Targeting Multiple Gut‐Brain Pathways in Obesity: Rationale for Combination Pharmacotherapy

Current and emerging medications for the management of obesity in adults.

Orlistat is the only weight loss drug currently licensed in the UK. Outside the UK, there are now four other agents approved for weight loss. Dr Kate Millar and Dr Ruth Poole here review the evidence regarding the comparative efficacy and adverse effects of the five different drug treatments. According to WHO data, the global prevalence of obesity has doubled between 1980 and 2014. By 2014, 39% of the world's adults (1.9 billion individuals) were overweight and 18% were obese (600 million individuals).1 As well as being a major risk factor for type 2 diabetes (T2DM), overweight and obesity contribute to morbidity and mortality from cardiovascular disease, osteoarthritis and some cancers such as endometrial, breast and colon. Excess weight now leads to more deaths than malnutrition worldwide.1 The reasons for this increase are complex. Easy access to energy rich foods and decreased activity have been recognised for many years2 but more recent evidence suggests that gut microbia, epigenetic mechanisms, increasing maternal age, greater fecundity among people with higher adiposity, and endocrine disrupting chemicals may all be having some effect.3 Lifestyle modifications are generally ineffective for weight loss in the long term due to the body's adaptations to lower energy expenditure in response to reduced calorific intake and the high levels of motivation needed to sustain significant changes. Even in clinical studies where patients are highly motivated, initial weight loss is followed by gradual weight regain.4 Equally, bariatric surgery is invasive and potentially dangerous. As more research has allowed a greater understanding of the pathways and signalling involved in regulating metabolism and appetite, this has fuelled interest into new potential therapeutic targets. The use of pharmacological agents for weight loss has historically been associated with significant side effect burden and safety concerns. Fenfluramine, a serotonin increasing anorectic, was withdrawn from the market in 1997 after being shown to cause potentially fatal pulmonary hypertension and cardiac valvulopathy. Rimonabant, a selective cannabinoid receptor blocker, was withdrawn in 2008 because of serious psychiatric side effects including risk of suicide. Sibutramine, a serotonin–norepinephrine reuptake inhibitor, was withdrawn in 2010 because of its association with increased cardiovascular events and strokes. Orlistat is the only weight loss drug currently licensed in the UK. It works by inhibiting pancreatic lipases and thereby decreasing dietary fat absorption and increasing faecal fat excretion. Weight loss in the first year of treatment is around 5–10 kg,5 and this has been shown to be maintained over four years with continued use.6 Orlistat reduces the risk of developing diabetes in obese patients with impaired glucose tolerance by around a third.6 In patients with diabetes, orlistat has been demonstrated to reduce HbA1c by 0.6% (7 mmol/mol) over 52 weeks.7 It has also been shown to improve blood pressure and serum lipids beyond expected levels from weight reduction alone.8, 9 Between 15–30% of patients experience gastrointestinal (GI) side effects associated with orlistat; generally these improve as patients learn to avoid high fat diets. Absorption rates of fat soluble vitamins A, D, E and K are lowered with orlistat therapy (vitamin D in particular) and supplements should be considered. Here we review four new weight loss drugs: lorcasarin (Belviq), high dose liraglutide (Saxenda), naltrexone/bupropion (Contrave or Mysimba) and phentermine/topiramate (Qsymia). We review their efficacy and their adverse effects. Saxenda is administered by subcutaneous injection while Belviq, Contrave and Qsymia are all oral tablets. Lorcaserin is a selective agonist of the serotonin 2C receptor which reduces food intake by increasing satiety. It was approved by the US Food and Drug Administration (FDA) in 2012 as an adjunct to lifestyle interventions for patients with BMI above 30 kg/m2 or above 27 kg/m2 with at least one medical comorbidity such as T2DM or obstructive sleep apnoea. It is not currently licensed in the UK. A multicentre placebo-controlled trial of lorcaserin found that at one year 47.5% of patients in the lorcaserin group had lost 5% or more of their body weight compared to 20.3% in the placebo group (p < 0.001) This corresponds to a 3–4 kg difference in weight loss between the two groups. They also showed that in year two weight loss was more likely to be maintained if they continued on lorcaserin rather than switching to placebo.10 A trial looking at the efficacy of lorcaserin for weight loss in patients with T2DM randomised patients to lorcaserin 10 mg once a day, 10 mg twice a day or placebo. Patients were being treated with metformin, a sulphonylurea or both. At one year, there was no difference in weight loss between the two active treatment groups, but both had lost three times more weight than the placebo group (6% vs 2%) and significantly more patients lost more than 5% of their body weight on lorcaserin (44.7% once-daily dose and 37.5% twice-daily dose) compared to placebo (16.1%). There was also a significant improvement in glycaemic control with HbA1c decreasing 0.9% to 1.0% (10–11 mmol/mol) in the lorcaserin groups and 0.4% (4 mmol/mol) in the placebo group.11 Adverse effects of lorcaserin are generally mild with headache, back pain and naso-pharyngitis occurring with greater frequency than compared to the placebo group. Neuropsychiatric effects were not significantly increased in any of the trials. With regard to concerns of serotonin-associated valvulopathy, pooled analysis of the phase 3 trials showed that the rates of FDA defined valvulopathy were 2.3% and 2.2% for patients taking lorcaserin or placebo respectively.12 Liraglutide is an analogue of the incretin hormone glucagon-like peptide 1 (GLP-1) and has dual therapeutic benefits in terms of glycaemic control and weight loss due to enhanced postprandial insulin secretion, delayed gastric emptying and decreased food intake. Liraglutide is established in Europe and America as a treatment option for patients with T2DM with BMI above 30 kg/m2 or above 27 kg/m2 with at least one weight-related comorbidity at doses of 0.6 mg to 1.8 mg daily, and is linked to a significant reduction in weight (2–3 kg) when compared to placebo or glimepiride.13 In the UK, liraglutide can only be prescribed for patients with a BMI above 35 kg/m2 unless there are comorbidities, and the maximum dose is 1.2 mg daily.14 High-dose liraglutide (3 mg) has been licensed as a treatment for weight loss in people without diabetes in the US since September 2014 under the trade name Saxenda, but is not yet licensed for this indication in the UK. There is evidence that liraglutide, at the doses licensed for patients with diabetes, is being used in the UK for obese patients without diabetes. Twenty-two obese individuals without diabetes attending a specialist obesity service were enrolled in a 12-month study to see if liraglutide 1.8 mg could avoid bariatric surgery. Fourteen completed the study with a mean weight loss of 12.1 kg. Two participants withdrew because of lack of efficacy, two because of GI side effects and the rest failed to complete the study as their primary care funding of the treatment was withdrawn.15 Other studies of the efficacy of liraglutide for inducing weight loss in those without diabetes have used higher doses. In a 56-week double-blind trial, 63.2% of patients receiving 3 mg liraglutide lost at least 5% of their body weight compared to 27.1% in the placebo group. Additionally, HbA1c, quality of life and cardio-metabolic risk factors all improved.16 A randomised controlled trial comparing the efficacy of liraglutide with that of orlistat showed that patients taking the two highest doses of liraglutide (2.4 and 3.0 mg) lost significantly more weight than those taking orlistat (6.3, 7.2 and 4.1 kg, respectively).17 The SCALE diabetes trial looked at the efficacy and safety of the higher liraglutide 3.0 mg dose in patients with T2DM and found that at 56 weeks weight loss was 6.0% (6.4 kg) with 3.0 mg dose, 4.7% (5.0 kg) with 1.8 mg dose and 2% (2.2 kg) with placebo. HbA1c significantly improved compared to placebo with treatment difference of −0.93% (10 mmol/mol) in the 3.0 mg dose group. Mean systolic blood pressure was significantly decreased (treatment difference −2.6 mmHg) in the liraglutide dose compared to placebo without a dose effect. Liraglutide 3.0 mg also significantly improved levels of total cholesterol, VLDL, HDL and triglycerides compared with placebo. Liraglutide was associated with a mean heart rate increase of 2.0 beats per minute compared to a reduction of 1.4 beats per minute for placebo. Given the improvements in the other cardiovascular risk factors, the long-term clinical relevance of this is unclear.18 The higher dosages of liraglutide are, however, associated with a higher incidence of GI side effects. The 3 mg dose caused GI side effects in 77% of participants and was the most common cause for cessation of treatment. There were eight people in the liraglutide groups who withdrew (2.2%) because of nausea, and five (1.3%; in the 2.4 mg and 3.0 mg groups) because of vomiting. Nobody in the placebo or orlistat groups withdrew because of such events.17 The combination of naltrexone and bupropion was approved by the FDA in September 2014 under the trade name Contrave and in some European countries in March 2016 as Mysimba. It is not currently licensed in the UK. Bupropion stimulates hypothalamic proopiomelanocortin (POMC) neurons while naltrexone blocks opioid-mediated POMC neurone auto-inhibition, inducing satiety. Given their established uses in addiction, it is also postulated that this combination may help modulate central nervous system reward pathways. Efficacy and safety of naltrexone/bupropion combination therapy were tested in the Contrave Obesity Research (COR) studies. COR-I compared two different doses of naltrexone (16 and 32 mg) combined with bupropion against placebo in 1742 participants.19 COR-II compared naltrexone/bupropion 32/360 mg against placebo in 1496 participants.20 Primary endpoints in each trial were percentage weight loss and proportion of subjects achieving more than 5% weight loss. All participants were either obese (BMI 30–45 kg/m2) or overweight (27–45 kg/m2) with dyslipidemia and/or hypertension. Both trials were conducted over 56 weeks. In COR-1, 48% of participants assigned to naltrexone 32 mg plus bupropion had a decrease in body weight of 5% or more compared with 16% of participants assigned to placebo. Mean reduction in body weight was 6.1% in the naltrexone 32 mg plus bupropion group versus 1.3% in the placebo group.19 Similar results were seen in COR-II with a 6.1% weight reduction by week 56 in the naltrexone/bupropion group against 1.2% in the placebo group, and 50.5% achieved a 5% weight loss compared to 17.1% of participants on placebo.20 Side effects were common, particularly nausea, headache and constipation. Drop-out rates were high with only 54% of participants in COR-II completing the study. In the active treatment arm, this was due to side effects while, in the placebo arm, the same proportion of patients withdrew due to insufficient weight loss.20 Pulse and blood pressure were not adversely affected. The LIGHT study was conducted to establish the cardiovascular safety of Contrave. More than 8000 participants were randomised either to naltrexone/bupropion or to placebo. However, the trial was stopped early after public release of confidential interim data by the sponsor suggesting a 40% reduction in major cardiovascular events in the naltrexone/bupropion group.21 This was not confirmed after further analysis, but cardiovascular safety was not established and further evaluation is required. Phentermine is a centrally-acting sympathomimetic and acts as an appetite suppressant. As a single agent it is the most frequently prescribed drug for weight loss in the US where it is approved only for short-term (up to 12 weeks) use because of its addictive potential. Topiramate is an anti-epileptic drug, also licensed for migraine prophylaxis which has been noted to have some weight loss effects. Qsymia was approved as a combination treatment in the US in 2012 but is not licensed in the UK. The benefits of low-dose Qsymia were assessed in the CONQUER trial. A total of 2487 patients were randomised to phentermine/topiramate at either 7.5/46 mg or 15/92 mg daily or to placebo; 20% of participants had T2DM at study entry. At 56 weeks, participants taking Qsymia had lost 8–10 kg while those on placebo had lost 1.4 kg. Five percent weight loss was achieved by 62% and 70% of participants in the two active arms and in 21% of participants taking placebo. There was a mean decrease in systolic blood pressure of 2.3 mmHg compared to placebo in the 7.5/46 mg dose and 3.2 mmHg in the 15/92 mg group following one year of treatment. Among the 388 subjects with T2DM, reductions in HbA1c from baseline were 0.1% (1 mmol/mol) for placebo compared to 0.4% (4 mmol/mol) with both doses of Qsymia.22 The SEQUEL trial was an extension of the CONQUER trial with participants continuing on the same dose of Qsymia or placebo for a further 52 weeks. Weight loss during the first 56 weeks in the Qsymia group was maintained over a further 52 weeks. Blood pressure was not different between the groups although 13.1% and 15.6% of patients in the two active treatment groups had reductions in their antihypertensive medications while 11% of participants taking placebo had their antihypertensive medications increased.23 The most common adverse effects were dry mouth, constipation and paraesthesia as well as a dose-related increase in incidence of depression, anxiety and attention difficulties. This is further underlined as a study examining its use in the real world environment of a multidisciplinary weight loss clinic noted an adverse event cessation rate of 40% with neurological side effects predominating.24 As the prevalence of obesity and related comorbidities continues to climb, pharmacological interventions for weight loss remain limited. Overall, the usefulness of weight loss medications are limited by side effects which result in high drop-out rates in medical trials as well as poor compliance in real world prescribing. In a population-based cohort, at one year after prescription of orlistat or sibutramine, less than 10% of patients were still on their medication and by two years only 2% continued on either medication.25 A further difficulty is that weight loss tends to slow and then plateau with continued treatment and the majority of patients regain weight when their weight loss drugs are stopped. However, it is of interest that trials have shown that a good initial response predicts long-term response and this underlines not only the importance of assessing responses within six months and discontinuing treatment in those with no measurable benefit, but also the potential value of further investigating the characteristics/phenotype associated with a good response. This may allow for more personalised treatments in the future. Belviq, Saxenda, Contrave and Qsymia have all been shown to be effective for weight management with the potential for weight loss of between 5.8–9.8% of starting weight over the first year of treatment (see Table 1). However, none are more effective than orlistat. There is also at this stage a lack of long-term data (more than two years) available for the new medications discussed in contrast to the established long-term safety profile of orlistat. These new weight loss drugs need to be considered with caution. Each has demonstrated significant benefits for weight reduction but none is without significant side effects. Weight loss alone may be beneficial for patient self-esteem and for reduction in weight-related joint disease and thrombo-embolic risk. An ideal drug would also reduce the metabolic complications of obesity including glycaemia, blood pressure and lipid profile and demonstrate significant reductions in cardiovascular endpoints. At this stage, some of the new weight loss treatments have demonstrated reductions in HbA1c, blood pressure and cholesterol (see Table 1), but until recently none have shown reduction in myocardial infarction (MI), stroke or mortality. This has changed with the recent publication of the LEADER trial. In all, 9340 patients with T2DM and high cardiovascular risk were randomised to 1.8 mg of liraglutide or placebo. Over 3.8 years of follow up, the primary outcome of death from cardiovascular disease, non-fatal MI or non-fatal stroke was 13% in the liraglutide arm and 14.9% in the placebo arm. Cardiovascular mortality was lower in the liraglutide group than in the placebo group (4.7% vs 6.0%) as was total mortality (8.2% vs 9.6%). Differences in non-fatal MI and stroke did not reach statistical significance.26 Arguably the most exciting and promising line of new pharmacological treatments are those targeted at gut hormones, given that research has proven their role in regulating appetite, metabolism, gut motility, secretion and even acting as neurotransmitters. GLP-1 analogues have paved the way towards developing gut hormones as therapeutics but have limited efficacy and dose-dependent side effects. However, other gut hormone pathways are also yet to be exploited and new combinations of hormone analogues are currently being developed. This includes peptide YY and pancreatic polypeptide analogues which are currently in phase 1 trials and hold potential to deliver better appetite suppression with fewer dose-dependent side effects. Furthermore, the use of agents to increase energy expenditure alongside appetite suppression is also under development which would represent a big step forward given that the body normally counter regulates weight loss by reducing energy expenditure and thus limiting weight loss. The potential use of glucagon receptor agonists in combination with GLP-1 in this way could therefore lead to a much greater weight loss than either peptide could achieve alone. New combinations of gut hormone analogues could thus mimic physiological processes to provide safe weight loss at a comparable level to surgery and this represents an exciting area of investigation for pharmacological agents in the future. In the UK, orlistat remains the only licensed weight reduction treatment although, for patients with T2DM, GLP-1 agonists such as liraglutide already used for treatment of hyperglycaemia also benefit patients in terms of weight loss. Whether the increased side effects with the higher dose as Saxenda will outweigh the additional weight loss benefits in clinical practice remains to be seen. The possibility of alternative oral medications such as Belviq, Contrave or Qsymia in the UK will depend on future studies of long-term efficacy and any long-term harms found during real world prescribing in the US and Europe. There are no conflicts of interest declared.

Comment on: Effect of laparoscopic Roux-en-Y gastric bypass versus laparoscopic sleeve gastrectomy on fasting gastrointestinal and pancreatic peptide hormones: A prospective nonrandomized trial

Appetite and the brain: you are what you eat

Paying the Price for Eating Ice Cream: Is Excessive GLP-1 Signaling in the Brain the Culprit?

these proportions had increased to 26% and 22%, respectively, with 55% of women and 66% of men being overweight (BMI > 25 kg/m 2 ; Health Survey for England, 2001), reflecting a worldwide trend which is most marked in, but not restricted to, the developed world. Most of us in affluent countries live in a privileged land of plenty where high calorie foods are easily available and in which we have a limited need for exercise. The rising prevalence of obesity in children is of particular concern (Chinn & Rona, 2001).

Obesity is basically caused by an imbalance between food intake and energy expenditure. It is well documented that the gastrointestinal tract plays a key role in the control of food intake, but the regulatory circuits and their interactions are complex. &#13;\nFood enters the gastrointestinal tract, which then trigger specific mechanisms that respond to specific components of food. The anatomical bases for the sensing machinery are enteroendocrine cells in the small intestine, which act as neural triggers or as intestinal satiation peptide secreting cells. These cells express chemosensory receptors that respond to luminal stimuli. This thesis addresses specific mechanisms regarding enteroendocrine cells and how nutrient components interact with this machinery to stimulate and regulate the secretion of gut peptides, which play a key role in the regulation of food intake and a wide range of metabolic functions. &#13;\nIn a first set of experiments, we investigated the involvement of two potential targets of peptide release, such as glucagon-like peptide 1 (GLP-1), peptide tyrosine tyrosine (PYY) and cholecystokinin (CCK): i) bile acids (BAs) as possible TGR5 agonists and ii) glucose stimulating the sweet receptor T1R2/T1R3.&#13;\nTo investigate the physiological role of BAs, subjects received intraduodenal infusions of different loads of chenodeoxycholic acid (CDCA, a primary BA in humans) in comparison to sodium-oleate (a potent secretagogue for the peptides mentioned above) or vehicle as a control. Administration of CDCA resulted in a significant increase of both plasma GLP-1 and CCK levels; however, the stimulatory potency was small, if we compare the magnitude of the GLP-1 and CCK responses to other well-known secretagogues such as glucose or fatty acids. &#13;\nTo investigate the physiological role of T1R2/T1R3 in the secretion of intestinal satiation peptides we used lactisole, a T1R2/T1R3 receptor antagonist. Subjects received i) intragastric and intraduodenal infusions of glucose and ii) intragastric and intraduodenal infusions of a liquid mixed meal, both with and without lactisole. Lactisole induced a significant reduction of plasma GLP-1 levels in both, the intragastric and intraduodenal glucose-stimulated parts. However, we observed no effect of lactisole on gastrointestinal peptide secretion in the mixed liquid meal-stimulated parts. The liquid meal consisted beside glucose also of proteins, fats and other complex carbohydrates. The lack of effect of lactisole suggests that these nutrients induced the release of gastrointestinal peptides probably via other receptor mechanisms and thus outweighed the effect of T1R2/T1R3 blockade. These findings indicate that the receptor is not alone responsible for peptide secretion; it is rather a complex interaction between different receptor mechanisms. In addition, we found that the inhibitory effect of lactisole on the secretion of GLP-1 was greater in response to intragastric glucose administration compared to the intraduodenal infusion. These results let assume interaction mechanisms between gastric signals and signals from the small intestine and indicate a relevant contribution of the stomach in the regulation of gastrointestinal peptide secretion.&#13;\nIndeed, several studies in animals and humans suggest that gastric and intestinal signals interact to elicit optimal satiation and adequate control of eating. In humans, little information is available on the underlying mechanisms of this interaction. In addition, uncertainties exist about the role of both gastric and intestinal parameters, as well as their interaction in the control of satiation in relation to body mass. In a second set of experience, we investigated the reciprocal control between gastric functions and intestinal parameters in the control of appetite in lean as well as in obese persons. &#13;\nTo investigate this potential interaction, lean subjects received either a rapid intragastric load or a continuous intraduodenal infusion of glucose or a mixed liquid meal. We found that infusions of glucose directly into the small intestine elicit only weak effects on appetite and the secretion of GLP-1 and PYY. In contrast, identical amounts of glucose delivered into the stomach markedly suppressed appetite paralleled by significantly greater plasma levels of GLP-1 and PYY. Administration of the mixed liquid meal showed a similar outcome. It seems that an initial more rapid rate of duodenal delivery after intragastric infusions account for the accelerated secretion of GLP-1 and PYY. These findings suggest again a role of the stomach in the control of appetite and indicate interaction mechanisms between gastric emptying rates and the release of intestinal satiation peptides.&#13;\nIn a last series of experiments, we compared gastric emptying, intestinal peptide release and satiation parameters in response to nutrients between normal weight and obese healthy subjects. We found that gastric emptying rates were delayed in obese subjects, possible due to impaired gastric sensory functions. In addition, the increase in post-prandial plasma GLP-1 and PYY levels was reduced and the caloric intake was higher in obese compared to lean subjects. These results document once more the importance of gastric signals in the control of appetite.&#13;\nTogether, chemosensing receptors like T1R2/T1R3 are involved in the secretion of gastrointestinal peptides, however each receptor by itself is probably not alone responsible for peptide release – it is rather a complex interaction between different receptor mechanisms. In addition, complex interactions between different gastrointestinal signals are responsible for the control of eating. The understanding of each of these signals and interaction mechanisms is essential and could constitute a promising therapeutic approach for the treatment of obesity.

WOODS, STEPHEN C. Dietary synergies in appetite control: distal gastrointestinal tract.

What Can We Learn From Mouse Models About Bile Acid-Mediated Changes After Bariatric Surgery?

The aim of this article is to review the research into the main peripheral appetite signals altered in human obesity, together with their modifications after body weight loss with diet and exercise and after bariatric surgery, which may be relevant to strategies for obesity treatment. Body weight homeostasis involves the gut–brain axis, a complex and highly coordinated system of peripheral appetite hormones and centrally mediated neuronal regulation. The list of peripheral anorexigenic and orexigenic physiological factors in both animals and humans is intimidating and expanding, but anorexigenic glucagon-like peptide 1 (GLP-1), cholecystokinin (CCK), peptide YY (PYY) and orexigenic ghrelin from the gastrointestinal tract, pancreatic polypeptide (PP) from the pancreas and anorexigenic leptin from adiposites remain the most widely studied hormones. Homeostatic control of food intake occurs in humans, although its relative importance for eating behaviour is uncertain, compared with social and environmental influences. There are perturbations in the gut–brain axis in obese compared with lean individuals, as well as in weight-reduced obese individuals. Fasting and postprandial levels of gut hormones change when obese individuals lose weight, either with surgical or with dietary and/or exercise interventions. Diet-induced weight loss results in long-term changes in appetite gut hormones, postulated to favour increased appetite and weight regain while exercise programmes modify responses in a direction expected to enhance satiety and permit weight loss and/or maintenance. Sustained weight loss achieved by bariatric surgery may in part be mediated via favourable changes to gut hormones. Future work will be necessary to fully elucidate the role of each element of the axis, and whether modifying these signals can reduce the risk of obesity.

ASGE EndoVators Summit: Defining the role and value of endoscopic therapies in obesity management

Factors leading to weight loss and weight stabilization after bariatric surgery are not fully understood. The aims of this study were to develop an animal model for biliopancreatic diversion (BPD) and to determine changes in gut hormones, malabsorption and small bowel histology postoperatively. 2 groups of Wistar rats underwent sham and BPD surgery. Daily postoperative weights and food intake were measured. 24-hour fecal collections were performed at Day 6 and 21. Bomb calorimetry was performed to determine the fecal calorific values. At day 23, levels of peptide YY (PYY), glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2) were determined and small bowel biopsies were taken. Animals in the BPD group had significant reduction in weight (P<0.001) and in food intake (P<0.001) compared to the sham group. Serum levels of PYY, GLP-1 and GLP-2 in the BPD group were significantly higher (P<0.005). Animals in the BPD group had significantly higher fecal energy content at Day 6 (P<0.001) but not at Day 21 when compared to the sham group. Small bowel histology confirmed the presence of significantly increased mitosis (P=0.03) and labelled cells (P=0.002) in the BPD animals when compared to sham. In our animal model, the higher levels of PYY, GLP-1 and GLP-2 after BPD may be due to gut adaptation and hypertrophy and could be important in inducing and maintaining weight loss after bariatric surgery.

Gastrointestinal signals regulating appetite in humans

To evaluate the physiologic importance of the satiety gut hormones. Controversy surrounds the physiologic role of gut hormones in the control of appetite. Bariatric surgery remains the most effective treatment option for obesity, and gut hormones are implicated in the reduction of appetite and weight after Roux-en-Y gastric bypass. We correlated peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) changes within the first week after gastric bypass with changes in appetite. We also evaluated the gut hormone responses of patients with good or poor weight loss after gastric bypass. Finally, we inhibited the gut hormone responses in gastric bypass patients and then evaluated appetite and food intake. Postprandial PYY and GLP-1 profiles start rising as early as 2 days after gastric bypass (P < 0.05). Changes in appetite are evident within days after gastric bypass surgery (P < 0.05), and unlike other operations, the reduced appetite continues. However, in patients with poor weight loss after gastric bypass associated with increased appetite, the postprandial PYY and GLP-1 responses are attenuated compared with patients with good weight loss (P < 0.05). Inhibiting gut hormone responses, including PYY and GLP-1 after gastric bypass, results in return of appetite and increased food intake (P < 0.05). The attenuated appetite after gastric bypass is associated with elevated PYY and GLP-1 concentrations, and appetite returns when the release of gut hormones is inhibited. The results suggest a role for gut hormones in the mechanism of weight loss after gastric bypass and may have implications for the treatment of obesity.

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.