Obesity and weight management Worldwide the incidence of overweight and obesity is rapidly increasing with negative impact on health and health care costs. The efficacy of the currently available treatments is relatively limited on the long term. So far, surgical intervention has been proven to be the only strategy to overcome severe obesity in the long-term. Furthermore, in a recent meta-analysis it was concluded that dietary supplements and exercise alone does not contribute to improved weight loss after caloric restriction diets. Therefore, it is important to develop new effective strategies that induce weight loss or help weight maintenance after weight loss. A promising mechanism for weight management is to activate the so called 'ileal brake'. Ileal brake The ileal brake refers to an intestinal feedback mechanism that is triggered by nutrients at a specific location in the small intestine, resulting not only in modulation of gastrointestinal secretions and motility but also of food intake and hunger. The ileal brake can be activated by ileal infusion of undigested lipid and recently it was found that ileal infusion of sucrose and casein suppresses food intake to the same extend as equicaloric amount of lipids8. In addition to the reduction of food intake, an increase in feelings of satiety and decrease in hunger was found. Since ileal brake activation seems to be a promising target for weight management strategies alternative nutrient delivery techniques have to be used. Several studies investigated the effects of nutrient infusion in all regions of the small intestine. However all studies used intestinal feeding catheters in order to infuse nutrients directly into the desired part of the small intestine. In order to investigate the effect of long-term ileal brake activation in overweight individuals, a different approach for nutrient delivery needs to be chosen. An alternative for distal small intestinal nutrient delivery via feeding catheters is encapsulation of nutrients. Encapsulation can be used to deliver nutrients to a specific intestinal location. By encapsulation, nutrients are covered/surrounded with an edible coating. This coating is defined as a thin layer of edible material applied to the surface of the nutrients. This provides a barrier against digestion in the stomach and the proximal parts of the small intestine. Comparable approaches have already been used for site-specific drug delivery. Two examples of systems able to deliver drugs to the ileo-colonic region are the ColoPulse system described by Schellekens et al. (2010) and the ileo-colonic delivery system described by Varum et al. (2013). Both methods are invented to accelerate drug release in the ileo-colonic region and use specific Eudragit® polymer coatings. Adjusting these polymer coatings results in a more proximal (ileum) delivery. However these techniques were developed for drug delivery. To activate the ileal brake it is preferred to use a completely food grade application. Another food grade approach to deliver nutrients to the distal small intestine is micro-encapsulation. This micro-encapsulation technique will be used in the present study to deliver a mixture of nutrients consisting mostly sucrose (60%) , casein (30%) in a shell of whey protein (10%) to the distal small intestine. The delivery method patented by AnaBio Technologies Ltd. (http://www.AnaBio.ie/) comprises an active component, encapsulated within a protein matrix of preferably whey protein. The mechanism by which their technique delivers the active to the preferred intestinal location is based on pH, surface porosity of the microspheres, and reaction to specific enzymes. These three parameters are used to design the micro-encapsulation beads to deliver the active ingredient to the preferred intestinal location (e.g. duodenum, jejunum or ileum). Furthermore the size of the micro-beads is important for intestinal transit time. AnaBio uses their data collected from human and animal studies to relate the size of the micro-beads to intestinal transit time, dose volume and physiological characteristics. The micro-bead size (micron range) can be chosen based on the population group and the required transit time, an average used size is 150 micron. The advantage of these small particles is that the particles can be mixed with a food product. The ratio active : encapsulated protein matrix is 95 : 5%. This means that if sucrose will be encapsulated 95% of the micro-bead is pure sucrose and 5% is whey protein. We know from our previous research8 that infusion with 13 grams of sucrose is able to activate the ileal brake. For the present study we will use a mixture of encapsulated sucrose microbeats (60%) and encapsulated casein microbeats (30%) in order to simulate the composition of a small mixed carbohydrate and protein rich meal. Efficacy small intestinal delivery AnaBio provided data (which cannot be shared due to IP applications) of four in vivo studies of which 3 were human studies and 1 pig study. In these studies the efficacy of their delivery method has been investigated. It can be concluded from these studies that the whey protein micro-encapsulation technique is a specific intestinal delivery method for specific to either the ileum (2 human studies and 1 pig study) or the jejunum (1 human study). Present study In the present study the effect of 6 weeks ileal brake activation on body weight, BMI and waist circumference will be investigated. It is hypothesized that 6 weeks ileal brake activation by delivery of an encapsulated nutrient mixture to the distal small intestine results in reduced body weight. This will be studied by daily ingestion of an encapsulated nutrient mixture (e.g. 60% sucrose and 30% casein encapsulated in 10% whey protein) either delivered to the distal small intestine (active) or stomach (placebo) before lunch and dinner for 6 weeks in a randomized, double blind parallel placebo controlled trial. This will be studied in the second phase of the study (phase 2). Pre intervention, study day 1 and 2 (SD1 and SD2), middle (SD4) and post (SD5) intervention period the efficacy of the to decrease food intake (\>68 kcal) will be evaluated. It is unknown whether the ileal brake will be activated by the encapsulated nutrient mixture delivered to the distal small intestine (active) to the same magnitude as ileal brake activation by ileal sucrose and casein infusion. Therefore, we will study the ileal brake activation efficacy of the encapsulated nutrient mixture ingestion on ad libitum food intake. This will be done in the first phase of the study (phase 1). Pre-intervention the efficacy will be tested in a randomized placebo controlled cross over design. Within every subject the difference in ad libitum food intake after active or placebo ingestion will be studied. If the active encapsulated nutrient mixture does not result in a reduction of food intake the intervention will not start.