To test the commonly held assumption that gastric bypass surgery lowers body weight because it limits the ability to eat large amounts of food.

Gastric bypass surgery is the most effective treatment and is often the only option for subjects with severe obesity. However, investigation of critical molecular mechanisms involved has been hindered by confounding of specific effects of surgery and side effects associated with acute surgical trauma. Here, we dissociate the two components by carrying out surgery in the lean state and testing its effectiveness to prevent diet-induced obesity later in life. Body weight and composition of female mice with RYGB performed at 6 weeks of age were not significantly different from sham-operated and age-matched non-surgical mice at the time of high-fat diet exposure 12 weeks after surgery. These female mice were completely protected from high-fat diet-induced obesity and accompanying metabolic impairments for up to 50 weeks. Similar effects were seen in male mice subjected to RYGB at 5-6 weeks, although growth was slightly inhibited and protection from diet-induced obesity was less complete. The findings confirm that RYGB does not indiscriminately lower body weight but specifically prevents excessive diet-induced obesity and ensuing metabolic impairments. This prevention of obesity model should be crucial for identifying the molecular mechanisms underlying gastric bypass surgery.

The mechanisms by which bariatric surgeries so effectively and lastingly reduce body weight and normalize metabolic dysfunction are not well understood. Fibroblast growth fator-21 (FGF21) is a key regulator of metabolism and is currently considered for treatment of obesity. Although elevated by acute food deprivation, it is downregulated after weight loss induced by chronic calorie restriction but not after Roux-en-Y gastric bypass surgery. Therefore, the goal of the present study was to assess the role of FGF21-signaling in the beneficial effects of Roux-en-Y gastric bypass surgery (RYGB).

The gut hormone peptide YY (PYY) secreted from intestinal L-cells has been implicated in the mechanisms of satiation via Y2-receptor (Y2R) signaling in the brain and periphery and is a major candidate for mediating the beneficial effects of bariatric surgery on appetite and body weight.

Nutrient-sensing receptors located on enteroendocrine (EEC) cells modulate appetite via detection of luminal contents. Colonic 'tasting' of luminal contents may influence changes to appetite observed in obesity and after weight loss induced by bariatric surgery. We assessed the effects of obesity and gastric bypass-induced weight loss on expression of nutrient-sensing G-protein coupled receptors (GPCRs), EEC and enterochromaffin (EC) cells and mucosal innervation.

Roux-en-Y gastric bypass surgery (RYGB) remains one of the most effective treatments for obesity and type 2 diabetes. Despite this, the mechanisms through which it acts are still not well understood. Bile acid signaling through the transmembrane G-protein-coupled receptor TGR5 has been shown to have significant effects on metabolism and has recently been reported to be necessary for the full effects of vertical sleeve gastrectomy (VSG), a bariatric surgery with similar effects to RYGB. The goal of the current study is therefore to investigate the role of bile acid signaling through TGR5 to see if it is necessary to obtain the full effects of RYGB.

Dieting often fails because weight loss triggers strong counter-regulatory biological responses such as increased hunger and hypometabolism that are thought to be critically dependent on the master fuel sensor in the mediobasal hypothalamus (MBH). Because prolonged starvation has been shown to increase AgRP and NPY, the expression level of these two orexigenic genes has been taken as an experimental readout for the presence or absence of hunger. Roux-en-Y gastric bypass (RYGB) surgery leads to a significant weight loss without inducing the associated hunger, indicating possible changes in hypothalamic neuropeptides and/or signaling. Our goal was to assess key genes in the MBH involved in regulating body weight, appetite, and inflammation/oxidative stress after RYGB surgery in mice.

Understanding the mechanisms underlying the remarkable beneficial effects of gastric bypass surgery is important for the development of non-surgical therapies or less invasive surgeries in the fight against obesity and metabolic disease. Although the intestinal L-cell hormones glucagon-like peptide-1 (GLP-1) and peptide tyrosine-tyrosine (PYY) have attracted the most attention, direct tests in humans and rodents with pharmacological blockade or genetic deletion of either the GLP1-receptor (GLP1R) or the Y2-receptor (Y2R) were unable to confirm their critical roles in the beneficial effects gastric bypass surgery on body weight and glucose homeostasis. However, new awareness of the power of combinatorial therapies in the treatment of metabolic disease would suggest that combined blockade of more than one signaling pathway may be necessary to reverse the beneficial effects of bariatric surgery.

Insulin-like growth factor-binding protein (IGFBP)-2 is a circulating biomarker of cardiometabolic health. Here, we report that circulating IGFBP-2 concentrations robustly increase after different bariatric procedures in humans, reaching higher levels after biliopancreatic diversion with duodenal switch (BPD-DS) than after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). This increase is closely associated with insulin sensitization. In mice and rats, BPD-DS and RYGB operations also increase circulating IGFBP-2 levels, which are not affected by SG or caloric restriction. In mice, Igfbp2 deficiency significantly impairs surgery-induced loss in adiposity and early improvement in insulin sensitivity but does not affect long-term enhancement in glucose homeostasis. This study demonstrates that the modulation of circulating IGFBP-2 may play a role in the early improvement of insulin sensitivity and loss of adiposity brought about by bariatric surgery.