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Nutrition and Health 1–16 Neuroendocrine regulation of energy ª The Author(s) 2017 Reprints and permission: sagepub.co.uk/journalsPermissions.nav balance: implications on the development DOI: 10.1177/0260106017719369 and surgical treatment of obesity journals.sagepub.com/home/nah

Gisele Farias1,Ba´rbara Dal Molin Netto2, Solange Cravo Bettini3, Ana Raimunda Daˆmaso2 and Alexandre Coutinho Teixeira de Freitas1

Abstract Introduction: Obesity, a serious public health problem, occurs mainly when food consumption exceeds energy expenditure. Therefore, energy balance depends on the regulation of the hunger–satiety mechanism, which involves interconnection of the central nervous system and peripheral signals from the , and , generating responses in short-term food intake and long-term energy balance. Increased body fat alters the gut- and adipose-tissue-derived signaling, which promotes modifications in appetite-regulating , decreasing satiety and increasing hunger senses. With the failure of conventional weight loss interventions (dietary treatment, exercise, drugs and lifestyle modifications), bariatric surgeries are well-accepted tools for the treatment of severe obesity, with long-term and sustained weight loss. Bariatric surgeries may cause weight loss due to restriction/malabsorption of nutrients from the anatomical alteration of the gastrointestinal tract that decreases energy intake, but also by other physiological factors associated with better results of the surgical procedure. Objective: This review discusses the neuroendocrine regulation of energy balance, with description of the predominant hormones and involved in the control of energy balance in obesity and all currently available bariatric surgeries. Conclusions: According to the findings of our review, bariatric surgeries promote effective and sustained weight loss not only by reducing calorie intake, but also by precipitating changes in appetite control, satiation and satiety, and physiological changes in gut-, neuro- and adipose- tissue-derived hormone signaling.

Keywords Appetite regulation, obesity, bariatric surgery, weight loss, energy balance

Introduction and are secreted by the adipose tissue, which are important in anorexigenic pathways; cholecysto- Obesity, currently considered one of the greatest public (CCK), like 1 (GLP-1), glucagon like health problems all over the world, is mainly due to dys- peptide 2 (GLP-2), peptide YY (PYY) and regulation of energy balance. In turn, energy balance is (OXM) are provided by the intestine and lead an individual to controlled by a complex process coordinated by a cross- end their meal by a feeling of satiety, and still and talk between the central and peripheral signals, including by the and , glucagon, and the central nervous system (CNS), adipose tissue, pancreas, polipeptide pancreatic (PP) by the pancreas. On the other gut peptides, and gastric peptides that regulate the food intake mechanism (appetite and hunger-satiety) and energy expenditure (Chakravartty et al., 2015). 1 According to an individual’s dietary intake and meta- Department of Surgery, Universidade Federal do Parana´,UFPR, Curitiba-Pr, Brazil bolic state, the adipose tissue and gastrointestinal tract 2 Universidade Federal de Sa˜o Paulo, UNIFESP-EPM, Sa˜o Paulo-SP, Brazil provide information to two neuronal groups in the arcute 3 Federal University of Parana´ (UFPR), Gastrointestinal Surgery Service of nucleus of the (ARC): the first, composed of Hospital de Clı´nicas, Curitiba-PR, Brazil Y (NPY) and agouti-related protein (AgRP) has orexigenic properties and the other group has an opposite Corresponding author: Gisele Farias, Surgical Clinic Post Graduate Program, Department of Surgery, function, that is, it inhibits the appetite, by the action of the pro- Hospital de Clı´nicas, Universidade Federal do Parana´, Rua General Carneiro, opiomelanocortin (POMC) and cocaine and amphetamine- 81 Centro, Curitiba/PR 80060-900, Brazil. regulated transcript (CART) . For instance, Email: [email protected] 2 Nutrition and Health XX(X) hand, note that ghrelin plays a key role in energy balance, surgery’, ‘gastric bypass’, ‘sleeve gastrectomy’, ‘biliopan- enhancing hunger and food intake (Bauer et al., 2016; creatic diversion’, ‘gastric band’; in conjunction with ‘appe- Camilleri, 2015; Larder and O’Rahilly, 2012; Moehlecke tite’, ‘satiety’; and together with: ‘alpha-melanocyte- et al., 2016; Ochner et al., 2011). stimulating hormone’, ‘agouti-related protein’, ‘amylin’, Research over the last several decades demonstrated that ‘AgRP’, ‘cocaine and amphetamine-regulated transcript’, in obesity, neural, gut- and adipose-tissue-derived hormone ‘CART’, ‘’, ‘CCK’, ‘gastrin’, ‘ghrelin’, signaling is altered. It promotes changes in appetite- ‘glucagon’, ‘glucagon-like peptide 1’, ‘GLP-1’, ‘glucagon- regulating hormones decreasing satiety and increasing hun- like peptide 2’, ‘GLP-2’, ‘insulin’, ‘leptin’, ‘ con- ger senses, such as leptin and insulin resistance, and also centrating hormone’, ‘MCH’, ‘’, ‘NPY’, causes a decrease in serum levels of gastrointestinal hor- ‘oxyntomodulin’, ‘’, ‘peptide YY’, mones: GLP-1, GLP-2, PYY and pancreatic polypeptide (PP) ‘PYY’, ‘’ and ‘POMC’. We selected 92 (Barazzonni et al., 2013; Buss et al., 2014; Gelisgen et al., articles published from January 2011 to February 2017, 2012; Gueugnon et al., 2012; Terra et al., 2013). Besides that, involving original prospective randomized clinical trials, as genetic polymorphisms associated with food intake control well as review articles in the English language. and energy expenditure, such as MC4R, POMC, LEP, LEPR, FTO and CPUs may also affect the response to dietary Mechanisms of appetite control and treatment and exercise (Joffe and Houghton, 2016). In addition, studies suggest that during weight loss, there energy balance may be alteration in the action of these hormones that could The regulation of metabolism is a result of the highly justify the difficulty of maintaining the weight lost and in complex balance between food consumption and energy some cases, induces weight regain (Fernandez et al., 2015; expenditure, primarily controlled by the CNS. The control Steinert et al., 2017). Some studies indicate an average of food intake depends on the regulation of appetite, which reduction of 3–6 kg body weight in individuals with obesity is also coordinated by the CNS. Despite this, the decision to after 12 months of lifestyle modification and dietary treat- eat or not to eat involves interconnection of the hypotha- ment, and up to 11% when associated with drugs, but with lamus and afferent signals from the adipose tissue, pan- poor long-term success and high prevalence of regaining creas, and gut; and efferent signals generating responses in almost all of their initial weight within 5 years (Attalah et al., short-term and long-term food intake (Bauer et al., 2016; 2014; Leblanc et al., 2011). Larder and O’Rahilly, 2012; Moehlecke et al., 2016; In this way, bariatric surgeries may cause massive Munzberg et al., 2015; Ochner et al., 2011). weight loss due to restriction/malabsorption of nutrients The hypothalamus acts as a protagonist on feeding and from the anatomical alteration of the GI tract, which would metabolism control. It comprises more than 40 distinct decrease energy intake. However, in addition to mechanical nuclei and areas, and each sub-region controls specific factors, there are other physiological factors, including facets of energy balance; the most important are the arcuate changes in some hormones, such as increase of adiponectin nucleus of the hypothalamus (ARC), the paraventricular levels, improvement of leptin and insulin sensitivity, nucleusofthe hypothalamus (PVH), theventromedialnucleus decrease in serum levels of ghrelin, and increase in serum of the hypothalamus (VMH), and the lateral hypothalamic levels of gut peptides, for example, CCK, GLP-1, and PYY, (LHA) areas (Ueno and Nakazato, 2016). which are associated with sustained weight loss and pre- The ARC, located outside the blood–brain barrier, is vention of weight regain (Abdeen and Le Roux, 2016; permeable to peripheral factors and receives afferent signals Chakravartty et al., 2015; Jonge et al., 2016; Michalakis and circulating hormones through the brainstem and nucleus and Le Roux, 2012; Munzberg et al., 2015). tractus solitarius. Therefore, it plays an important role in This review focused on recent literature regarding the controlling food intake and is considered the main regulatory neuroendocrine regulation of energy balance and provided system of energy balance (Posovszky and Wabitsch, 2015). a brief summary of the predominant hormones and peptides The cross-talk between peripheral signals and hypotha- involved in the control of energy balance before and after lamic and brainstem centers is regulated by two subpopulations all currently available bariatric surgeries, including Roux- of neurons in the system of ARC. POMC and en-Y gastric bypass (RYGB), laparoscopic adjustable cocaine and amphetamine-regulated transcript (CART) form a gastric banding (LAGB), sleeve gastrectomy (SG), and subgroup with catabolic function. On the other hand, agouti- biliopancreatic diversion with duodenal switch (BPD/DS). related protein (AgRP) and neuropeptide Y (NPY) form the subpopulation with anabolic activity. POMC releases alpha- melanocyte-stimulating hormone (a-MSH), which acts as an Evidence acquisitions of the -4 (MC4R). In turn, A narrative review of current literature was performed using MC4R suppresses appetite and enhances energy expenditure. online databases, such as Pubmed, Lilacs, Medline, and In contrast, NPY/AgRP neurons stimulate food consumption Science Direct. Original studies in humans, published within and reduce energy expenditure, acting as an antagonist at the the previous 6 years or less were identified by searching for MC4R (Lima-Ju´nior et al., 2015; Moehlecke et al., 2016; the MeSH terms in the title or abstract: ‘obesity’, ‘bariatric Posovszky and Wabitsch, 2015; Ueno and Nakazato, 2016). Farias et al. 3

In the PVH, there are neuronal inputs from the ARC responsible for the use of glucose as an energy source after and LHA and also anorexigenic neurons, such as meals and their serum levels are proportional to body fat corticotropin-releasing hormone (CRH), nesfatin, oxy- weight (especially visceral fat) and acts similarly to leptin tocin, and thyrotropin-releasing hormone (TRH) (Ueno (Meek et al., 2016; Ochner et al., 2011). Pancreatic poly- and Nakazato, 2016). peptide (PP) is a 36-amino-acid respon- Since 1940, VMH has been known as the ‘satiety center’ sible for the control of exocrine and endocrine pancreatic and expresses hormone receptors for leptin and MC4R with enzymes (Camilleri, 2015; Lean and Malkova, 2016). anorexigenic activities. In contrast, the LHA has been The presence of food stimulates the stomach to produce classically referred to as the ‘feeding center’ of the brain. hormones, such as gastrin, that reduce appetite, increase The LHA is influenced by vagal signals, memory and the acid secretion, and stimulate gastric motility and emptying. reward system. Neurons in the LHA express two neuro- In contrast, ghrelin, a 28-amino-acid peptide secreted when peptides that stimulate appetite: melatonin-concentrating the stomach is empty, is the only gastric hormone known to hormone (MCH) and (Brown et al., 2015; Moeh- control the connection between the stomach and CNS by lecke et al., 2016; Ueno and Nakazato, 2016). sending positive feedback to NPY/AgRP neurons. Addi- The adipose tissue is considered a long-term reservatory tionally, ghrelin is responsible for stimulating hunger and of energy, since it is the biggest energy storage in the body food intake, and also influences gastric acid secretion and and transmits information about the amount of body fat. gastric motility (Churm et al., 2017; Steinert et al., 2017). There are two hormones produced in the white adipose Ghrelin circulates in active form, known as acyl-ghrelin, tissue that appear to play an important role in the mod- which represents less than 10% of total ghrelin and is ulation of energy balance: adiponectin and leptin (Moeh- responsible for stimulating appetite and reducing energy lecke et al., 2016). expenditure. Desacyl-ghrelin, the inactive form, acts in Adiponectin acts in the , muscle, and in the CNS. It glucose metabolism, while ghrelin and leptin are hormones increases insulin sensitivity and reduces hepatic glucose that exert the greatest influence on energy balance, production. It also acts in the modulation of lipid metabo- although they also have antagonistic functions (Churm lism, stimulates fatty acid oxidation, and has an important et al., 2017; Simpson et al., 2012; Steinert et al., 2017). anti-inflammatory function, since it suppresses pro- inflammatory and increases other anti- inflammatory markers. A study on adults showed that Gut–brain axis high visceral abdominal fat and low adiponectin levels The gut–brain axis is a communication system of the associated with waist circumference, blood pressure, glu- enteric nervous system and the CNS through efferent cose and lipid profile were independent predictors for and afferent neurotransmitters (Bauer et al., 2016; Chen metabolic syndrome (Cho et al., 2017). Another investi- et al., 2016). gation with animal models found that adiponectin reduces The size of a meal, the caloric content, and the quality insulin resistance and enhances leptin sensitivity through of food stimulate chemo- and mechano-receptors that the suppression of NPY/AgRP neurons, and consequently, inform about the amount of nutrients stored in the gas- exerts influence in energy balance control (Sun et al., trointestinal tract. It is done through the secretion of gut 2016). peptides and neuronal signals that act directly within Leptin is an anorexigenic hormone and circulating leptin different brain areas (Bauer et al., 2016; Moehlecke et al., levels are highly associated with body mass index. Leptin 2016; Posovszky and Wabitsch, 2015). accesses its targets in the hypothalamus and other regions Macronutrients, especially protein and fat, stimulate the of the brain because it can penetrate the blood–brain bar- to produce CCK, which sends satiety signals rier. It binds to receptors in the ARC and reduces food via the gut–brain-axis to the CNS. The same happens in the intake and increases energy expenditure by stimulating the lower intestine in response to the presence of nutrients and expression of POMC/CART and by inhibiting the expres- as a reflex originating from the upper portion of the gut. sion of NPY/AgRP. However, increased body fat results in Satiety hormones responsible for termination of feeding are increased leptin, but the response to that hormone is produced, such as glucose-dependent insulinotropic poly- eliminated, characterized by leptin resistance, and does not peptide (GIP), GLP-1, GLP-2, PYY, and oxintomodulin prevent the development of obesity (Michalakis and Le (OXM)5. GLP-1, a 30-amino-acid peptide hormone, is an Roux, 2012; Moehlecke et al., 2016) transcription product derived from the Some studies have demonstrated that high protein- , and its biologically active forms are GLP-1 (7-37) containing meals stimulate the pancreas to release satiety- and GLP-1 (7-36), and they control glycemia and satiety inducing hormones, such as amylin, pancreatic polypeptide (Mishra et al., 2016; Ochner et al., 2011). Another product (PP), insulin and glucagon (Meek et al., 2016; Riediger, from the proglucagon cleavage is GLP-2, which is a 33- 2012). For example, glucagon is a 29-amino-acid peptide amino-acid that exerts influence hormone that favors the increase of circulating levels of on energy balance, such as increase on the permeability of glucose and stimulates glycogenolysis (Lean and Malkova, gut mucosa, and consequently, enhances nutrient absorp- 2016). Insulin is a 51-amino-acid peptide hormone tion, besides improving insulin sensitivity, control of bone 4 Nutrition and Health XX(X) resorption, and regulation of food intake (Baldassano et al., however, also due to a physiological adaptation to the long- 2016; Cazzo et al., 2016, 2017). term state of positive energy balance, higher leptin levels PYY is a 36-amino-acid peptide hormone that belongs may downregulate ghrelin levels (Fernandez et al., 2015; to the family of NPY and PP. It circulates in two forms: Moehlecke et al., 2016; Reinehr and Roth, 2015; Simpson PYY 1-36 and PYY 3-36, the latter being the predominant et al., 2012; Steinert et al., 2017). form. Secretion begins 15 minutes after food intake, Moreover, genetic polymorphisms can modify energy peaking between 60 and 90 minutes. Its half-life is 7–10 balance and negatively influence the response to lifestyle minutes but its effects can last for up to 6 hours. The interventions for weight loss. It occurs in associated secretion is proportional to the caloric content of the meal with food intake control, such as MC4R, POMC, LEP, and does not suffer the influence of gastric distension. PYY LEPR, and FTO; energy expenditure, such as ADBRs and participates in the regulation of insulin secretion and gly- CPUs; and adipocytokinesynthesis, such as ADIPOQ and cemic control; it inhibits gastric, pancreatic, and intestinal IL6 (Joffe and Houghton, 2016). secretions and delays gastrointestinal transit time (Micha- Figure 2 illustrates the effects of obesity on the main lakis and Le Roux, 2012; Mishra et al., 2016; Moehlecke hormones and associated with neuroendo- et al., 2016; Ochner et al., 2011). Table 1 shows a brief crine control of energy balance. summary of the main hormones and neuropeptides asso- ciated with the neuroendocrine control of energy balance. Mechanisms of action and resetting energy The hunger–satiety mechanism is illustrated in Figure 1. balance following bariatric surgery Bariatric surgeries are well-accepted tools for the treatment The ‘obese brain’ of individuals with obesity, especially in comparison with It is known that the increase in body fat is a consequence of conventional weight-loss interventions, such as nutritional high dietary energy intake and low energy expenditure, counseling, exercise and pharmacological treatments. which results in a positive energy balance. It is not known Surgery is beneficial in expressive weight loss (20–40% what causes increased appetite and why some people have of initial weight) and long-term weight maintenance; also resistance to weight loss or difficulty in maintaining weight in the improvement or control of associated comorbid- loss (Joffe and Houghton, 2016). ities, hormonal and inflammatory parameters, and quality Moreover, strong evidence suggests that energy home- of life (Farias et al., 2016; Mechanick et al., 2008). ostasis is influenced by many other factors, such as environ- According to the consensus of the National Institute of mental, behavioral, hormonal, changes in food processing, Health (NIH) of 1991, reformatted by the guidelines for nutrient intake, macronutrient composition, metabolic func- clinical pre-operative, trans-operative, and postoperative tions, hedonic/reward brain systems, genes, and the interac- nutritional and metabolic practice, surgical treatment of tions of these factors (Amin and Mercer, 2016; Joffe and patients with obesity is indicated for those with BMI Houghton, 2016). 40 kg/m2 or 35 kg/m2 with associated comorbidities, for at Recent studies identified that there are hormonal differ- least 2 years and with previous unsuccessful conventional ences in individuals with obesity compared with normal- treatments or weight recovery programs (Mechanick weight individuals. Increased body fat enhances secretion et al., 2008, 2013). of leptin and insulin, making individuals with obesity resis- Surgical techniques are divided into three types according tant to the action of these hormones. They affect negative to operating mechanisms: restrictive, disabsorptive and both. feedback to the NPY/AgRP and cause increased hunger. Pure disabsorptive procedures are no longer used and con- They also modify energy balance through changes in sig- sidered only for historical purposes. Restrictive techniques naling involved in food choices, appetite, satiety and energy promote weight-loss controlling or reducing early satiety expenditure. As a result, leptin determines a new set point on through gastric-volume reduction. Sleeve gastrectomy (SG) energy balance that makes it difficult to lose weight due to the removes the greater gastric curvature, and adjustable gastric maintenance of the ‘obese brain’ (Chen et al., 2012; Gelisgen banding (AGB) is an inflatable silicone ring that encircles et al., 2012; Gueugnon et al., 2012; Haluzı´kova´etal.,2013; the upper portion of the stomach. Illa´n-Gomez et al., 2012; Lima-Ju´nior et al., 2015; Lips et al., Roux-en-Y gastric bypass (RYGB) and biliopancreatic 2013; Moehlecke et al., 2016; Munzberg et al., 2015; Palikhe diversion (BPD) are a combination of restrictive and et al., 2014; Sysko et al., 2013; Terra et al., 2013). malabsorptive procedures. In RYGB, the restrictive com- Additionally, it has been suggested by researchers that ponent is more important. It is obtained through the divi- in individuals with obesity, the levels of ghrelin and satiety sion of the stomach into a small, 30 mL gastric pouch, hormones, such as GLP-1, GLP-2, PP, PYY, are lower significantly decreasing food intake. The malabsorptive compared with lean individuals (Barazzonni et al., 2013; component is less important and is obtained through a Buss et al., 2014; Gelisgen et al., 2012; Gueugnon et al., Roux-en-Y reconstruction that creates a 50–100 cm bilio- 2012; Haluzı´kova´ et al., 2013; Sysko et al., 2013; Terra pancreatic limb excluding food transit from the remaining et al., 2013). One possible explanation for lower levels of segment of the stomach, the and the proximal ghrelin is in regard to leptin and insulin resistance; (Amin and Mercer, 2016; Dixon et al., 2015). Table 1. Summary of the main hormones and neuropeptides associated with neuroendocrine control of energy balance.

Production Stimulus for Production Effects Hormone site secretion inhibitors on appetite Likely actions References

Central nervous system

AgRP ARC Fasting a-MSH " Opposes the action of MC4R Moehlecke et al., 2016 Ghrelin Leptin PYY a-MSH ARC Leptin AgRP # Favors action of MC4R; Moehlecke et al., 2016 Energy homeostasis CART ARC Food intake Fasting ##Food intake GLP-1 Ghrelin Leptin PYY MCH LHA Food MSH-producing " Regulation of feeding behaviour and energy Moehlecke et al., 2016 palatability neurons homeostasis AgRP/NPY NPY ARC Fasting CCK ""Food intake and lipogenesis; Moehlecke et al., 2016 Ghrelin Leptin # Energy expenditure Insulin PYY POMC ARC Food intake Fasting # Precursor of products that act in MC3R and MC4R, Leptin Ghrelin for example, a-MSH PYY Adipose tissue

Adiponectin White adipose tissue Peroxisome Catecholamines, " Energy homeostasis; Moehlecke et al., 2016 proliferator- TNF-a " Insulin sensitivity and fatty acid oxidation; activated # Hepatic glucose production and inflammatory receptor-g process (PPAR-g) Leptin White adipose tissue Body fat Fasting # Reports amount of body fat " lipolysis; activation of Buchwald, 2014; Farr et al., 2016; Lean and Insulin GLP-1 POMC/CART, CRH and the satiety effects of Malkova, 2016; Moehlecke et al., 2016; Ochner CCK#: lipogenesis and release of NPY/AgRP et al., 2011 Pancreas

Amylin Pancreatic b-cells Hypoglycemia # Delayed gastric emptying; Reinehr and Roth, 2015; Riediger, 2012 Protein Participates in the glucose homeostasis Glucagon Pancreatic a-cells Fast GLP-1 " Blood sugar levels; glycogenolysis and Reinehr and Roth, 2015 gluconeogenesis.

(continued) 5 6 Table 1. (continued)

Production Stimulus for Production Effects Hormone site secretion inhibitors on appetite Likely actions References

Insulin Pancreatic b-cells Food intake Fasting # Optimizes glucose use for energy after ingestion of Camilleri, 2015; Moehlecke et al., 2016; Reinehr Body adiposity food; and Roth, 2015 Hyperglycemia " Glycogen synthesis; Production of catabolic neuropeptides PP Pancreatic PP cells Exercise ##Gastric emptying rate; Lean and Malkova, 2016; Mishra et al., 2016; Insulin " Exocrine pancreatic secretion and gallbladder Reinehr and Roth, 2015 Gastric motility distension CCK Gastrin Food intake Gut peptides

CCK I-cells of proximal Lipids Fasting #"Gallbladder contraction; pancreatic; satiety; Bauer et al., 2016; Lean and Malkova, 2016; Meek small intestine Protein enzyme secretion; et al., 2016; Mishra et al., 2016; Insulin Delays gastric emptying; Moehlecke et al., 2016; Ochner et al., 2011; Leptin # NPY and provides feedback to reduce food intake Reinehr and Roth, 2015 and meal duration GIP K-cells of the GLP-1 Fasting #"Insulin secretion Buchwald, 2014 duodenum GLP-1 L-cells in distal small Carbohydrate Fasting # Activates ileal brake and reduces GI motility; Bauer et al., 2016; Buchwald, 2014; Lean and intestine and Proteins " Lipolysis; adiponectin expression; energy Malkova, 2016; Meek et al., 2016; Melvin et al., larger intestine Lipids expenditure; insulin secretion; GIP secretion 2016; Mishra et al., 2016; Moehlecke et al., Exercise # Glucagon secretion; glucagon release; gastric acid 2016; Ochner et al., 2011; Reinehr and Roth, Insulin secretion; gastric emptying 2015 Leptin GLP-2 L-cells in distal small Proteins Fasting #"Gut cell proliferation; capacity of absorption of Baldassano et al., 2016; intestine and Lipids nutrients; insulin sensitivity; satiety Cazzo et al., 2016, 2017; larger intestine # Enterocyte and crypt cell apoptosis; acid secretion Meek et al., 2016; Reinehr and Roth, 2015 and gastric emptying; gastrointestinal motility; bone resorption; food intake OXM L-cells in distal small Lipids Fasting #"Satiety; energy expenditure; insulin secretion; Meek et al., 2016; Reinehr and Roth, 2015 intestine and large Agonist of and GLP-1 receptors intestine

(continued) Table 1. (continued)

Production Stimulus for Production Effects Hormone site secretion inhibitors on appetite Likely actions References

PYY L-cells in distal small Food intake: Fasting #"Satiety; in water and electrolyte absorption; Bauer et al., 2016; Lean and Malkova, 2016; Meek intestine and proportional Activates ileal brake; et al., 2016; Melvin et al., 2016; Michalakis and larger intestine to the size and # Gastric emptying, gastric acid and pancreatic Le Roux, 2012; Mishra et al., 2016; Ochner type of exocrine secretions et al., 2011; Reinehr and Roth, 2015; macronutrient Sweeney and Morton, 2014; Ueno and Nakazato, (mainly lipids) 2016 Low-carb diet Exercise Low duodenal pH Gastric peptides

Gastrin G-cells in the gastric Food in the Somastatin #"Production of hydrochloric acid, pepsinogen, Meek et al., 2016; Reinehr and Roth, 2015 antrum and stomach Secretin intrinsic factor, pancreatic secretions and bile duodenum Gastric GIP " Satiety distension Alcohol Low pH Caffeine High-fat diet Protein Ghrelin X/A-cells of the Fasting After feeding ""NPY/AgRP neurons in the ARC; gut motility and the Buchwald, 2014; Meek et al., 2016; Melvin et al., gastric fundus Hunger During rate of gastric emptying; gastrointestinal motility 2016; Mishra et al., 2016; Moehlecke et al., Prolonged hyperglycemia # Insulin secretion 2016; Ochner et al., 2011; Reinehr and Roth, state of Obesity Modulates pancreatic function and is involved in 2015 negative Carboydrates energy balance regulation and glucose homeostasis energy balance and lipids release

AgRP: agouti-related protein; ARC: arcute nucleus of the hypothalamus; a-MSH: alpha-melanocyte-stimulating hormone; MC4R: melanocortin-4 receptor; CART: cocaine and amphetamine-regulated transcript; GIP: glucose- dependent insulinotropic polypeptide; GLP-1: glucagon-like peptide 1; CCK: cholecystokinin; PYY: peptide YY; POMC: pro-opiomelanocortin; GI: gastrointestinal; MCH: melatonin-concentrating hormone; MC3R: melanocortin-3 receptor; LHA: lateral hypothalamic; TNF: ; NPY: neuropeptide Y; CRH: corticotropin-releasing hormone; PP: polipeptide pancreatic; GLP-2: glucagon-like peptide 2; OXM: oxyntomodulin; I-Cells, K-Cells; L-Cells: Cells type in the gut; X/A Cells; G-Cells: Cells type in the stomach. 7 8 Nutrition and Health XX(X)

Figure 1. Hunger–satiety mechanism in 10 steps. Figure 2. The ‘obese brain’. Increased body fat enhances the secretion of leptin and insulin, 1. In a fasted state (hunger or negative energy balance), and consequently, favors resistance to the action of these hor- secretion of orexigenic hormone ghrelin is stimulated in the mones. Additionally, in individuals with obesity, the levels of stomach (1–2 h before meal). ghrelin and satiety hormones, such as GLP-1, GLP-2, and PYY, are 2. Ghrelin acts on the arcuate nucleus of the hypothalamus and lower compared with lean individuals. They affect the signaling vagus nucleus in the brainstem to stimulate hunger: AgRP/ network to the brain, which contributes to increased hunger and NPY. reduces satiety. 3. AgRP inhibits the action of MC4R, which enhances the AgRP: agouti-related protein; a-MSH: alpha-melanocyte- expression of other orexigenic neurotransmitters, such as stimulating hormone; MC4R: melanocortin-4 receptor; CART: MCH and orexins A and B. cocaine and amphetamine-regulated transcript; POMC: pro- 4. After food consumption, plasma levels of the ghrelin fall opiomelanocortin; MCH: melatonin-concentrating hormone; shortly. NPY: neuropeptide Y; GLP-1: glucagon-like peptide 1; GLP-2: 5. Immediately after meal, with the distension of the stomach or in glucagon-like peptide 2; PYY: peptide YY. response to intraluminal food content (mainly protein or fat) in the small intestine and beginning of food, there is stimulation of the vagus and spinal nerves to release CCK, GLP- gastrectomy identical to SG. In this procedure, the 1, OXM, and PYY. malabsorptive component is more important and is also 6. CCK, GLP-1, GLP-2, OXM, and PYY act on the ARC, inhi- obtained through a Roux-en-Y reconstruction, along biting NPY/AgRP and determining the end of the meal. with a very long biliopancreatic limb, an alimentary 7. Meanwhile, in accordance with the increase of body fat and positive energy balance situations, other peripheral regula- limb anastomosed to the 400 mL remanescent stomach, tors, such as leptin, amylin, insulin, and pancreatic peptide andaveryshortcommonlimbof50cminlength.This (PP) are released. common limb is the only portion of the small intestine 8. The adipose-tissue-derived and the pancreas-derived hor- where food is mixed with bile and pancreatic enzymes mones stimulate the transcription of anorexigenic POMC/ (Sweeney and Morton, 2014). CART peptides. Maintaining body-weight loss after bariatric surgery is 9. POMC neurons synthesize and release a-MSH. not only limited to mechanical restriction or malabsorp- 10. a-MSH acts on MC4R and sends negative feedback to tion. Modifications in gut–brain–neuroendocrine signal- orexigenic peptides NPY and AGRP, leading to reduced ing also occur that cause changes in appetite, energy food intake, signaling the end of the meal. expenditure, food-choice decision and resetting energy AgRP: agouti-related protein; a-MSH: alpha-melanocyte- balance (Dixon et al., 2015; Lean and Malkova, 2016; stimulating hormone; MC4R: melanocortin-4 receptor; CART: Michalakis and Le Roux, 2012; Munzberg et al., 2015; cocaine and amphetamine-regulated transcript; GLP-1: Sweeney and Morton, 2014). glucagon-like peptide 1; CCK: cholecystokinin; PYY: peptide Reduction in food intake is primarily responsible for YY; POMC: pro-opiomelanocortin; NPY: neuropeptide Y; PP: early weight loss after bariatric surgery. Weight loss during polipeptide pancreatic; GLP-2: glucagon-like peptide 2; OXM: low calorie diet causes changes in hormones involved in the oxyntomodulin. regulation of hunger–satiety in an attempt to maintain body energy storage and prevent starvation. In the first 2 weeks In BPD, the restrictive component is less important after RYGB, a decrease in serum levels of ghrelin is and is obtained through a distal gastrectomy (removal of observed, as a rise in satiety hormones is also induced the distal two-thirds of the stomach) or a vertical (Evans et al., 2012; Jacobsen et al., 2012). Table 2. Summary of gastrointestinal peptide changes after bariatric operations: studies from January 2011 to February 2017.

AGB/VGB RYGB SG BPD

Hormone T1 T2 T3 T4 T5 T1 T2 T3 T4 T5 T1 T2 T3 T4 T5 T1 T2 T3 T4 T5

Central nervous system AgRPa ↔1 (fasting) a-MSHa ↔1 (fasting) CART MCHa ↔1 (fasting) NPYa ↔1 (fasting) POMC ↔1 Adipose tissue Adiponectin ↔2 "2,3 "4 ↔2,5 "6 "2,4,7–11 "11,12 "13 "14 "2,9,10 "15 "13 (fasting)b ↔2

Leptin "16 #4 ↔18 #2,5,19 #1,20 #2,4,10,11,20,21 #11 #13 #14,20 #2,10,20,21 #15 #13 #16 (fasting)b #2,3,17

Leptin #18 #21,22 #21 (postprandial)b Pancreas Amylin ↔18 #23 ↔23 #15 (fasting)a Glucagon ↔24 ↔25 ↔22,23 ↔23 #27 (fasting)a #26 #27

Insulin ↔24 #40 #3,16 #4 #18 #5,26 #4,7,8,10, 22,28,41 ↔32 #13,29 #31 #10,27,30 ↔15 #13 #31 #16,27 (fasting)b ↔25

(continued) 9 10

Table 2. (continued)

AGB/VGB RYGB SG BPD

Hormone T1 T2 T3 T4 T5 T1 T2 T3 T4 T5 T1 T2 T3 T4 T5 T1 T2 T3 T4 T5

PP ↔33 #18 "23 "23 (fasting)b ↔21,22 ↔21

Gut peptides CCK ↔18 (fasting)a CCK "18 "34 "34 (postprandial)b GIP (fasting)a ↔24 ↔18 ↔5,35 #22 ↔35 ↔15 ↔28 GIP ↔24 ↔26,35 "22 "35 ↔31 #31 (postprandial)a #28 GLP-1 total ↔24 "36 ↔5,25,26, 35,37 ↔20 ↔20,22,28 "32 ↔29,35,37 ↔20 ↔20,23,30, ↔15 ↔27,36 (fasting)a ↔18 #23 #27

GLP-1 ↔24 "18,36 "25,35,37 "20 "20,21,22, "42 "35,37 "20,31 "30,34 "31 "27,36 (postprandial)b 28,34,38 ↔23,27 ↔23

GLP-2 total ↔18 ↔35 ↔35 ↔36 (fasting)a GLP-2 "18 "35 "38 "35 "36 (postprandial)a OXMa "22

(continued) Table 2. (continued)

AGB/VGB RYGB SG BPD

Hormone T1 T2 T3 T4 T5 T1 T2 T3 T4 T5 T1 T2 T3 T4 T5 T1 T2 T3 T4 T5

PYY3-36 #33 "36 ↔37 "1,20 "23,20 "32 ↔29,37 ↔20 "20,23 #15 "27 (fasting)a #18 ↔27,30

PYY3-36 "18,36 "37 "20 "20,23,34 "37 "20 "20,23,30 "27 (postprandial)b ↔21 ↔21,27,34

Gastric peptides Gastrin ↔18 (fasting)a Gastrin #18 (postprandial)a Ghrelin active "40 #18 ↔5,37 #37 #15,39 (fasting)a Ghrelin active #18 ↔37 "41 #39 #37 #39 (postprandial)a Ghrelin total ↔17 #18 ↔5 "20 ↔41 #32 #29 #14,20 #9,20, 21,23,27 ↔27 (fasting)b #23 "20 Ghrelin total #18 "41 ↔21,34 ↔27 (postprandial)b ↔34 #23,27 #21,23

AGB: adjustable gastric banding; VGB: Vertical Gastric Banding; RYGB: Roux-en-Y gastric bypass; SG: sleeve gastrectomy; BPD: biliopancreatic diversion; AgRP: agouti-related protein; a-MSH: alpha-melanocyte-stimulating hormone; CART: cocaine and amphetamine-regulated transcript; MCH: melatonin-concentrating hormone; NPY: neuropeptide Y; POMC: pro-opiomelanocortin; PP: polipeptide pancreatic; CCK: cholecystokinin; GIP: glucose-dependent insulinotropic polypeptide; GLP-1: glucagon-like peptide 1; GLP-2: glucagon-like peptide 2; OXM: oxyntomodulin; PYY: peptide YY; ": postsurgical increase; #: postsurgical decrease; ↔: no significant postsurgical change; T1: until 30-day follow up; T2: 3-month follow up T3: 6-month follow up; T4: 12-month follow up; T5: 24-month follow up. aObservational clinical studies only; brandomized clinical trials and observational clinical studies. 1Netto et al. (2016); 2Tam et al. (2016); 3Urbanavicius et al. (2013); 4Bradley et al. (2012); 5Hansen et al. (2011); 6Netto et al. (2015); 7Chen et al. (2012); 8Illa´n-Gomez et al. (2012); 9Carrasco et al. (2014); 10 Woelnerhanssen et al. (2011); 11Biagioni et al. (2017); 12 Hoffstead et al. (2017); 13Garrido-Sanche´z et al. (2012); 14 Palikhe et al. (2014); 15 Haluzı´kova´ et al. (2013); 16Alam et al. (2012); 17 Krieger et al. (2012); 18Jacobsen et al. (2012); 19Lips et al. (2013); 20Alamuddin et al. (2017); 21Ramo´n et al. (2012); 22Falke´n et al. (2011); 23Nannipieri et al. (2013); 24Usinger et al. (2011); 25 Umeda et al. (2011); 26Dirksen et al. (2013); 27Tsoli et al. (2013); 28Jorgensen et al. (2012); 29Rigamonti et al. (2017); 30Papamargaritis et al. (2013); 31 Mallipedhi et al. (2014); 32Basso et al. (2011); 33Dixon et al. (2011); 34 Peterli et al. (2012); 35Romero et al. (2012); 36 Evans et al. (2012); 37Yousseif et al. (2014); 38 Cazzo et al. (2017); 39Malin et al. (2014); 40 Gelisgen et al. (2012); 41Barazzonni et al. (2013); 42 Dar et al. (2012). 11 12 Nutrition and Health XX(X)

Figure 3. Energy balance changes in response to different surgeries. One of the first effects after bariatric surgery is the reduction of hunger, which can be partly explained by a decrease in serum levels of ghrelin. Majority of studies show that changes in ghrelin levels after RYGB and SG occur within the first weeks following surgery, but in the long term, it is maintained only in the SG technique. Studies that compared gut peptides (GLP-1, GLP-2, and PYY) between pre- and postoperative periods observed higher concentrations of these hormones after surgical procedure, mainly after RYGB and BPD. Adapted from Netto et al. (2016) Credits: Fabı´ola Grigoletto Lupion GLP-1, glucagon-like peptide 1; GLP-2, glucagon-like peptide 2; PYY, peptide YY; RYGB, Roux-en-Y gastric bypass; SG, sleeve gas- trectomy; BPD, biliopancreatic diversion.

Additionally, in response to food intake restriction or et al., 2015; Munzberg et al., 2015; Ochner et al., 2011; reduced body fat mass, there are changes in signaling fat- Stefater et al., 2012). derived hormones, such as increase in adiponectin levels, One of the first effects after bariatric surgery is the leptin and insulin sensitivity, and consequently, decrease reduction of hunger, which can be partly explained by a in leptin and insulin levels. Note that these changes are decrease in serum levels of ghrelin, but the exact mechanism observed during the early postoperative period, and are behind it remains unclear. The majority of studies show that not always associated with a significant and long-term changes in ghrelin levels after RYGB and SG occur within weight loss. This may be explained by the theory that the first weeks following surgery (Basso et al., 2011; leptin resistance can be caused by an unknown factor Jacobsen et al., 2012). produced in the duodenum and jejunum, and the bypass Studies that compared gut peptides (CCK, GLP-1, GLP- created by RYGB and BDP excludes this factor and 2 and PYY) between pre- and postoperative periods restores normal levels of leptin, favoring weight loss observed higher concentrations of these hormones after (Camilleri, 2015; Dixon et al., 2015; Lima-Ju´nior et al., surgical procedure, mainly after RYGB and BPD (Table 2). 2015). Bariatric surgeries, with exclusion of the proximal part This activates the NPY system and decreases energy of the small intestine, particularly the duodenum, such as expenditure, facilitating weight regain. This is a long- RYGB and BPD, inhibit the secretion of a putative signal lasting (even after 1 year) counter-regulatory effect of with anti-incretin effect, which improves glucose tolerance. appetite-regulating hormones that contribute to increased These hormones delay gut transit time (‘ileal brake’ the- food intake and weight regain (Moehlecke et al., 2016; ory), reducing hunger and increasing satiety. This Posovszky and Wabitsch, 2015). mechanism is known as the ‘foregut hypothesis’ or prox- Changes in the GI tract anatomy following surgical imal hypothesis, proposed by Rubino et al. (2006). procedures may promote physiological changes on gastric Similar results are observed after SG and can be justified emptying and delivery of nutrients to the enteroendocrine by the ‘hindgut hypothesis’ or distal hypothesis, created by cells. This exerts influence on afferent vagal gut–brain Cummings et al. (2007) and Patrita et al. (2007) as an nerve function that plays a role in neuroendocrine status alternative to the ‘foregut hypothesis’. The idea is that following bariatric surgery, and which may modify energy quick transit of nutrients to the distal intestine stimulates balance and metabolism (Baldassano et al., 2016; Dixon secretion of GLP-1, PYY, and OXM from the Farias et al. 13 enteroendocrine L-cells, increasing insulin secretion and Declaration of conflicting interests improving glucose homeostasis, which, consequently, The author(s) declared no potential conflicts of interest enhances satiety, reduces food intake and contributes to with respect to the research, authorship, and/or publication weight loss (Chakravartty et al., 2015; Sweeney and Mor- of this article. ton, 2014). Finally, there are some limitations in the literature Funding included in this study. For instance, the studies’ designs are The author(s) received no financial support for the different, only a few included a control group (Basso et al., research, authorship, and/or publication of this article. 2011; Chen et al., 2012; Dar et al., 2012; Evans et al., 2012; Falke´n et al., 2011; Gelisgen et al., 2012; Haluzı´kova´ et al., References 2013; Jorgensen et al., 2012; Lips et al., 2013; Palikhe Abdeen G and Le Roux CW (2016) Mechanism underlying the et al., 2014; Malin et al., 2014; Romero et al., 2016; weight loss and complications of Roux-en-Y gastric bypass. Urbanavicius et al., 2013; Yousseif et al., 2014). Review. Obesity Surgery 26(2): 410–421. In addition, most of the studies have a small sample size Alam I, Stephens JW, Fielding A, et al. (2012) Temporal changes (<30 participants) (Alam et al., 2012; Barazzonni et al., in glucose and insulin homeostasis after biliopancreatic diver- 2013; Basso et al., 2011; Bradley et al., 2012; Carrasco sion and laparoscopic adjustable gastric banding. Surgery for et al., 2014; Cazzo et al., 2016; Chen et al., 2012; Dirksen et al., Obesity and Related Diseases 8(6): 752–763. 2013; Dixon et al., 2011; Evans et al., 2012; Jacobsen et al., Alamuddin N, Vetter ML, Ahima RS, et al. (2017) Changes in 2012; Papamargaritis et al., 2013; Peterli et al., 2012; Ramo´n fasting and prandial gut and adiposity hormones following et al., 2012; Rigamonti et al., 2017; Romero et al., 2012; vertical sleeve gastrectomy or Roux-en-Y gastric bypass: an 18-month prospective study. Obesity Surgery 27(6): Tsoli et al., 2013; Umeda et al., 2011; Usinger et al., 2011; 1563–1572. Woelnerhanssen et al., 2011; Yousseif et al., 2014), and of Amin T and Mercer JG (2016) Hunger and satiety mechanisms the 43 studies evaluated, only five (Biagioni et al., 2017; Dar and their potential exploitation in the regulation of food intake. et al., 2012; Haluzı´kova´ et al., 2013; Hoffstead et al., 2017; Current Obesity Reports 5(1): 106–112. Malin et al., 2014) included subjects that underwent bar- Attalah R, Filion KB, Wakil SM, et al. (2014) Long-term effects iatric surgery at least 24 months previously, which may of 4 popular diets on weight loss and cardiovascular risk impair understanding of the mechanism behind weight loss factors: a systematic review of randomized controlled trials. after bariatric surgeries. In addition, the studies have a small Circulation. Cardiovascular Quality and Outcomes 7(6): number because biochemical measurements for 815–827. and hormones are expensive. Baldassano S, Amato A and Mule` F (2016) Influence of glucagon- There are a few studies on CNS changes after bariatric like peptide 2 on energy homeostasis. Peptides 86: 1–5. Barazzonni R, Zanetti M, Nagliati C, et al. (2013) Gastric bypass surgery. In the last 5 years, some observational or rando- does not normalize obesity-related changes in ghrelin profile mized studies have described the characteristic of hormonal and leads to higher acylated ghrelin fraction. Obesity 21(4): changes after the interventions: AGB, BPD, RYGB, and 718–722. SG. A summary of these findings is presented in Table 2. Basso N, Capoccia D, Rizzello M, et al. (2011) First-phase insulin Figure 3 shows the main hormonal changes after bariatric secretion, insulin sensitivity, ghrelin, GLP-1, and PYY surgery in the two most-performed techniques in the world. changes 72 h after sleeve gastrectomy in obese diabetic patients: the gastric hypothesis. Surgical Endoscopy 25(11): 3540–3550. Bauer PV, Hamr SC and Duca FA (2016) Regulation of energy Summary and direction for balance by a gut–brain axis and involvement of the gut future research microbiota. Cellular and Molecular Life Sciences 73(4): 737–755. In summary, the regulation of body weight depends on the Biagioni MFG, Mendes AL, Nogueira CR, et al. (2017) Bariatric complex interplay between gut, brain and other organs Roux-en-Y gastric bypass surgery: adipocyte proteins involved involved in energy metabolism. The mechanisms that in increase bone remodeling in humans. Obesity Surgery.Epub promote effective and sustained weight loss after bariatric ahead of print 13 January 2017. DOI: 10.1007/s11695-017- surgeries can be explained not only by reducing calorie 2546-4. intake, but also by changes in appetite control, satiation Bradley D, Conte C, Mittendorfer B, et al. 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