Boosting Gut Endocrinology With Brain Imaging
Article Outline
The increasing incidence of obesity and associated diseases has spurred enormous interest in the mechanisms controlling feeding and energy homeostasis.1, 2 Peripheral signals involved in regulation of body weight may be classified into those that are long acting, such as leptin and insulin, whose plasma levels reflect energy stores in adipose tissue and act via a negative feedback mechanism in the hypothalamus, brainstem, and other areas of the brain to influence food intake, energy expenditure, and neuroendocrine responses.1 Short-acting signals emanating from mechanoreceptors and chemoreceptors detect changes in gut distension and nutrients, and trigger the release of hormones to regulate intestinal motility, satiation, meal termination, and insulin secretion.2 Short-term gut signals are typically transmitted by vagal afferents to the brainstem and then relayed to the hypothalamus and other areas of the forebrain.2
The physiology of 2 key gut hormones, cholecystokinin (CCK) and peptide YY (PYY), has been highlighted in recent studies, one of which was published in GASTROENTEROLOGY.3, 4 CCK is a prototypical, gut-derived satiety hormone. CCK is synthesized by I-cells mainly in the duodenum and jejunum, rapidly released into the surrounding tissues and circulation in response to meals rich in fat and protein, delays gastric emptying, and stimulates pancreatic enzyme secretion and gall bladder contraction. CCK-1 receptors are localized on vagal afferent and enteric neurons and pancreas, and widely distributed in the brain, including the nucleus of the solitary tract, area postrema, and dorsomedial hypothalamus. Administration of CCK in rodents and humans inhibits food intake by reducing meal size and duration. This effect is mediated via the sulfated form of CCK, that binds to CCK-1 receptors expressed by vagal afferent neurons, which projects to the dorsal vagal complex to induce satiety, inhibit gastric emptying, and stimulate gallbladder contraction and secretion of digestive enzyme by the pancreas.
PYY is synthesized by enteroendocrine L-cells in the intestine, that is, the same source of glucagon-like peptide-1. PYY is released into the circulation following meals and peaks 1–2 hours postprandially. PYY secretion occurs via a neural reflex, likely involving the vagus nerve. PYY3–36; the major circulating form binds mainly to the Y2 receptor. Peripheral administration of PYY increases the absorption of fluids and electrolytes from the ileum, and inhibits pancreatic and gastric secretions, gastric emptying and gallbladder contraction. Peripheral administration of PYY3–36 has been reported to inhibit feeding in rodents, although other investigators were unable to reproduce this result.5, 6, 7 In humans, intravenous infusion of PYY3–36 inhibited appetite and food intake.8 It seems the secretion of PPY is impaired in obesity, but whether this is an important contributor to the development of obesity is uncertain.9 Based on rodent studies, PYY3–36 exerts its anorectic action in the arcuate nucleus of the hypothalamus by inhibiting the expression and release of neuropeptide Y.5 PYY3–36 also acts at the level of the vagus and of the dorsal vagal complex to inhibit feeding.5
Our knowledge of the mechanisms by which the gastrointestinal tract communicates with the brain has benefitted immensely from experiments in rodents.2 However, rodent models have a limited capacity to unravel conscious and subjective aspects of feeding behavior. Thus, it is gratifying that studies have begun to explore the gut–brain connection in humans by combining physiologic manipulations of gut hormones, brain imaging, and subjective ratings of feeding behavior. Lassman et al3 studied the effects of CCK on brain activity in nonobese healthy subjects in a blinded, randomized, and balanced manner. In humans, free fatty acids, and not triglycerides, stimulate the release of CCK. Dodecanoic acid (C12) was administered via a gastric feeding tube after an overnight fast. This method of lipid infusion avoided the confounding effects of visual, taste, and smell sensations on brain responses. Plasma CCK levels doubled after C12 infusion, whereas saline infusion had no effect on CCK levels. As expected, the rise in CCK after intragastric C12 infusion was associated with gallbladder contraction. This effect was abrogated when the subjects were pretreated with a CCK-1 receptor antagonist, dexloxiglumide. Infusion of C12 resulted in a mild, but insignificant, sensation of fullness and reduction in hunger.
Functional magnetic resonance imaging (fMRI) showed a rapid increase (2–4 minutes) in blood oxygen level dependent signal bilaterally in the medulla and pons after C12 but not saline infusion, consistent with neuronal activation. This was followed by bilateral activation of the hypothalamus. Interestingly, brain areas not associated with homeostatic regulation, such as the motor cortex, anterior and posterior cerebellum, left caudate, precuneus, cingulate and middle temporal gyrus, and the thalamus, responded to C12 infusion and rise in plasma CCK levels. Dexloxiglumide had no independent effect on brain activity, but blocked the effects of C12 infusion, suggesting the induction of activity in the brainstem, hypothalamus, and other areas was dependent on the CCK-1 receptor. The experimental design did not reflect the changes in brain activity, which may be elicited by ingestion of an actual meal. However, the results are independent of sensory awareness, or hedonic or aversive factors associated with orally ingested meals, and thus provide information on gut–brain signaling of fatty acids and CCK.3 The spatiotemporal activation of brainstem and hypothalamic, as well as brain regions not typically associated with nutrient signaling in the gut, sheds new light on the potential role of CCK-1 receptor in feeding behavior. Further work is needed to elucidate whether the rapid effects of C12 and CCK on brain activity are mediated via vagal afferents, and whether fatty acid metabolites known to induce anorexia, for example, oleylethanolamine and N-acylphosphatidylethanolamine, interact with the CCK-1 receptor.
An earlier study by Batterham et al4 examined the effects of PYY levels mimicking the fed and fasted states on brain activity. Normal weight subjects were fasted overnight and participated in a randomized, double-blind, placebo-controlled, cross-over study. fMRI scanning of the brain was performed at baseline (fasting) while saline was infused intravenously for 10 minutes, followed by saline or PYY infusion and fMRI scanning for 90 minutes. Subjective feelings toward food and non-food items were assessed with visual analog scales. A test meal was administered 30 minutes after the PYY versus saline infusion, and fMRI scanning and feeding behavior were studied. As expected, PYY levels were low during fasting and increased in response to feeding. The PYY infusion increased plasma PYY concentration to levels seen in postprandial states.4 Hunger rating was increased during fasting, and PYY infusion blocked food-related feelings of hunger. The consumption of the test meal was negatively correlated with PYY levels, which was inversely associated with ghrelin, which normally drives feeding. The greatest increase in brain activation in response to PYY infusion occurred in the left caudolateral orbitofrontal cortex, a region implicated in reward processing.4 PYY infusion activated limbic areas (insula and anterior cingulated cortex), ventral striatum, and frontal, parietal, and temporal cortex, as well as the cerebellum. A positive association between PYY and activation also occurred in the posterior hypothalamus, and right subtantia nigra and parabrachial nucleus. In the presence of elevated PYY levels, activity in the orbitofrontal cortex was highly predictive of suppression of food intake, whereas the hypothalamus seemed to play a lesser role. Thus, the major function of PYY in these human subjects was to regulate the hedonic rather than homeostatic aspect of feeding behavior.4
These studies provide important information about the spatiotemporal responses of the brain to 2 key gut hormones, CCK and PYY. With the help of fMRI and metabolic imaging of the brain, such as positron emission tomography, we can now explore the roles of gut hormones, sensory, hedonic, and other complex aspects of eating behavior. Such detailed studies will provide insight into how pleasurable sensations can override homeostatic signals, and lead to overconsumption of food and obesity. Functional brain imaging has the potential to provide objective data on brain responses to food that cannot be measured with subjective tests. An area that could benefit from a thorough analysis of gut–brain interaction is bariatric surgery. Although studies have shown that bariatric surgery, particularly roux-en-Y gastric bypass, potently reduces food intake, the underlying mechanisms are still uncertain.10 Longitudinal studies of changes in gut hormones after gastric bypass surgery, and how these affect brain activity would be a major step forward. The combination of gut endocrinology and brain imaging reported by Lassman, Batterham, and colleagues, offers a template for translation of knowledge gained in rodent models to normal human physiology, and will lead to new understanding of obesity and associated metabolic diseases.
References
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PII: S0016-5085(10)00884-X
doi:10.1053/j.gastro.2010.06.025
© 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
