helped to increase appetite and caloric consumption in both end-stage renal disease [ 47 ] and cancer patients [ 38 ]. Since it has been established that both insulin [ 36 , 46 , 48 ] and cortisol [ 33 , 36 ] have negative and regulatory effects on the levels of ghrelin, a novel approach for weight control and weight loss would be to attempt to control ghrelin levels by attempting to moderate the preprandial increase.
Such control could cause a concomitant decrease in appetite with the possible implication of caloric restriction due to lower levels of hunger. Control of ghrelin, behaviorally, could occur through the increase of meal frequency and smaller meals. The same amount of calories in smaller more frequent meals can help to regulate glucose and therefore insulin and cortisol and indirectly affect the levels of ghrelin in plasma and ghrelin secretion.
Conversely, any attempts to control ghrelin endogenously may have the opposite effect and help reduce the caloric consumption in each meal. Combining both an increased meal frequency with endogenous control of ghrelin could help in the decrease of caloric consumption.
More research is needed to confirm these findings with longitudinal outcomes measured. The response of total plasma ghrelin to bouts of exercise has been investigated in humans [ 49 — 52 ], horses [ 53 , 54 ], and rats [ 55 , 56 ]. In humans, studies reporting the observed levels of ghrelin following acute bouts of exercise are conflicting. More specifically, ghrelin concentrations remained constant during a single bout of treadmill running for one hour at Moderate-intensity resistance exercises in which both eccentric and concentric contractions were performed [ 60 ] and acute incremental exercise in healthy men [ 61 ] have shown decreases in ghrelin concentrations [ 62 ].
While it is inconclusive how ghrelin concentration alone changes in response to an acute bout of exercise, ghrelin can potentially stimulate the release of growth hormone GH during exercise [ 50 ]. Since the process of releasing GH occurs through the activation of the GH secretagogue receptor [ 63 ], and GH increases during acute bouts of exercise, the relationship between exercise, plasma ghrelin levels, and GH has been investigated [ 50 ].
In most studies, GH levels increased while plasma ghrelin levels remained unchanged regardless of the duration or intensities of the exercise protocols [ 49 , 58 — 60 ]. It is suggested that under these conditions, peripheral circulating ghrelin does not mediate pituitary GH secretion [ 50 ]. However, there are studies that contradict the results of the aforementioned studies. For example, a study by Borer et al.
Ghrelin concentrations have also been investigated concurrently with exercise, hunger, and food intake responses. Recently, Erdmann et al. One group of subjects exercised with a bicycle and performed one control protocol and two uninterrupted exercise protocols: Though there was an initial increase in ghrelin concentration observed during the first protocol, the concentration remained unchanged during the second protocol.
Hunger and food intake responses were not significantly different from the controls. Another group of subjects exercised with a bicycle and performed one control protocol and three uninterrupted exercise protocols: This study suggests that duration has more of an impact than intensity with respect to an increased ghrelin response after a continuous bout of exercise. Studies that utilize long-term exercise protocols have shown ghrelin concentrations to increase in response to the subsequent exercise-induced decrease in body weight that acts via a negative feedback loop that controls body weight [ 51 , 52 , 66 ].
Circulating ghrelin levels have demonstrated an increase over time in healthy women who lost weight during a three month, energy-deficit-imposing diet and exercise regimen [ 52 ]. However, Morpurgo et al. Much like the ghrelin response, the insulin response is also sensitive to acute bouts of both endurance and resistance exercise. Endurance exercise promotes oxidation in the skeletal muscle, which is a major component in the mediation of insulin action [ 68 — 71 ].
Although an acute bout of endurance exercise enhances insulin sensitivity [ 72 — 74 ], it has been reported that an acute bout of sprint interval exercise has no effect on insulin sensitivity in healthy subjects [ 75 ].
Since insulin controls the metabolism and uptake of glucose in muscle cells and mediates blood glucose levels, serum insulin concentrations correlate with fluctuations in blood glucose [ 76 ].
This response is increased when proteins and carbohydrates are consumed at any stage of a workout, including pre-, mid-, and postworkout [ 77 — 80 ]. For example, Raastad et al. Resistance exercise protocols that utilize hypertrophy lifting strategies also show that the acute insulin response remains unchanged [ 79 , 82 — 84 ].
Hypertrophy schemes and other resistance exercise protocols are known to produce acute increases in other hormones, without supplementation, including the catabolic hormone cortisol [ 85 ]. The antagonistic effects of catabolic hormones and anabolic hormones, such as testosterone, promote muscle growth and protein metabolism during rest in between workouts [ 86 — 89 ]. These processes are accomplished through the inhibitory actions of cortisol in the synthesis of contractile muscle proteins [ 90 ], as opposed to testosterone, which has the opposite effect [ 91 , 92 ], resulting in increased muscle mass [ 93 , 94 ].
Furthermore, cortisol promotes triglycerides to be hydrolyzed into free fatty acids and glycerol [ 95 — 97 ], thereby allowing for increases in exercise performance and recovery [ 98 ]. Circulating cortisol can also be a source for energy production, as high levels of the hormone can initiate gluconeogenesis in the liver [ 97 ].
Increases in cortisol concentration may also lead to an increase in appetite and energy intake. This was demonstrated by Tataranni et al. Conversely, low cortisol concentration results in hypophagia and possibly decreased energy intake [ ]. An acute bout of resistance exercise has been shown to cause significant increases in cortisol in men although the changes observed in the hormone levels are influenced by intensity, duration, muscle mass and loading schemes, and the degree to which the subject has been trained for this type of exercise [ 94 , ].
Increases in circulating cortisol concentrations are typically proportional to the intensity of the exercise performed, but reach a maximum threshold value that is dependent upon the duration of the exercise protocol [ 96 , 98 ]. Increases in circulating cortisol levels have also been observed in women after an acute bout of resistance exercise [ 94 ] and have similar responses to men performing the same protocol [ ].
With regards to an acute bout of endurance training, cortisol normally increases with respect to exercise intensity [ — ], but the correlation is not necessarily linear [ ].
Circulating cortisol concentrations have been demonstrated to increase in trained men after repeated m sprints [ ] and increase in type 1 diabetics during and after sprinting exercises [ ]. Although no change or even a reduced change in cortisol concentrations at low exercise intensities has been reported [ 98 ], this observation has been refuted [ ]. Similarly, the effects of acute bouts of high-intensity endurance exercise in athletes are conflicting. The cortisol response to exercise is also influenced by subject training status.
In untrained men, postexercise cortisol concentrations, measured after one, six and eight weeks from starting a heavy resistance exercise protocol, increased compared to preexercise values while resting cortisol concentrations decreased at eight weeks from starting the program [ ].
In moderately trained men, cycling at moderate to high intensities provokes increases in circulating cortisol concentrations, while cycling at low intensities reduces circulating levels of the hormone [ 98 ]. No changes have been observed in cortisol concentrations among untrained females who trained for eight weeks and were divided into four groups: Cortisol concentrations also differ among trained subjects who have different training histories.
For example, cortisol levels are less pronounced in endurance-trained subjects compared to resistance-trained subjects who performed the same exercise program, which included both endurance and resistance exercises [ ]. Other factors that can influence the observed elevations in circulating cortisol concentrations during resistance exercise include plasma volume reductions when corrected still result in elevated cortisol levels [ ] and anabolic steroid use [ ].
Exercise can help to control weight through an increase in the number of calories expended. The amount of calories expended during exercise has an equivalent effect on body composition as the same amount of calories being restricted from the diet with the added benefit of cardiovascular and muscular conditioning [ ]. In fact, substantially increasing the amount of calories expended by exercise during weight loss may lead to better long-term weight control and markers of health [ ].
However, one negative result of such high exercise volume may be the accompanying rise in cortisol. Such an increase in cortisol could possibly be blunted through nutritional supplementation of fish oil and phosphatidylserine. The fish oil supplementation did not result in a statistically significant decrease in salivary cortisol compared with the placebo group, but there was an existing trend.
The proposed mechanism of lowering cortisol is through a decrease of IL-6 which has been shown to be a stimulator of the hypothalamic-pituitary-adrenocortical HPA axis independent of corticotropin-releasing hormone CRH activity [ ]. Ten male subjects were administered phosphatidylserine or placebo for 10 days and then subjected to a moderate-intensity treadmill exercise protocol. Before the postsupplementation testing session, basal cortisol levels were lower than presupplementation levels for the phosphatidylserine group compared with placebo.
Testosterone levels in the phosphatidylserine group also increased compared to the placebo group, but these results were not statistically significant.
The resulting testosterone to cortisol ratio for the phosphatidylserine group was improved which may lead to further positive physiological consequences [ ]. The findings of this study suggest that phosphatidylserine is effective in attenuating the cortisol response to exercise and may potentially prevent the physical deterioration that can result from increased training volume [ ].
In conclusion, exercise, especially at higher volumes, is an important part of any weight loss regimen. Exercise may exert its weight control benefits through its positive effects on insulin and ghrelin. Exercise can also help one adapt to the physiological effects of cortisol, but, exercising at very high volumes in an attempt to maximize energy expenditure may lead to an excessive cortisol response. Therefore, blunting the cortisol response associated with very high volumes of exercise through the use of fish oil and phosphatidylserine supplementation may be a viable option.
An often-overlooked aspect of weight control is that of sleep duration. An inverse relationship between sleep duration and body mass has been reported in both adult [ ] and adolescent [ ] populations as well as in different cultures [ — ]. Since metabolism, endocrinology, and circadian rhythms are tightly linked, this finding should be intuitive.
While there are several hormones that affect weight control, leptin, ghrelin, cortisol, and insulin are a few affected by sleep. Given the roles each hormone plays in metabolism or appetite control, learning how to manipulate the hormonal response behaviorally could be of benefit in managing weight control with or without caloric restriction.
The effects of these hormones are interconnected, but each hormone will be briefly papered independently to elucidate the effects sleep has on each. Well-controlled studies have demonstrated the effect of sleep duration on leptin. Under normal, healthy circumstances, leptin levels peak between midnight and early morning with a nadir between midday to midafternoon [ ].
Thus the peak occurs during the dark phase of the hour cycle and the nadir during the bright phase. Furthermore, leptin peaks and nadirs were shifted, yet again, when meal consumption was altered by 6. Additionally, chronic sleep deprivation has been shown to reduce the amplitude of diurnal variation with leptin [ ].
Similar reductions occur in leptin levels and amplitude of diurnal variation when sleep duration is reduced from 8 hours to 4 hours [ ]. This phenomenon has also been reported in a large population-based study where short sleep duration was associated with low leptin levels [ ]. The same population-based study reported shortened sleep duration to be associated with high ghrelin levels and increased BMI [ ]. While ghrelin levels increase in the fasting state and are known to decrease shortly after food consumption [ ], levels are also known to peak during the night and decrease before waking hours [ — ].
Relative to sleep, ghrelin has been shown to promote slow-wave sleep SWS , which is important for recovery of metabolic function [ ]. In sleep-deprived states, the nocturnal rise in ghrelin was blunted [ ].
Furthermore, Dzaja et al. If sleep duration is shortened and peak levels of ghrelin are blunted but those levels do not fall to nadir until after normal breakfast hours, the result could be an increase in appetite leading to increased caloric consumption. Additionally, it has also been demonstrated that growth hormone secretion would be blunted [ ]. It is believed that ghrelin may act in a synergistic fashion with growth-hormone-releasing hormone [ ] as well as act as an interface between the hypothalo-pituitary-adrenocortical system and the hypothalamo-pituitary-somatotrophic system [ ].
In accordance with this role as an interface between these two systems, ghrelin not only increased the duration of SWS sleep, but it also increased cortisol levels [ ].
As has been reported for leptin and ghrelin, a relationship between sleep and cortisol levels exists [ , , ]. In normal, healthy conditions, cortisol levels decline prior to sleep onset and rise again during late night hours reaching a peak during early morning [ , ]. During acute sleep restriction cortisol levels were reduced in early morning hours [ , ], but increased during evening hours when leptin levels were blunted [ ].
This relationship points to the interaction between cortisol and leptin and a possible role for sleep on weight control via hormonal regulation. While cortisol increases leptin production in a dose-dependent manner [ ], the regulation of leptin by glucocorticoids is not absolute [ ]. Conversely, leptin has a suppressive effect on the HPA axis [ ]. Thus, a feedback loop exists between the two.
Additionally, cortisol increases food consumption [ 99 ]. The cortisol and leptin response to reduced sleep duration would indicate that in a sleep deprived state, as leptin levels fall, which has a decreased effect on appetite suppression, concomitant increases in cortisol may cause an increase in food consumption [ ].
The cortisol response to acute sleep restriction appears to be similar in a chronic situation. In a large study using self-reported sleep duration, sleep restriction and high sleep disturbance resulted in elevated cortisol levels during evening hours [ ] supporting the results observed in the acute studies.
Finally, sleep loss has been proposed as a risk factor for insulin resistance and type 2 diabetes [ ]. After six days of sleep restricted to 4 hours, peak glucose responses after breakfast were elevated indicating decreased glucose tolerance [ ].
Journal of Nutrition and Metabolism
Whereas the effects of hypoxia on the above parameters could thus be Life Under Hypoxia Lowers Blood Glucose Independently of Effects on Appetite and Body 1Division of Endocrinology & Metabolism, Department of Medicine III, Factors that may affect the outcome include, e.g., differences in the. Similar effects have been shown in rainbow trout (). . These peptides act on several tissues, including the GI-tract itself, exocrine glands, and the CNS ( epidemic, focus on endocrine appetite signals for cravings of palatable foods, as effect on the appetite-regulating hormones as CCK and ghrelin further in pigs . Blood glucose following an oral glucose tolerance test (OGTT) in pigs, with or.