EDITORIALS Hunger Games: Is Your Stomach Making You Fat? See “Quantitative gastrointestinal and psychological traits associated with obesity and response to weight-loss therapy,” by Acosta A, Camilleri M, Shin A, et al, on page 537.

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s a digestive organ, the stomach often gets no respect. Its powerful enzymes are treated as physiologic curiosities, serving no obvious purpose and its acid is regarded as the bane of human existence, to be neutralized by any means. Its apparent irrelevance is embodied in the name of a popular bariatric procedure, where almost all of the stomach can be bypassed and made dormant for years. With increasing clarity about the role of the hypothalamus and peripherally derived peptides (largely from the small intestine),1 gastric factors in the pathogenesis of obesity were largely dismissed. However, it was not always like this—at the turn of the last century, gastric motility was thought to drive hunger, as suggested by no less a luminary than Walter Cannon.2 More recently, with the discovery of ghrelin and its origin from the stomach, attention is rightfully being paid to the stomach as a physiologic regulator of hunger and food intake. Mucosal endocrine cells concentrated in the fundus produce ghrelin, whose role as a hunger signal/meal initiator appears is reasonably established,3 although our understanding of how it may lead to obesity is still evolving and likely to be far more complex.4 However, ghrelin is not the only reason to focus on the role of the stomach in obesity. The stomach is necessary to store and process solid meals before they reach the small intestine. This “storage period,” known as the lag phase, can last between 30 and 60 minutes and is used by the stomach to break down food particles to a size that allows them to traverse the pylorus. This implies that we generally stop eating long before significant amounts of nutrients can reach the intestine to invoke feedback from incretin, insulin, and other hormones (eg, cholecystokinin [CCK] and peptide tyrosine tyrosine [PYY]). Therefore, one can infer that “satiation” (the sensation of fullness associated with a desire to end the current meal) at least (as opposed to “satiety,” which in the scientific literature reflects the ability to eat the next meal) originates from the stomach because more distal mechanisms have not been activated yet. Further, because it is unlikely that the stomach (apart perhaps from the pylorus) has the ability to sense nutrient or caloric intake, most of these signals emanate from mechanical forces related to the physical dimensions of the food and the biomechanical properties of the stomach wall.5 Gastric biophysical factors can theoretically affect food intake in several ways. Changes in pressure/volume in the stomach (both proximally and in the antrum) in response to ingestion of food can signal satiation and meal size via vagal afferents.6 This signaling presumably requires integration

between the nucleus tractus solitarius and hypothalamic circuits controlling eating behavior. In turn, central motor nuclei coordinate neural and endocrine inputs to provide signals to the stomach via vagal efferents, setting both baseline tone and the relaxation response (accommodation) to a meal. This also implies that larger gastric “capacity,” as measured by surrogate markers such as fasting gastric volume, may result in larger meal sizes before achieving satiation. Finally, the role of gastric emptying deserves special attention. It has been postulated that a slow gastric emptying rate can result in greater residual volumes in the stomach and distention, leading to satiety.5 However, a large study of patients with chronic dyspeptic symptoms showed no difference in the severity of stomach fullness, fullness after meals, or inability to complete meals in groups with normal emptying compared with those with delayed emptying.7 Other studies have suggested that antral distention rather than emptying per se correlates best with fullness.8 Perhaps a more important mechanism is that the rate of transpyloric nutrient delivery is important in determining intestinal neuroendocrine feedback for modulating satiation and satiety. In this regard, it should be noted that it is gastric emptying of calories (energy) rather than gastric emptying of volume per se that seems to correlate with satiety.9 Higher energy density meals, therefore, result in slower gastric emptying in both healthy and overweight patients,10 an effect that may be further augmented by high fat content. Although one would expect that such diets will therefore produce greater satiation, the effect on gastric emptying may be countered, partially at least, by a lesser dietinduced thermogenesis (which is an independent contributor to satiation).11 Very little is known about these aspects of gastric function in obesity, and what has been published is mostly inconclusive and occasionally contradictory with respect to gastric volume, emptying, or other parameters.12 In this regard, the study published by Acosta et al in this issue of Gastroenterology13 is of considerable significance, being the largest and most comprehensive analysis of prospectively collected data in subjects across the body mass index spectrum. In terms of gastric motility, their most significant results show that higher fasting gastric volume as well gastric emptying rates (solids and liquids) are associated with obesity (they did show an association with a higher volume to fullness using a liquid test meal, but this was only when they combined data with a retrospective group). They also confirmed previous reports of an association between obesity and lower postprandial PYY. Theoretically, this could potentially explain why obese patients may consume higher calories. However, caution is advised before leaping to causation. The investigators found no association between caloric ingestion and body mass index in an ad libitum buffet meal paradigm (although they did show an association with waist circumference in the combined study). Second, levels of several other anorexigenic Gastroenterology 2015;148:491–505

EDITORIALS

Figure 1. Some of the signals (both positive and negative) regulating hunger, satiation, and satiety emanating from the stomach directly or as a consequence of gastric emptying. The boxes indicate the latent domains or clusters found by Acosta et al; their position in the figure reflects the predominant site where such factors may theoretically act to influence food intake and weight gain.

hormones such as GLP-1 and CCK were elevated and ghrelin levels were depressed. To their credit, the investigators have acknowledged these limitations and focused more on using these findings to make a first attempt to phenotype subjects with obesity. Using a principal components analysis, the authors found four latent dimensions that accounted for about 80% of the observed variation (Figure 1). The investigators then went on to test the predictive value of these measurements in a small, placebo-controlled trial of the weight loss agent phentermine–topiramate. A modest weight loss was seen in the active treatment group which, out of 5 prespecified variables, was associated significantly with calorie intake at the prior satiety buffet meal (the other variables being satiation by volume to fullness, gastric emptying of solids, fasting gastric volume, and peak plasma PYY). Acosta et al are to be congratulated on doing such a laborious and difficult study, which has advanced our knowledge of how the stomach regulates how much we eat or can eat. Such knowledge also has the potential to lead to better therapies for obesity. However, even though these results are provocative, we are still a considerable way from going beyond the current, relatively crude measures for targeting the stomach (including restrictive and balloon approaches). Important gaps in our knowledge remain, such as whether the changes in satiety/ satiation are central or peripheral (eg, changes in gastric accommodation) in origin and whether regional specificity is important for mechanosensitivity in obesity. Targeting gastric emptying, although attractive in concept, is even more complex for multiple reasons. First, there are few approaches that can slow down emptying in a highly specific manner, without affecting gastric volume or distention pressures (such as surgery). Botulinum toxin potentially represents one such approach and a previous trial from the same institution showed that antral injections of the toxin could 492

slow gastric emptying, but did not affect weight loss, satiation volume, caloric intake, gastrointestinal symptoms, or changes in eating behavior when compared with controls.14 Second, an inherent confounder in modifying gastric emptying is that by definition this also alters the intestinal response, which may be counter to the gastric effects on satiation/satiety. Many operative procedures in fact result in profound weight loss but accelerate gastric emptying,15 suggesting that emptying per se may not be a critical therapeutic target. Perhaps the answer lies in focusing on caloric emptying rather than volume emptying, although it has been suggested that such regulatory mechanisms are intact in obese subjects,10 and larger, more systematic studies are needed. In conclusion, as with every aspect of obesity, the story of the stomach in regulating hunger, satiation, and satiety is complex and full of subtleties. There is no clear answer, therefore, to the question posed by the title of this editorial. The “gastric phenotypes” described by Acosta et al13 needs to be validated prospectively in other studies and it remains to be seen whether they have predictive value to allow individualizing approaches to weight loss or refining current treatments. Further, even if these physiologic findings are valid, we do not know how easily hedonic eating behavior can override gastric signals. Nevertheless, the study has provided a basis for going forward for other investigators, and its results will expand our current concepts about obesity to include gastric physiology and pathophysiology. PANKAJ JAY PASRICHA Johns Hopkins Center for Neurogastroenterology Food Body and Mind Center at Johns Hopkins Department of Medicine and Neurosciences Johns Hopkins School of Medicine Department of Innovation Management Johns Hopkins Carey School of Business Baltimore, Maryland

EDITORIALS References 1. Horvath TL, Diano S. The floating blueprint of hypothalamic feeding circuits. Nat Rev Neurosci 2004;5:662–667. 2. Cannon WB, Washburn AL. An explanation of hunger. 1911. Obes Res 1993;1:494–500. 3. Wren AM, Bloom SR. Gut hormones and appetite control. Gastroenterology 2007;132:2116–2130. 4. Schellekens H, Finger BC, Dinan TG, et al. Ghrelin signalling and obesity: at the interface of stress, mood and food reward. Pharmacol Ther 2012;135:316–326. 5. Janssen P, Vanden Berghe P, Verschueren S, et al. Review article: the role of gastric motility in the control of food intake. Aliment Pharmacol Ther 2011;33:880–894. 6. Schwartz GJ. The role of gastrointestinal vagal afferents in the control of food intake: current prospects. Nutrition 2000;16:866–873. 7. Pasricha PJ, Colvin R, Yates K, et al. Characteristics of patients with chronic unexplained nausea and vomiting and normal gastric emptying. Clin Gastroenterol Hepatol 2011;9:567–576. e1–4. 8. Abell TL, Familoni B, Voeller G, et al. Electrophysiologic, morphologic, and serologic features of chronic unexplained nausea and vomiting: lessons learned from 121 consecutive patients. Surgery 2009;145:476–485. 9. Carbonnel F, Lemann M, Rambaud JC, et al. Effect of the energy density of a solid-liquid meal on gastric emptying and satiety. Am J Clin Nutr 1994;60:307–311. 10. Horowitz M, Collins PJ, Shearman DJ. Effect of increasing the caloric/osmotic content of the liquid component of a mixed solid and liquid meal on gastric emptying in obese subjects. Hum Nutr Clin Nutr 1986; 40:51–56. 11. Luscombe-Marsh ND, Seimon RV, Bollmeyer E, et al. Acute effects of oral preloads with increasing energy

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density on gastric emptying, gut hormone release, thermogenesis and energy intake, in overweight and obese men. Asia Pac J Clin Nutr 2013;22:380–390. Camilleri M. Peripheral mechanisms in appetite regulation. Gastroenterology 2014 Sep 21 [Epub ahead of print]. Acosta A, Camilleri M, Shin A, et al. Quantitative gastrointestinal and psychological traits associated with obesity and response to weight-loss therapy. Gastroenterology 2015;148:537–546. Topazian M, Camilleri M, Enders FT, et al. Gastric antral injections of botulinum toxin delay gastric emptying but do not reduce body weight. Clin Gastroenterol Hepatol 2013;11:145–150 e1. Shah S, Shah P, Todkar J, et al. Prospective controlled study of effect of laparoscopic sleeve gastrectomy on small bowel transit time and gastric emptying half-time in morbidly obese patients with type 2 diabetes mellitus. Surg Obes Relat Dis 2010;6:152–157.

Reprint requests Address requests for reprints to: Pankaj Jay Pasricha, MD, Director, Johns Hopkins Center for Neurogastroenterology, Director, Food Body and Mind Center at Johns Hopkins, Professor of Medicine and Neurosciences, Johns Hopkins School of Medicine, Professor of Innovation Management, Johns Hopkins Carey School of Business, 720 Rutland Street, Ross 958, Baltimore, Maryland 21205. e-mail: [email protected].

Conflicts of interest The author discloses no conflicts. Funding Supported by National Institute of Diabetes and Digestive and Kidney Diseases grant U01DK073983. © 2015 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2015.01.010

The Changing Liver Transplant Waitlist: An Emerging Liver Purgatory? See “Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States,” by Wong RJ, Aguilar M, Cheung R, et al, on page 547.

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palpable change has occurred over the last decade in the type of patients listed for liver transplantation (LT): we are listing and transplanting sicker patients at higher Model for End-Stage Liver Disease (MELD) scores with more comorbid conditions.1,2 In this issue of Gastroenterology, Wong et al3 used the United Network for Organ Sharing/ Organ Procurement and Transplantation Network (UNOS/OPTN) registry data to describe these dynamic changes occurring on the liver transplant waiting list from 2004 to 2013. Their primary focus was on longitudinal trends in waitlist characteristics of the 4 most common

diagnoses: hepatitis C (HCV), alcoholic liver disease (ALD), HCV/ALD, and nonalcoholic steatohepatitis (NASH). A modified NASH category was created: patients with NASH were combined with cryptogenic cirrhosis patients with a body mass index (BMI) of >30 kg/m2 (although dry weight was not known and 80% of patients had ascites). Etiology specific annual trends in new registrants, 90-day and 1-year wait list survival, and probability of undergoing LT were calculated after adjusting for sex, age, race/ethnicity, presence of diabetes, MELD score, ascites, and hepatocellular carcinoma. Between 2004 and 2013, the percentage of wait list registrants for the top 4 diagnoses were HCV (35.2%), ALD (18.3%), NASH (15.8%) and HCV/ALD (9.7%). Waitlist patients with NASH were older, more often had diabetes mellitus (46.3%), had the highest median BMI (31.6 kg/m2), and the lowest glomerular filtration rate (55.2 mL/min), but not the highest MELD scores at listing. The increase in new waitlist registrants was highest for NASH (170%), although 493

Hunger games: is your stomach making you fat?

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