胃肠道激素与肥胖

胃肠道是能量摄取和吸收器官,也是重要的内分泌器官.其分泌的多种激素可通过调节胃肠道功能、食欲、脂代谢甚至是机体代谢率等多条途径,影响体内能量平衡.另外,肥胖患者体内亦存在胃肠道激素的异常分泌,可见肥胖与胃肠道激素的分泌密切相关.深入认识胃肠道激素与肥胖的关系及其作用机制,有助于研发新的减肥方法或药物.     

Obesity and functional gastrointestinal disorders

Obesity is prevalent in Korea. An increase in food intake and a decrease in energy expenditure are responsible for obesity. Gut hormones play a role in controlling food intake. Obesity is suggested to be linked to common gastrointestinal functional disorders. Obesity is associated with an increased risk of gastroesophageal reflux disease, Barrett esophagus and esophageal adenocarcinoma. Epidemiologic studies indicate that obesity is associated with chronic gastrointestinal symptoms. This association suggests the possibility that obesity and functional gastrointestinal disorders may be pathophysiologically linked. However, data on the relationship between obesity and functional gastrointestinal disorders are inconsistent. In this paper, we review the role of gastrointestinal hormones in food intake and the relationship between obesity and functional gastrointestinal disorders.     

胃瘦素的研究新进展

瘦素是一种主要由脂肪组织产生的蛋白质激素,在中枢性调控摄食和能量代谢上起重要作用。近年来发现胃组织也可产生瘦素（胃瘦素）。现有文献表明胃瘦素可能参与调节胃肠道碳水化合物、蛋白质和脂肪的吸收,有独立的心血管调节作用以及可能对肥胖的预防和治疗产生重要影响;并与脂肪瘦素协同控制着摄食行为和能量贮存。本文总结了近年来胃瘦素在营养物吸收、摄食和能量平衡调控、心血管调节等方面的研究进展;我们也期待更多的研究来探索和证实胃瘦素的新作用。     

Fasting oxyntomodulin,glicentin, and gastric inhibitory polypeptide levels are associated with activation of reward- and attention-related brain centres in response to visual food cues in adults with obesity: A cross-sectional functional MRI study

Postprandial increases in gastrointestinal hormones are associated with reduced energy intake, partially through direct effects on the brain. However, it remains unknown whether the fasting levels of gastrointestinal hormones are associated with altered brain activity in response to visual food stimuli. We therefore performed a whole-brain regression cross-sectional analysis to assess the association between fasting brain activations according to functional magnetic resonance imaging, performed during viewing of highly desirable versus less desirable food images, with fasting levels of five gastrointestinal hormones (glucagon-like peptide [GLP]-1, GLP-2, oxyntomodulin, glicentin and gastric inhibitory polypeptide [GIP]) in 36 subjects with obesity. We observed that fasting blood levels of GIP were inversely associated with the activation of attention-related areas (visual cortices of the occipital lobe, parietal lobe) and of oxyntomodulin and glicentin with reward-related areas (insula, putamen, caudate for both, and additionally orbitofrontal cortex for glicentin) and the hypothalamus when viewing highly desirable as compared to less desirable food images. Future studies are needed to confirm whether fasting levels of oxyntomodulin, glicentin and GIP are associated with the activation of brain areas involved in appetite regulation and with energy intake in people with obesity.     

Gut peptides in the regulation of food intake and energy homeostasis

Gut hormones signal to the central nervous system to influence energy homeostasis. Evidence supports the existence of a system in the gut that senses the presence of food in the gastrointestinal tract and signals to the brain via neural and endocrine mechanisms to regulate short-term appetite and satiety. Recent evidence has shown that specific gut hormones administered at physiological or pathophysiological concentrations can influence appetite in rodents and humans. Gut hormones therefore have an important physiological role in postprandial satiety, and gut hormone signaling systems represent important pharmaceutical targets for potential antiobesity therapies. Our laboratory investigates the role of gut hormones in energy homeostasis and has a particular interest in this field of translational research. In this review we describe our initial studies and the results of more recent investigations into the effects of the gastric hormone ghrelin and the intestinal hormones peptide YY, pancreatic polypeptide, glucagon-like peptide-1, and oxyntomodulin on energy homeostasis. We also speculate on the role of gut hormones in the future treatment of obesity.     

Gastrointestinal targets to modulate satiety and food intake

This review discusses the role of enteroendocrine cells in the gastrointestinal tract as chemoreceptors that sense intraluminal contents and induce changes in food intake through the release of signalling substances, such as satiety hormones. Recent evidence supports the concept that chemosensing in the gut involves G protein‐coupled receptors (GPCRs) that are known to mediate gustatory signals in the oral cavity. GPCRs can be grouped into several families, depending on the stimuli to which they respond, e.g. proteins, amino acids, carbohydrates, fatty acids, or tastants. Sensing of these stimuli by GPCRs results in hormone secretions of enteroendocrine cells, which participate in the control of food intake. A better understanding of the stimuli that induce the strongest binding with these receptors, and thus induce a strong release of hormones, can be a very useful strategy for the development of novel foods in the treatment of obesity.     

Gastrointestinal regulation of food intake: do gut motility, enteric nerves and entero-hormones play together?

The gastrointestinal system can be considered the gateway for food entry in our body. Rather than being a passive player, it is now clear that gut strongly influence the feeding behavior and contribute to maintain energy balance with different signals. The aim of this review is to summarize the current knowledge about the role of gastrointestinal tract in the control of food intake, by focusing on the interplay existing between the enteric nervous system and gastrointestinal hormones and their ability to modulate digestive motility and sensitivity. Also the latest advances about the contribution of gut microbiota and gastrointestinal taste receptors are described. From the reported data it clearly emerges that gut hormones together with nervous signals likely contribute to the regulation of energy balance and modulate food intake through the control of digestive motility and sensations. The close linkage among gastrointestinal hormones, the gut and the central nervous systems appears very intriguing and has induced the development of a new field of research: the gastroendocrinology.     

Role of cholecystokinin in appetite control and body weight regulation

Summary Cholecystokinin (CCK), a peptide that is distributed widely throughout the gastrointestinal tract and the central nervous system, has a number of physiological effects including the stimulation of gallbladder contraction and pancreatic and gastric acid secretion, slowing of gastric emptying and suppression of energy intake. This review focuses on current knowledge relating to (i) the effects of CCK on energy intake; (ii) the role for CCK in the pathophysiology of obesity; and (iii) the therapeutic potential for strategies which modulate the action or secretion of CCK in the management of obesity. While CCK plays a role in the acute regulation of appetite and energy intake, there is little evidence to suggest that specific CCK receptor agonists, or modulation of the actions of endogenous CCK by dietary manipulation, have sustainable inhibitory effects on energy intake. Hence, it appears unlikely that manipulating the pathways by which CCK modulates energy intake will prove to be an effective strategy in the long term management of obesity.     

Regulation of food intake: The gastric X/A-like endocrine cell in the spotlight

Nutritional status influences hormone secretion from specialized enteroendocrine cells within the gut mucosa. These hormones regulate food intake by mediating information to central neurocircuitries in the brainstem and forebrain (eg, hypothalamic nuclei). Intestinal enteroendocrine cells were believed to be the main source of gut peptides regulating food intake. However, recent evidence highlights a specific endocrine cell within the oxyntic glands of the stomach as an important player in appetite control. Acylated ghrelin is the only known orexigenic hormone peripherally produced in gastric X/A-like cells and centrally acting to stimulate food intake. Recent advances led to the assumption that des-acylated ghrelin, coreleased with acylated ghrelin, is also involved in regulating food intake. This, and the novel observation that nesfatin-1, which inhibits food intake, is expressed in ghrelin-producing cells of the stomach, supports an important role for gastric X/A-like cells in regulating food intake. Another peptide, obestatin, was initially described as a ghrelin gene product inhibiting food intake, but subsequent studies produced controversial data and its action as an anorexic factor is doubtful. Importantly, synergistic interactions between ghrelin and intestinal peptides seem to orchestrate food intake and body weight regulation, which may have implications for understanding mechanisms leading to the treatment of obesity.     

Luminal amino acid-sensing cells in gastric mucosa

Chemosensing of nutrients in the gastrointestinal tract plays physiologically important roles in the regulation of food intake behaviors, including digestion, absorption, metabolism and other subsequently occurring body functions via brain activation. Free amino acids, liberated from ingested foods, are of course essential nutrients which compose the body proteins and sometimes determine the taste of the food. Glutamate, one of the most abundant amino acids in the foods and the liberated free form, critically contributes to the 'umami' taste perception. Recently, it has been revealed that dietary glutamate has many beneficial functions in the gastrointestinal tract. However, the precise mechanism of glutamate sensing still remains unclear. Using primary rat gastric mucosal cell cultures, we demonstrated that somatostatin-secreting D cells are candidate cells for glutamate sensing in the stomach through inhibition of somatostatin release. Considering that somatostatin is one of the major negative regulators of gastric functions, it is suggested that some parts of glutamate's beneficial effects could be explained by suppression of the inhibitory somatostatin effects, i.e. stimulation, by glutamate.     

Bariatric surgery – time to replace with GLP-1?

Obesity with a body mass index (BMI) over 30?kg/m² represents a significant risk for increased morbidity and mortality, with reduced life expectancy of about 10 years. Until now, surgical treatment has been the only effective longterm intervention. The currently standardized method of bariatric surgery, gastric bypass, means that many gastrointestinal peptide hormones are activated, yielding net reductions in appetite and food intake. Among the most important gut peptide hormones in this perspective is glucagon-like peptide-1 (GLP-1), which rises sharply after gastric bypass. Consistent with outcomes of this surgery, GLP-1 suppresses appetite and reduces food intake. This implies that GLP-1 has the potential to achieve a similar therapeutic outcome as gastric bypass. GLP-1 analogs, which are used for the treatment of type 2 diabetes mellitus, also lead to significant weight loss. Altered hormonal profiles after gastric bypass therefore indicate a logical connection between gut peptide hormone levels, weight loss and glucose homeostasis. Furthermore, combinations of GLP-1 with other gut hormones such as peptide YY (PYY) and cholecystokinin (CCK) may be able to reinforce GLP-1 driven reduction in appetite and food intake. Pharmacological intenvention in obesity by use of GLP-1 analogs (exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, taspoglutide) and inhibitors of dipeptidyl peptidase-IV (DPP-IV) degradation that inactivate GLP-1 (sitagliptin, vildagliptin), leading to reduced appetite and weight with positive effects on metabolic control, are realistically achievable. This may be regarded as a low-risk therapeutic alternative to surgery for reducing obesity-related risk factors in the obese with lower BMIs.     

Oxyntomodulin

The prevalence of obesity is increasing rapidly and the associated morbidity and mortality has led to an urgent need for potential therapeutic targets to reduce appetite and food intake. Gut hormones released after eating that coordinate digestive activity and promote satiety are novel potential treatments for obesity. Oxyntomodulin is a gut hormone that is produced by the L cells in the small intestine and reduces food intake. It is timely to review some of the original literature on oxyntomodulin, to evaluate what is already known about the peptide, and also to set the recent findings on its effects on food intake and bodyweight into context.Recent studies have shown that long-term peripheral administration of oxyntomodulin to rats leads to reduced food intake and reduced weight gain. Studies in humans have demonstrated that acute administration reduces food intake by 19%. When given preprandially by subcutaneous injection three times daily, oxyntomodulin resulted in a reduction in food intake and mean weight loss of 2.8kg over 4 weeks. Oxyntomodulin thus represents a potential therapy for obesity.The mechanism of action of oxyntomodulin is not known. Current evidence suggests that it acts via the glucagon-like peptide 1 (GLP-1) receptor. There may be an additional receptor in the gastric mucosa mediating its effects on gastric acid secretion. Although oxyntomodulin probably acts via the GLP-1 receptor, the two peptides differentially regulate food intake and energy expenditure in the mouse.Oxyntomodulin represents a potential therapy for obesity. Further work will help to clarify its mechanisms of action.     

Clinical endocrinology and metabolism. Regulation of energy homeostasis by peripheral signals

The increased incidence of obesity makes it imperative to understand the regulation of food intake and body weight. We review the signals that interact with the brain to control energy homeostasis, i.e. energy intake and expenditure. Three broad categories can be distinguished. Signals generated in the gastrointestinal tract during meals ('satiety' signals, e.g. cholecystokinin) elicit satiation and contribute to stopping the meal. The potency of these acutely acting signals must be increased if they are to be used therapeutically. Hormonal signals whose secretion is proportional to body fat (adiposity signals, leptin and insulin) robustly reduce food intake and body weight by directly stimulating receptors locally in the brain. Therapeutic applications will have to find ways to circumvent the systemic actions of these hormones, targeting only the brain. Satiety and adiposity signals interact with neuronal circuits in the brain that utilize myriad neurotransmitters to cause net catabolic or anabolic responses. Considerable effort is being directed towards finding ways to intervene in specific circuits to help accomplish weight loss.     

Mechanisms of disease: the role of gastrointestinal hormones in appetite and obesity

The obesity epidemic is fast becoming one of the leading causes of mortality and morbidity worldwide. Over the past 30 years, gastrointestinal hormones have been increasingly understood to have an important role as regulators of appetite and energy balance in obese individuals. The levels of these hormones are modulated by bariatric surgery, and understanding how they are affected by such procedures can contribute to our comprehension of the underlying mechanisms by which these hormones affect obesity and its treatment. In this Review, we consider several gastrointestinal hormones that can contribute to obesity by modulating the activity of the gut-brain axis, and examine their specific effects on appetite, hunger and energy balance. Better understanding of the mechanisms by which these peptides exert their effects may enable the development of improved weight-loss medications and new treatments for obesity.     

Minireview: Gut peptides regulating satiety

The gastrointestinal tract and the pancreas release hormones regulating satiety and body weight. Ghrelin stimulates appetite, and glucagon-like peptide-1, oxyntomodulin, peptide YY, cholecystokinin, and pancreatic polypeptide inhibit appetite. These gut hormones act to markedly alter food intake in humans and rodents. Obesity is the current major cause of premature death in the United Kingdom, killing almost 1000 people per week. Worldwide, its prevalence is accelerating. There is currently no effective answer to the pandemic of obesity, but replacement of the low levels of peptide YY observed in the obese may represent an effective antiobesity therapy.     

Brain regulation of energy balance and body weight

Body weight is determined by a balance between food intake and energy expenditure. Multiple neural circuits in the brain have evolved to process information about food, food-related cues and food consumption to control feeding behavior. Numerous gastrointestinal endocrine cells produce and secrete satiety hormones in response to food consumption and digestion. These hormones suppress hunger and promote satiation and satiety mainly through hindbrain circuits, thus governing meal-by-meal eating behavior. In contrast, the hypothalamus integrates adiposity signals to regulate long-term energy balance and body weight. Distinct hypothalamic areas and various orexigenic and anorexigenic neurons have been identified to homeostatically regulate food intake. The hypothalamic circuits regulate food intake in part by modulating the sensitivity of the hindbrain to short-term satiety hormones. The hedonic and incentive properties of foods and food-related cues are processed by the corticolimbic reward circuits. The mesolimbic dopamine system encodes subjective “liking” and “wanting” of palatable foods, which is subjected to modulation by the hindbrain and the hypothalamic homeostatic circuits and by satiety and adiposity hormones. Satiety and adiposity hormones also promote energy expenditure by stimulating brown adipose tissue (BAT) activity. They stimulate BAT thermogenesis mainly by increasing the sympathetic outflow to BAT. Many defects in satiety and/or adiposity hormone signaling and in the hindbrain and the hypothalamic circuits have been described and are believed to contribute to the pathogenesis of energy imbalance and obesity.     

Effects of gastrointestinal surgery on ingestive behavior in animals

Surgical manipulations of the gastrointestinal system can have a major impact on the ingestive behavior of animals. Particularly well-documented are the feeding and drinking effects of JIB and vagotomy. These two surgical procedures are similar in that they reduce the food intake and body weight of obese animals more than that of lean animals, and of hypothalamic obese rats more than that of genetically obese rats. Intermediate effects are obtained with other obesity models. Given the multiple etiologies of human obesity, it is not surprising that gastrointestinal surgery has variable effects in obese humans. The effects of gastric surgery on the ingestive behavior of animals have received relatively little attention. This is unfortunate because gastric bypass is now one of the most widely used methods for surgical treatment of human obesity. In light of recent developments in gastric surgical techniques and new findings concerning the gastric modulation of food intake, the effects of gastric surgery on the feeding behavior of animals should be further investigated. Much remains to be learned about the physiologic and behavioral mechanisms by which gastrointestinal surgery influences ingestive behavior and body weight. Surgical manipulations of the gastrointestinal system may affect ingestive behavior by directly altering the neural and hormonal feedback signals to the brain from the stomach, intestines, and other organs (liver, pancreas), or they may indirectly alter these feedback signals by modifying the preabsorptive and/or postabsorptive flow of nutrients. Seen from a functional perspective, the gut sends to the brain different types of messages that modulate ingestive behavior. Most attention has focused on gut satiety signals, but the gut can also be the source of painful sensations that suppress ingestive behavior. The distinction between satiety and discomfort is not always clear-cut. For example, gut distention may be satiating when it is moderate, but painful when it is extreme. Nevertheless, the distinction is an important one, and the nature of the feeding-inhibitory effects obtained in animal studies must be carefully evaluated. Ideally, obesity surgery should produce minimal aversive consequences, although whether it is possible to reduce food intake and body weight without producing any discomfort remains to be established. In addition to being a source of feeding-inhibitory cues, the gastrointestinal system may also provide excitatory cues that stimulate feeding and modify food preferences. For example, intestinal infusions of carbohydrates increase subsequent food intake under certain conditions.(ABSTRACT TRUNCATED AT 400 WORDS)     

Appetite regulation and weight control: the role of gut hormones

The overwhelming increase in the prevalence of overweight and obesity in recent years represents one of the greatest threats to the health of the developed world. Among current treatments, however, gastrointestinal (GI) surgery remains the only approach capable of achieving significant weight loss results with long-term sustainability. As the obesity prevalence approaches epidemic proportions, the necessity to unravel the mechanisms regulating appetite control has garnered significant attention. It is well known that physical activity and food intake regulation are the two most important factors involved in body weight control. To regulate food intake, the brain must alter appetite. With this realization has come increased efforts to understand the intricate interplay between gut hormones and the central nervous system, and the role of these peptides in food intake regulation through appetite modulation. This review discusses the central mechanisms involved in body weight regulation and explores a suite of well characterized and intensely investigated anorexigenic and orexigenic gut hormones. Their appetite-regulating capabilities, post-GI surgery physiology and emerging potential as anti-obesity therapeutics are then reviewed.