Roux-en-Y gastric bypass : effects on feeding behavior and underlying mechanisms

Introduction Increased caloric intake as a key driver of the obesity crisis. Epidemiological data suggest that increased ease of food accessibility over the last 30 years is the primary driver of the current obesity pandemic (1). It is clear, however, that population variation in body weight is heavily dependent on genetic susceptibility or heritable factors (2, 3). The majority of identified monogenic obesity arises from gene defects affecting the leptin/melanocortin pathway (4), placing this pathway at the center of energy balance control (Figure 1 and refs. 5, 6). Through a combination of experimental medicine and translational research, we now understand that hyperphagia is a consistent phenotype in patients with congenital leptin, leptin receptor, pro-opiomelanocortin (POMC) and melanocortin-4 receptor (MC4R) deficiencies, with strong genotype-phenotype correlations (4). While monogenic causes of obesity illuminate the central pathways involved in the control of energy balance in humans, such mutations are rare and account for a small proportion of obesity in adults (4). Studies using a novel approach called genome-wide complex trait analysis have suggested that a multitude of common genetic variants, each with very small causal effects (7), could together account for 17% to 37% of the overall 35.0 k variance (8, 9). Polygene risk score based on 32 common variants with the largest effects on BMI, as identified in genomewide association studies (10), are also predictive of severe obesity (11), suggesting that severe obesity represents an extreme of the population BMI distribution. The association of such polygene risk scores with obesity is strengthened with higher consumption of fried foods, highlighting the importance of gene-environment interactions (12). Of the SNPs associated with increased BMI, those in the first intron of the fat mass and obesity associated (FTO) gene bear the strongest association with obesity and are strongly associated with extremes of obesity (13). Importantly, evidence to date suggests that the association between SNPs in FTO and BMI is predominantly driven by increased energy intake and not energy expenditure (14). Brain imaging studies utilizing functional MRI (fMRI) and PET have provided insights into the role of obesity risk variants in modulating the neural response to food cues. For example, BMI-matched groups of obese patients with or without MC4R deficiency exhibited differential neural responses in key brain reward centers when viewing appetizing food images (15). In relation to common obesity risk alleles, a study incorporating fMRI with gut hormone measurement in FTO-locus genotyped subjects found that the FTO-linked obesity risk genotype affected neural responses to food cues in a ghrelin-dependent manner (16). Furthermore, fMRI studies have demonstrated altered activation in key areas of the brain reward system in obese patients compared with normal-weight control subjects (17). For example, increased activation of prefrontal and parahippocampal reward centers observed in obese individuals might theoretically lead to an increased motivation to acquire food (18). On the other hand, a more pronounced inhibition of specific reward centers, such as the dorsal striatum, in obese individuals compared with normal-weight control subjects (19) might result in blunted reward responses after eating palatable foods, with subsequent compensatory overeating. A recent fMRI study found stronger functional connectivity between brain areas involved in cognitive control, motivation, and reward in the fasted but not in the fed state in obese compared with lean women (20). One hypothesis that provides a basis for these studies is that obesity may be characterized by a reward-deficiency state that involves reduced perception of the reward or hedonic value of food and resultant compensatory overeating (21). In support of this model, PET studies have demonstrated that lower striatal dopamine D2 receptor (D2R) availability is associated with higher BMI (22, 23). Supporting these findings, Guo et al. found Bariatric surgery is the most effective treatment for severe obesity, producing marked sustained weight loss with associated reduced morbidity and mortality. Roux-en-Y gastric bypass surgery (RYGBP), the most commonly performed procedure, was initially viewed as a hybrid restrictive-malabsorptive procedure. However, over the last decade, it has become apparent that alternative physiologic mechanisms underlie its beneficial effects. RYGBP-induced altered feeding behavior, including reduced appetite and changes in taste/food preferences, is now recognized as a key driver of the sustained postoperative weight loss. The brain ultimately determines feeding behavior, and here we review the mechanisms by which RYGBP may affect central appetite-regulating pathways. Roux-en-Y gastric bypass: effects on feeding behavior and underlying mechanisms