Effect of combined naltrexone and bupropion therapy on the brain's reactivity to food cues.

OBJECTIVE: The significant weight loss observed with combination naltrexone-sustained release (SR) 32 mg and bupropion SR 360 mg (NB32) therapy is thought to be due, in part, to bupropion stimulation of hypothalamic pro-opiomelanocortin (POMC) neurons, and naltrexone blockade of opioid receptor-mediated POMC autoinhibition, but the neurobiological mechanisms are not fully understood. We assessed changes in brain reactivity to food cues before and after NB32 treatment. METHODS: Forty women (31.1±8.1 years; body mass index: 32.5±3.9) received 4 weeks of NB32 or placebo, and were instructed to maintain their dietary and exercise habits. Functional magnetic resonance imaging responses (analyzed using SPM2 and clusters (>100 pixels)) to a 5-min food video (preparation of the subject's favorite food) and a 5-min neutral video (manipulation of neutral objects) under conditions of mild food deprivation (∼14 h) were assessed before and after treatment. RESULTS: The food cues video induced positive brain activation in visual and prefrontal cortices, insula and subcortical brain regions. The group-by-treatment interaction on regional brain activation was significant and showed that whereas NB32 attenuated the activation in the hypothalamus in response to food cues (P<0.01), it enhanced activation in regions involved in inhibitory control (anterior cingulate), internal awareness (superior frontal, insula, superior parietal) and memory (hippocampal) regions (whole-brain analysis; P<0.05). CONCLUSIONS: Blunting the hypothalamic reactivity to food cues while enhancing the activation of regions involved with self-control and internal awareness by NB32 might underlie its therapeutic benefits in obesity.

Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial.

AIM: Inhibition of diacylglycerol acyltransferase 1 (DGAT1) is a potential treatment modality for patients with type 2 diabetes mellitus and obesity, based on preclinical data suggesting it is associated with insulin sensitization and weight loss. This randomized, placebo-controlled, phase 1 study in 62 overweight or obese men explored the effects and tolerability of AZD7687, a reversible and selective DGAT1 inhibitor. METHODS: Multiple doses of AZD7687 (1, 2.5, 5, 10 and 20 mg/day, n = 6 or n = 12 for each) or placebo (n = 20) were administered for 1 week. Postprandial serum triacylglycerol (TAG) was measured for 8 h after a standardized 45% fat meal. Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured and a paracetamol challenge was performed to assess gastric emptying. RESULTS: Dose-dependent reductions in postprandial serum TAG were demonstrated with AZD7687 doses ≥5 mg compared with placebo (p < 0.01). Significant (p < 0.001) increases in plasma GLP-1 and PYY levels were seen at these doses, but no clear effect on gastric emptying was demonstrated at the end of treatment. With AZD7687 doses >5 mg/day, gastrointestinal (GI) side effects increased; 11/18 of these participants discontinued treatment owing to diarrhoea. CONCLUSIONS: Altered lipid handling and hormone secretion in the gut were demonstrated during 1-week treatment with the DGAT1 inhibitor AZD7687. However, the apparent lack of therapeutic window owing to GI side effects of AZD7687, particularly diarrhoea, makes the utility of DGAT1 inhibition as a novel treatment for diabetes and obesity questionable.

Anorexigenic effects of miglitol in concert with the alterations of gut hormone secretion and gastric emptying in healthy subjects.

Although the α-glucosidase inhibitor miglitol (MG) has been reported to have anorexigenic effects, the mechanism remains to be elucidated. The objective of this study was to explore the effects of MG on appetite in relation to concomitant changes in postprandial gut hormone levels. This randomized open-label crossover study included 20 healthy volunteers. The effects of 50 mg MG on glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and ghrelin levels were assessed in conjunction with a simultaneous determination of appetite scores using visual analogue scales (VAS) over 3 h after the ingestion of a 592 kcal test cookie. Additionally, the gastric emptying rate (GER) was measured using breath ¹³CO2 appearance in 10 subjects. 12 subjects were administered 50 mg MG thrice a day for 1 week, and alterations of the gut hormone levels and the VAS scores for appetite were evaluated. MG pre-administration resulted in a significant enhancement of GLP-1 and PYY responses induced by the cookie ingestion. Following MG administration, ghrelin level declined at 1 h, with a persistent suppression during the postprandial phase in contrast to the restoration to the basal level without MG. Furthermore, MG pre-administration suppressed appetite and maintained satiety evaluated using a VAS rating with concomitant inhibition of GER after cookie ingestion. One-week administration of MG did not influence either gut hormone levels before a meal or VAS rating during a whole day. These observations suggest that MG exerts an anorexigenic effects with concomitant alterations of gut hormone secretions and gastric emptying after meal ingestion.

Bariatric surgeries: beyond restriction and malabsorption.

Behavioral and pharmaceutical intervention to treat obesity and its comorbidities typically results in only a 5-10% weight loss. Thus, bariatric surgery is the most effective obesity treatment with some surgeries resulting in 30% sustained weight loss. Although this degree of weight loss has profound metabolic impact, these surgeries seem to have metabolic effects that are independent of weight loss. In support of this is the clinical literature showing rapid resolution of Type 2 diabetes mellitus (T2DM) that occurs before significant weight loss. To gain a complete understanding of the weight loss-independent effects of bariatric surgery, animal models have been developed. These are becoming more widely implemented and allow the use of pair-fed or weight-matched sham-operated controls in order to gain mechanistic insights into the mode of action of bariatric surgery. Increases in anorectic gut hormones, such as glucagon-like peptide-1 and peptide YY, or decreases in the orexigenic hormone ghrelin have been seen and are implicated as mediators of weight loss-independent actions of bariatric surgery. Changes in nutrient processing and sensing may also have a mechanistic role that is independent of, or that regulates, gut hormone responses to these surgeries. Ultimately, the hope is that understanding the mechanisms of bariatric surgeries will aid in the development of less invasive surgeries or pharmacological therapies that are more specifically, and perhaps individually, targeted at weight loss and/or resolution of T2DM.

Effect of honey versus sucrose on appetite, appetite-regulating hormones, and postmeal thermogenesis.

OBJECTIVE: Increased per capita consumption of sweeteners may be responsible in part for the rising prevalence of obesity in the United States. Recent studies suggest that consumption of honey is not associated with this same obesogenic effect and may have beneficial effects neuro on body weight. The purpose of this study was to evaluate whether the meal-induced responses of ghrelin and peptide YY(3-36) (PYY(3-36)) and/or meal-induced thermogenesis differ following a honey- versus a sucrose-containing meal. METHODS: In a double-blind randomly assigned study, appetite hormones (ghrelin, PYY(3-36), leptin) and glycemic and thermic responses were evaluated following isoglucidic ∼450 kcal honey- or sucrose-containing breakfasts in 14 healthy, nonobese women (22 ± 3 y). Blood samples and hunger ratings were obtained at baseline and every 30 minutes for 240 minutes following the meal. Meal-induced thermogenesis was measured by indirect calorimetry. Ad libitum food intake was evaluated from a free-choice meal following the test meal. RESULTS: Honey consumption delayed the postprandial ghrelin response (p = 0.037), enhanced the total PYY (p = 0.007) response, and blunted the glucose response (p = 0.039) compared with consumption of the sucrose-containing meal. Meal-induced insulin response, hunger ratings, thermogenesis, and subsequent ad libitum food intake, however, did not differ (p > 0.10) between diet treatments. CONCLUSIONS: Alterations in meal-induced responses of ghrelin and PYY(3-36) but not meal-induced thermogenesis may be responsible in part for the potential "obesity protective" effect(s) of honey consumption. A blunted glycemic response may be beneficial for reducing glucose intolerance. Further research is required to determine if these findings hold true for obese individuals, for males, or with habitual consumption.

Changes of dipeptidyl peptidase IV (DPP-IV) in obese children with weight loss: relationships to peptide YY, pancreatic peptide, and insulin sensitivity.

AIM: Gastrointestinal (GI) hormones are involved in satiety regulation and in glucose metabolism. Most GI hormones are hydrolyzed and inactivated by the same enzyme, dipeptidyl peptidase IV (DPP-IV). We analyzed changes of DPP-IV after weight loss in obese children and its relationships to the GI hormones pancreatic peptide (PP), peptide YY (PYY), and insulin sensitivity. METHODS: We measured at baseline and one year later anthropometrics, percentage body fat based on skinfold thickness, DPP-IV, PP, PYY, insulin, and glucose concentrations in 18 obese children (mean age 10.9 years, 44% male, mean BMI 28.5 kg/m2) who participated in a one-year lifestyle intervention program based on physical activity, nutrition course, and behavioral therapy. Insulin sensitivity was calculated using QUICKI. RESULTS: Changes of DPP-IV correlated significantly to the changes of percentage body fat (r = 0.47) and BMI SDS (r = 0.60). In partial regression analysis adjusted for change in weight status, changes of DPP-IV correlated significantly to changes of PYY (r = -0.43), PP (r = -0.49), QUICKI (r = -0.53), and insulin (r = 0.57). The 10 children with substantial weight loss significantly reduced their DPP-IV and insulin concentrations, while QUICKI, PYY, and PP levels significantly increased. In children without substantial weight loss no significant changes were observed. CONCLUSIONS: These findings suggest that the increase of fasting PP and PYY in weight loss is influenced at least in part by a decrease of their cleavage enzyme DPP-IV. Further research is necessary to evaluate the mechanisms in weight loss leading to a decrease of DPP-IV activity and consequently to an improvement of insulin sensitivity.

Reducing dietary fat from a meal increases the bioavailability of exogenous carbohydrate without altering plasma glucose concentration.

The primary goal of this study was to determine the acute glycemic and endocrine responses to the reduction of fat content from a meal. On three separate occasions, nine overweight subjects (body mass index = 30 +/- 1 kg/m(2); 5 men, 4 women) consumed 1) a control meal ( approximately 800 kcal; 100 g of carbohydrate, 31 g of fat, and 30 g of protein), 2) a low-fat meal ( approximately 530 kcal; 100 g of carbohydrate, 1 g of fat, and 30 g of protein), or 3) a low-fat meal plus lipid infusion [same meal as low-fat meal, but the total energy provided was the same as control (800 kcal), with the "missing" fat ( approximately 30 g) provided via an intravenous lipid infusion]. All three meals contained [(13)C]glucose (3 mg/kg body wt) to assess the bioavailability of ingested glucose. During the 5-h period after each meal, we measured the recovery of [(13)C]glucose in plasma, plasma glucose, and insulin concentrations. We also measured plasma concentration of the gastrointestinal peptides: glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and peptide YY(3-36) (PYY(3-36)). The recovery of the ingested [(13)C]glucose in the hour after ingestion was greater (P < 0.05) after the low-fat than after the control meal [area under the curve (AUC): 1,206 +/- 252 and 687 +/- 161 microM.h, respectively]. However, removing dietary fat from the meal did not affect the plasma concentration of glucose or insulin. Importantly, [(13)C]glucose recovery was not different during the low-fat and lipid infusion trials (AUC: 1,206 +/- 252 and 1,134 +/- 247 microM.h, respectively), indicating that the accelerated delivery of exogenous glucose found after removing fat from the meal is due exclusively to the reduction of fat in the gastrointestinal tract. In parallel with these findings, the reduction in fat calories from the meal reduced plasma concentration of GIP, GLP-1, and PYY(3-36). In summary, these data suggest that removing fat from the diet expedited exogenous glucose delivery into the systemic circulation and reduced the concentration of key gastrointestinal peptides, yet maintained plasma glucose concentration at control levels.

Efficacy and safety of sotagliflozin in treating diabetes type 1.

INTRODUCTION: Sotagliflozin is the first dual SGLT1/SGLT2 inhibitor developed for use in diabetes. Sotagliflozin blocks SGLT2 in the kidneys and SGLT1 in the intestines resulting in reduced early phase glucose absorption and increased blood levels of GLP-1 and PYY. Urinary glucose excretion is lower than with other agents as a result of decreased glucose absorption. The primary development effort to date has been in Type 1 diabetes. Areas covered: The published information on sotagliflozin is reviewed, along with the recent results of several pivotal Type 1 diabetes trials. Expert opinion: Sotagliflozin treatment lowers HbA1c and reduces glucose variability, with a trend to less hypoglycemic events. In the Type 1 trials, sotagliflozin treated individuals experienced DKA at a higher rate than placebo treated patients. An additional safety issue arises from the as yet unknown potential risks in women of child bearing potential in whom DKA is of utmost concern. The sotagliflozin development program has now been extended to trials in Type 2 diabetes, and long term studies will be needed to assess the benefits and risks of the agent in comparison to other currently marketed SGLT2 inhibitors.

Gut hormones and the control of appetite.

Obesity is the main cause of premature death in the UK. Worldwide its prevalence is accelerating. It has been hypothesized that a gut nutriment sensor signals to appetite centres in the brain to reduce food intake after meals. Gut hormones have been identified as an important mechanism for this. Ghrelin stimulates, and glucagon like peptide-1, oxyntomodulin, peptide YY (PYY), cholecystokinin and pancreatic polypeptide inhibit, appetite. At physiological postprandial concentrations they can alter food intake markedly in humans and rodents. In addition, in obese humans fasting levels of PYY are suppressed and postprandial release is reduced. Administration of gut hormones might provide a novel and physiological approach in anti-obesity therapy. Here, we summarize some of the recent advances in this field.

Jejunal overexpression of peptide YY in celiac disease complicated with pneumatosis cystoides intestinalis.

A 61-year old man with coeliac disease and chronic lack of appetite, malabsorption and weight loss, despite the gluten-free diet, was operated because of a sub-diaphragmatic free air due to a small-bowel pneumatosis cystoides intestinalis (PCI). The jejunum showed granulomatous lesions with a honeycombed appearance of air cysts in the submucosa/subserosa. We found overexpression of peptide YY (PYY) into only the jejunum with PCI, while the expression was very weak or absent in the tissue without cysts. One year after surgery, he had no abdominal pain or PCI recurrence. The above chronic symptoms were plausibly attributable to the PYY.

Effects of dietary polyphenols on neuroregulatory factors and pathways that mediate food intake and energy regulation in obesity.

Polyphenols are natural substances and are enriched in vegetables, fruits, grains, bark, tea, and wine. Some polyphenols have insulin-potentiating and anti-inflammatory effects, both of which are important in obesity. Dietary supplementation with polyphenolic compounds is associated with reduced diet-induced obesity and/or metabolic syndrome in animal and human studies. Insights into mechanisms that regulate food intake and satiety have led to an increased understanding of obesity but the pathogenesis underlying obesity is lacking. Food intake is subject to a complex regulation by the hypothalamus and other brain centers including the brain stem and the hippocampus. An intricate network of interacting feedback mechanisms that involve the aforementioned neural centers along with the stomach, gut, liver, thyroid, and adipose tissue in the periphery, influence the eventual outcome of food intake and satiety. Key peripheral signals, such as leptin, insulin, and ghrelin, have been linked to hypothalamic neuropeptide systems in energy regulation. This review will examine the neural centers important in food intake, the role of various neuropeptides, and the neurohormonal influence on food intake. The potential role of polyphenols in influencing the neuroregulatory factors, the neural signaling pathways and/or the peripheral feedback mechanisms that modulate food intake will also be examined.

Surgical treatments for obesity.

Bariatric surgery is currently the most effective and durable treatment option for extreme obesity. Restrictive procedures, such as AGB and SG, limit gastric capacity and, thus, food intake while leaving the gastrointestinal tract intact. Malabsorptive procedures, such as BPD, shorten the length of the intestine to decrease nutrient absorption. Combined procedures, such as RYGB, include restriction and gastrointestinal rearrangement. Procedures that bypass segments of the gut are associated with greater weight loss and greater improvements in comorbid conditions than is gastric banding. This may be due, in part, to the differential effects of gastrointestinal rearrangement on the secretion of orexigenic and anorexigenic gut peptides that regulate appetite, glucose homeostasis, and body weight. Bariatric surgery is generally associated with low rates of perioperative and postoperative morbidity and mortality, although rigorous comparative safety data are lacking. High-quality, long-term, randomized, controlled trials are needed to compare the efficacy, safety, and cost effectiveness of the various bariatric surgery procedures with each other, as well as with intensive nonsurgical weight loss interventions.

Therapeutic potential of gut peptides.

A great deal of research interest is directed toward understanding the control of appetite and regulation of metabolism. It seems as if an epidemic of obesity is sweeping the world, and type II diabetes (T2DM) is following in its wake. The regulation of energy homeostasis is an area that straddles neurobiology, classical endocrinology and metabolism. It is currently one of the most exciting and rapidly advancing topics in medical research, and is also one of the most frustrating areas. The availability of highly palatable, calorie-dense food, together with the low requirement for physical activity in our modern environment, are major factors contributing to the obesity epidemic. If energy intake exceeds energy use, the excess calories are stored as body fat. Knowledge of the homeostatic system that controls body weight has increased dramatically over the last years and has revealed new potential targets for the treatment of obesity. One therapeutic approach is the development of agents based on the gastrointestinal hormones that control food intake and appetite. This review discusses several gut hormones and ligands for their receptors as potential anti-obesity treatments.