Changes in Alcohol Use after Metabolic and Bariatric Surgery: Predictors and Mechanisms.

PURPOSE OF REVIEW: This review synthesized the literature on predictors and mechanisms of post-bariatric alcohol problems, in order to guide future research on prevention and treatment targets. RECENT FINDINGS: Consistent evidence suggests an elevated risk of developing problems with alcohol following bariatric surgery. While there is a paucity of empirical data on predictors of problematic alcohol use after bariatric surgery, being male, a younger age, smoking, regular alcohol consumption, pre-surgical alcohol use disorder, and a lower sense of belonging have predicted alcohol misuse post-operatively. This review synthesizes potential mechanisms including specific bariatric surgical procedures, peptides and reinforcement/reward pathways, pharmacokinetics, and genetic influences. Finally, potential misperceptions regarding mechanisms are explored. Certain bariatric procedures elevate the risk of alcohol misuse post-operatively. Future research should serve to elucidate the complexities of reward signaling, genetically mediated mechanisms, and pharmacokinetics in relation to alcohol use across gender and developmental period by surgery type.

Central & peripheral glucagon-like peptide-1 receptor signaling differentially regulate addictive behaviors.

Recent data implicate glucagon-like peptide-1 (GLP-1), a potent anorexigenic peptide released in response to nutrient intake, as a regulator for the reinforcing properties of food, alcohol and psychostimulants. While, both central and peripheral mechanisms mediate effects of GLP-1R signaling on food intake, the extent to which central or peripheral GLP-1R signaling regulates reinforcing properties of drugs of abuse is unknown. Here, we examined amphetamine reinforcement, alcohol intake and hedonic feeding following peripheral administration of EX-4 (a GLP-1 analog) in FLOX and GLP-1R KD(Nestin) (GLP-1R selectively ablated from the central nervous system) mice (n=13/group). First, the effect of EX-4 pretreatment on the expression of amphetamine-induced conditioned place preference (Amp-CPP) was examined in the FLOX and GLP-1R KD(Nestin) mice. Next, alcohol intake (10% v/v) was evaluated in FLOX and GLP-1R KD(Nestin) mice following saline or EX-4 injections. Finally, we assessed the effects of EX-4 pretreatment on hedonic feeding behavior. Results indicate that Amp-CPP was completely blocked in the FLOX mice, but not in the GLP-1R KD(Nestin) mice following EX-4 pretreatment. Ex-4 pretreatment selectively blocked alcohol consumption in the FLOX mice, but was ineffective in altering alcohol intake in the GLP-1R KD(Nestin) mice. Notably, hedonic feeding was partially blocked in the GLP-1R KD(Nestin) mice, whereas it was abolished in the FLOX mice. The present study provides critical insights regarding the nature by which GLP-1 signaling controls reinforced behaviors and underscores the importance of both peripheral and central GLP-1R signaling for the regulation of addictive disorders.

Aversion learning can reduce meal size without taste avoidance in rats.

OBJECTIVE: Nausea and aversive food responses are commonly reported following bariatric surgery, along with post-surgical reduction in meal size. This study investigates whether a meal size limit can be conditioned by associating large meals with aversive outcomes. METHODS: In rats, the intake of meals exceeding a pre-defined size threshold was paired with lithium chloride-induced gastric illness, and the effects on self-determined food intakes and body weight were measured. RESULTS: Rats given LiCl contingent on the intake of a large meal learned to reliably reduce intake below this meal size threshold, while post-meal saline or LiCl before meals did not change meal size. It was further demonstrated that this is not a conditioned taste aversion and that this effect transferred to foods not explicitly trained. Finally, when rats received LiCl following all large meals, the number of small meals increased, but total food intake and body weight decreased. CONCLUSIONS: While further work is needed, this is the first demonstration that meal size may be conditioned, using an aversion procedure, to remain under a target threshold and that this effect is distinct from taste avoidance. Corresponding reduction in food intake and body weight suggests that this phenomenon may have implications for developing weight loss strategies and understanding the efficacy of bariatric surgery.

Insulin Sensitivity and ß-Cell Function Improve after Gastric Bypass in Severely Obese Adolescents.

OBJECTIVE: To test the hypothesis that insulin secretion and insulin sensitivity would be improved in adolescents after Roux-en-Y gastric bypass (RYGB). STUDY DESIGN: A longitudinal study of 22 adolescents and young adults without diabetes undergoing laparoscopic RYGB (mean age 17.1 ± 1.42 years; range 14.5-20.1; male/female 8/14; Non-Hispanic White/African American 17/5) was conducted. Intravenous glucose tolerance tests were done to obtain insulin sensitivity (insulin sensitivity index), insulin secretion (acute insulin response to glucose ), and the disposition index as primary outcome variables. These variables were compared over the 1 year of observation using linear mixed modeling. RESULTS: In the 1-year following surgery, body mass index fell by 38% from a mean of 61 ± 12.3 to 39 ± 8.0 kg/m(2) (P < .01). Over the year following surgery, fasting glucose and insulin values declined by 54% and 63%, respectively. Insulin sensitivity index increased 300% (P < .01), acute insulin response to glucose decreased 56% (P < .01), leading to a nearly 2-fold increase in the disposition index (P < .01). Consistent with improved ß-cell function, the proinsulin to C-peptide ratio decreased by 21% (P < .01). CONCLUSIONS: RYGB reduced body mass index and improved both insulin sensitivity and ß-cell function in severely obese teens and young adults. These findings demonstrate that RYGB is associated with marked metabolic improvements in obese young people even as significant obesity persists. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00360373.

Longitudinal trends in food cravings following Roux-en-Y gastric bypass in an adolescent sample.

BACKGROUND: Food cravings are more prevalent and potentially problematic for many individuals with obesity. Initial evidence suggests that bariatric surgery has some short-term beneficial effects on cravings in adults, but little is known about the effect on adolescents or the trajectory beyond 6 months. METHODS: The purpose of the present study was to determine the longitudinal effect of Roux-en-Y gastric bypass (RYGB) on food cravings in a sample of adolescents with severe obesity (body mass index (BMI)≥40 kg/m2). Sixteen adolescents were recruited and underwent RYGB. Participants completed the Food Craving Inventory before RYGB, and 3, 6, 12, 18, and 24 months postoperatively. The present study took place in a single pediatric tertiary care hospital. RESULTS: RYGB produced a negative (cravings decreased as time increased) nonlinear trend for total food cravings as well as for each individual subscale (sweets, high fat foods, carbohydrates, fast food) over the 24-month study period. This means that while cravings decrease postsurgically, there is a decline in the slope with the line reaching asymptote at approximately 18 months. BMI change was not a significant predictor of food cravings, but low statistical power may account for this lack of significance. CONCLUSION: These findings provide preliminary evidence that RYGB decreases food cravings in adolescents.

Weight loss by calorie restriction versus bariatric surgery differentially regulates the hypothalamo-pituitary-adrenocortical axis in male rats.

Behavioral modifications for the treatment of obesity, including caloric restriction, have notoriously low long-term success rates relative to bariatric weight-loss surgery. The reasons for the difference in sustained weight loss are not clear. One possibility is that caloric restriction alone activates the stress-responsive hypothalamo-pituitary-adrenocortical (HPA) axis, undermining the long-term maintenance of weight loss, and that this is abrogated after bariatric surgery. Accordingly, we compared the HPA response to weight loss in five groups of male rats: (1) high-fat diet-induced obese (DIO) rats treated with Roux-en-Y gastric bypass surgery (RYGB, n = 7), (2) DIO rats treated with vertical sleeve gastrectomy (VSG, n = 11), (3) DIO rats given sham surgery and subsequently restricted to the food intake of the VSG/RYGB groups (Pair-fed, n = 11), (4) ad libitum-fed DIO rats given sham surgery (Obese, n = 11) and (5) ad libitum chow-fed rats given sham surgery (Lean, n = 12). Compared with Lean controls, food-restricted rats exhibited elevated morning (nadir) non-stress plasma corticosterone concentration and increased hypothalamic corticotropin-releasing hormone and vasopressin mRNA expression, indicative of basal HPA activation. This was largely prevented when weight loss was achieved by bariatric surgery. DIO increased HPA activation by acute (novel environment) stress and this was diminished by bariatric surgery-, but not pair-feeding-, induced weight loss. These results indicate that the HPA axis is differentially affected by weight loss from caloric restriction versus bariatric surgery, and this may contribute to the differing long-term effectiveness of these two weight-loss approaches.

Hippocampal lipoprotein lipase regulates energy balance in rodents.

Brain lipid sensing is necessary to regulate energy balance. Lipoprotein lipase (LPL) may play a role in this process. We tested if hippocampal LPL regulated energy homeostasis in rodents by specifically attenuating LPL activity in the hippocampus of rats and mice, either by infusing a pharmacological inhibitor (tyloxapol), or using a genetic approach (adeno-associated virus expressing Cre-GFP injected into Lpl (lox/lox) mice). Decreased LPL activity by either method led to increased body weight gain due to decreased locomotor activity and energy expenditure, concomitant with increased parasympathetic tone (unchanged food intake). Decreased LPL activity in both models was associated with increased de novo ceramide synthesis and neurogenesis in the hippocampus, while intrahippocampal infusion of de novo ceramide synthesis inhibitor myriocin completely prevented body weight gain. We conclude that hippocampal lipid sensing might represent a core mechanism for energy homeostasis regulation through de novo ceramide synthesis.

Use of bariatric outcomes longitudinal database (BOLD) to study variability in patient success after bariatric surgery.

BACKGROUND: This study was conducted to determine the contributions of various predictors to the large variations in absolute weight loss and percent body mass index (BMI) loss after bariatric surgery. METHODS: The data source was the Bariatric Outcomes Longitudinal Database(SM) by the Surgical Review Corporation. Eligibility criteria included a first bariatric surgery for adjustable gastric band (AGB), Roux-en-Y gastric bypass (RYBG), or sleeve gastrectomy (SG) between January 2007 and February 2010; age 21 years or older; presurgery BMI > 30 kg/m2; and at least one preoperative visit within 6 months and at least one postoperative visit 30 days or more after surgery. Potential predictor variables included procedural details, patient demographics, comorbidities, and prior surgical history. Linear regression models of absolute weight loss and %BMI loss were fitted at 12, 18, and 24 months. The 12-month absolute weight loss endpoint was then chosen for a more in-depth analysis of variability through variable transformations and separate models by procedure. RESULTS: A total of 31,443 AGB, 40,352 RYGB, and 2,194 SG patients met all inclusion criteria. Regression models explained 37 to 55% of the variability in %BMI loss and 52 to 65% of variability in absolute weight loss. The key predictors for absolute weight loss at 12 months were procedure (44.8%) and baseline weight (18.5%), with 34.2% of the variability unexplained. Other significant predictors, each of which accounted for <1% of variability, included age, race, and diabetes. CONCLUSIONS: Research on additional sources of variability is still needed to help explain the remaining differences in outcomes after bariatric surgery.

GLP-1R responsiveness predicts individual gastric bypass efficacy on glucose tolerance in rats.

Several bariatric operations are currently used to treat obesity and obesity-related comorbidities. These vary in efficacy, but most are more effective than current pharmaceutical treatments. Roux-en-Y gastric bypass (RYGB) produces substantial body weight (BW) loss and enhanced glucose tolerance, and is associated with increased secretion of the gut hormone glucagon-like peptide 1 (GLP-1). Given the success of GLP-1-based agents in lowering blood glucose levels and BW, we hypothesized that an individual sensitivity to GLP-1 receptor agonism could predict metabolic benefits of surgeries associated with increased GLP-1 secretion. One hundred ninety-seven high-fat diet-induced obese male Long-Evans rats were monitored for BW loss during exendin-4 (Ex4) administration. Stable populations of responders and nonresponders were identified based on Ex4-induced BW loss and GLP-1-induced improvements in glucose tolerance. Subpopulations of Ex4 extreme responders and nonresponders underwent RYGB surgery. After RYGB, responders and nonresponders showed similar BW loss compared with sham, but nonresponders retained impaired glucose tolerance. These data indicate that the GLP-1 response tests may predict some but not all of the improvements observed after RYGB. These findings present an opportunity to optimize the use of bariatric surgery based on an improved understanding of GLP-1 biology and suggest an opportunity for a more personalized therapeutic approach to the metabolic syndrome.

Longitudinal trends in hedonic hunger after Roux-en-Y gastric bypass in adolescents.

BACKGROUND: Initial outcome studies have reported that Roux-en-Y gastric bypass (RYGB) is safe and efficacious for adolescents with extreme obesity. Although rapid weight loss is seen initially, data also show that modest weight regain typically occurs as early as the second postoperative year. The contribution of various psychological factors, including hedonic hunger, to postoperative weight regain has not previously been studied in adolescents. The objective of this study was to examine the variability in hedonic hunger and body mass index (BMI) over the initial 2-year period of weight loss and modest weight regain in adolescent RYGB recipients. METHODS: A total of 16 adolescents completed the Power of Food Scale before surgery and at 3, 6, 12, 18, and 24 months postoperatively. Height and weight were measured at each time point, from which BMI was calculated. RESULTS: Nonlinear trends were observed for time on both overall hedonic hunger and hedonic hunger specifically related to food available in the adolescent's environment. The BMI reduction during the first 18 months postoperatively was paralleled by reduction in hedonic hunger; increases in hedonic hunger also paralleled the modest BMI increase at 24 months. In growth analysis, significant power gains are available to models using 4 or more points of data. However, only large effect sizes that are>.85 were detectable with a sample of 16 patients. CONCLUSION: These data provide preliminary evidence that hedonic hunger is in need of further study in adolescent patients receiving RYGB both preoperatively and postoperatively.

Roux en Y gastric bypass increases ethanol intake in the rat.

Roux en Y gastric bypass (RYGB) surgery is currently the most effective therapy employed to treat obesity and its associated complications. In addition to weight loss and resolution of metabolic syndromes, such as diabetes, the RYGB procedure has been reported to increase alcohol consumption in humans. Using an outbred rodent model, we demonstrate that RYGB increases postsurgical ethanol consumption, that this effect cannot be explained solely by postsurgical weight loss and that it is independent of presurgical body weight or dietary composition. Altered ethanol metabolism and postsurgical shifts in release of ghrelin were also unable to account for changes in alcohol intake. Further investigation of the potential physiological factors underlying this behavioral effect identified altered patterns of gene expression in brain regions associated with reward following RYGB surgery. These findings have important clinical implications as they demonstrate that RYGB surgery leads directly to increased alcohol intake in otherwise alcohol nonpreferring rat and induces neurobiological changes in brain circuits that mediate a variety of appetitive behaviors.

Gastric bypass surgery attenuates ethanol consumption in ethanol-preferring rats.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery is an effective weight loss strategy employed to treat obesity and associated complications. Importantly, the RYGB procedure has been reported to attenuate reward-related consummatory behaviors. The present work examined the hypothesis that RYGB surgery attenuates ethanol intake and reward in the context of frequent ethanol consumption. METHODS: To do this, self-report of ethanol intake was examined in human bariatric patients (n = 6165) before and following the RYGB procedure. In addition, we utilized a rodent model of RYGB and examined ethanol consumption and ethanol reward in male ethanol-preferring (P) rats, which are selectively bred to consume large volumes of ethanol. RESULTS: Patients that reported frequent consumption of ethanol before RYGB reported decreased consumption following RYGB surgery. Moreover, the RYGB procedure decreased ethanol intake and the reinforcing properties of ethanol in P rats. Notably, the attenuating effect of RYGB surgery on ethanol consumption was associated with ethanol-induced increases in the gut hormone glucagon-like peptide-1 (GLP-1). Pharmacologic administration of GLP-1 agonists attenuated ethanol consumption in sham P rats. In addition, pharmacologic replacement of the gut hormone ghrelin restored drinking behavior in P rats following RYGB. CONCLUSIONS: Collectively, these findings unveil the potential of RYGB surgery to attenuate ethanol consumption in some humans and rats. Furthermore, our data indicate that this regulation is achieved, in part, through reduction of reward and is modified by the gut hormones GLP-1 and ghrelin.

Voluntary exercise improves high-fat diet-induced leptin resistance independent of adiposity.

The efficacy of exercise as primary prevention of obesity is the subject of intense investigation. Here, we show that voluntary exercise in a mouse strain susceptible to diet-induced obesity (C57B6J) decreases fat mass and increases energy expenditure. In addition, exercise attenuates obesity in mice fed a high-fat diet (HFD). Using FosB immunoreactivity as a marker of chronic neuronal activation, we found that exercise activates leptin receptor-positive neurons in the ventromedial hypothalamic nucleus, involved in homeostatic control of energy balance. FosB immunoreactivity in the ventromedial hypothalamic nucleus is decreased in sedentary mice exposed to HFD but is increased in exercised mice independent of adiposity. To determine whether the antiobesity effects of voluntary exercise improve central nervous system (CNS) leptin action, we measured the anorectic and weight reducing effects of intracerebroventricular (ICV) leptin in sedentary and exercised mice exposed to HFD (EH), as well as in sedentary mice that have been calorie restricted (SR) to match the fat mass of EH mice. ICV leptin was ineffective in lowering food intake and body weight (BW) in sedentary mice exposed to HFD mice. The anorectic potency of leptin was partially restored in EH and SR groups. However, ICV leptin significantly lowered BW in EH but not SR mice. Thus, exercise leads to the maintenance of a lower BW and leaner composition, as well as to improved CNS leptin action, independent of fat mass. These results support the notion that physical exercise directly influences the responsiveness of the CNS circuits involved in energy homeostasis by allowing the defense of a lowered BW.

Hippocampal lesions impair retention of discriminative responding based on energy state cues.

The present research investigated the hypothesis that the hippocampus is involved with the control of appetitive behavior by interoceptive "hunger" and "satiety" signals. Rats were trained to solve a food deprivation intensity discrimination problem in which stimuli produced by 0-hr and 24-hr food deprivation served as discriminative cues for the delivery of sucrose pellets. For Group 0+, sucrose pellets were delivered at the conclusion of each 4-min session that took place under 0-hr food deprivation, whereas no pellets were delivered during sessions that took place when the rats had been food deprived for 24 hr. Group 24+ received the reverse discriminative contingency (i.e., they received sucrose pellets under 24-hr but not under 0-hr food deprivation). When asymptotic discrimination performance was achieved (indexed by greater incidence of food magazine approach behavior on reinforced compared with nonreinforced sessions), half of the rats in each group received hippocampal lesions, and the remaining rats in each group were designated as sham- or nonlesioned controls. Following recovery from surgery, food deprivation discrimination performance was compared for lesioned and control rats in both Groups 0+ and 24+. Discriminative responding was impaired for rats with hippocampal lesions relative to their controls. This impairment was based largely on elevated responding to nonreinforced food deprivation cues. In addition, hippocampal damage was associated with increased body weight under conditions of ad libitum feeding. The results suggest that the inhibition of appetitive behavior by energy state signals may depend, in part, on the hippocampus.

Contributions of the hippocampus and medial prefrontal cortex to energy and body weight regulation.

The effects of selective ibotenate lesions of the complete hippocampus (CHip), the hippocampal ventral pole (VP), or the medial prefrontal cortex (mPFC) in male rats were assessed on several measures related to energy regulation (i.e., body weight gain, food intake, body adiposity, metabolic activity, general behavioral activity, conditioned appetitive responding). The testing conditions were designed to minimize the nonspecific debilitating effects of these surgeries on intake and body weight. Rats with CHip and VP lesions exhibited significantly greater weight gain and food intake compared with controls. Furthermore, CHip-lesioned rats, but not rats with VP lesions, showed elevated metabolic activity, general activity in the dark phase of the light-dark cycle, and greater conditioned appetitive behavior, compared with control rats without these brain lesions. In contrast, rats with mPFC lesions were not different from controls on any of these measures. These results indicate that hippocampal damage interferes with energy and body weight regulation, perhaps by disrupting higher-order learning and memory processes that contribute to the control of appetitive and consummatory behavior.

Bsx, a novel hypothalamic factor linking feeding with locomotor activity, is regulated by energy availability.

We recently reported that the hypothalamic homeobox domain transcription factor Bsx plays an essential role in the central nervous system control of spontaneous physical activity and the generation of hyperphagic responses. Moreover, we found Bsx to be a master regulator for the hypothalamic expression of key orexigenic neuropeptide Y and agouti gene-related protein. We now hypothesized that Bsx, which is expressed in the dorsomedial and arcuate nucleus (ARC) of the hypothalamus, is regulated by afferent signals in response to peripheral energy balance. Bsx expression was analyzed using in situ hybridization in fed vs. fasted (24 h) and ghrelin vs. leptin-treated rats, as well as in mice deficient for leptin or the ghrelin signaling. Ghrelin administration increased, whereas ghrelin receptor antagonist decreased ARC Bsx expression. Leptin injection attenuated the fasting-induced increase in ARC Bsx levels but had no effect in fed rats. Dorsomedial hypothalamic nucleus Bsx expression was unaffected by pharmacological modifications of leptin or ghrelin signaling. Obese leptin-deficient (ob/ob) mice, but not obese melanocortin 4 receptor-knockout mice, showed higher expression of Bsx, consistent with dependency from afferent leptin rather than increased adiposity per se. Interestingly, exposure to a high-fat diet triggered Bsx expression, consistent with the concept that decreased leptin signaling due to a high-fat diet induced leptin resistance. Our data indicate that ARC Bsx expression is specifically regulated by afferent energy balance signals, including input from leptin and ghrelin. Future studies will be necessary to test if Bsx may be involved in the pathogenesis of leptin resistance.

Simultaneous deletion of ghrelin and its receptor increases motor activity and energy expenditure.

Administration of chemically synthesized ghrelin (Ghr) peptide has been shown to increase food intake and body adiposity in most species. However, the biological role of endogenous Ghr in the molecular control of energy metabolism is far less understood. Mice deficient for either Ghr or its receptor (the growth hormone secretagogue receptor, GHS-R1a) seem to exhibit enhanced protection against high-fat diet-induced obesity but do not show a substantial metabolic phenotype on a standard diet. Here we present the first mouse mutant lacking both Ghr and the Ghr receptor. We demonstrate that simultaneous genetic disruption of both genes of the Ghr system leads to an enhanced energy metabolism phenotype. Ghr/Ghr receptor double knockout (dKO) mice exhibit decreased body weight, increased energy expenditure, and increased motor activity on a standard diet without exposure to a high caloric environment. Mice on the same genetic background lacking either the Ghr or the Ghr receptor gene did not exhibit such a phenotype on standard chow, thereby confirming earlier reports. No differences in food intake, meal pattern, or lean mass were observed between dKO, Ghr-deficient, Ghr receptor-deficient, and wild-type (WT) control mice. Only dKO showed a slight decrease in body length. In summary, simultaneous deletion of Ghr and its receptor enhances the metabolic phenotype of single gene-deficient mice compared with WT mice, possibly suggesting the existence of additional, as of yet unknown, molecular components of the endogenous Ghr system.

Behavioral controls of food intake.

Recent conceptualizations of food intake have divided ingestive behavior into multiple distinct phases. Here, we present a temporally and operationally defined classification of ingestive behaviors. Importantly, various physiological signals including hypothalamic peptides are thought to impact these distinct behavioral phases of ingestion differently. In this review, we summarize a number of behavioral assays designed to delineate the effects of hormone and peptide signals that influence food intake on these ingestive mechanisms. Finally, we discuss two issues that we have encountered in our laboratory which may obstruct the interpretation of results from these types of studies. First, the influence of previous experience with foods used in these behavioral tests and second, the importance of the nutrient composition of the selected test foods. The important conclusion discussed here is that the behavioral analysis of ingestion is accompanied by theoretical constructs and artificial divisions of biological realities and the appreciation of this fact can only increase the opportunities of contemporary behavioral scientists to make significant and novel observations of ingestive behaviors.

Intraventricular (i3vt) ghrelin increases food intake in fatty Zucker rats.

Ghrelin is an orexigenic peptide secreted from the stomach and also made in the brain. Ghrelin receptors are expressed on hypothalamic cells important in appetite and energy balance. We determined that intra-3rd-ventricular (i3vt) ghrelin dose-dependently increases acute (1 and 2 h) food intake in lean and fatty Zucker rats (0, 0.01, 0.1 and 1.0 nmol ghrelin). The percentage increase of food intake in fatty Zucker rats was significantly greater than that in lean rats. Fatty Zucker rats had 4.5 times more ghrelin receptor mRNA in the hypothalamus than lean Zucker rats, suggesting a possible mechanism for the increased sensitivity.