Search

Objective Bariatric surgery acutely improves glucose control, an effect that is generally sustained for years in most patients. The acute postoperative glycemic reduction is at least partially mediated by enhanced incretin secretion and islet function, and occurs independent of caloric restriction, whereas the sustained improvement in glucose control is associated with increased insulin sensitivity. However, studies in humans with bariatric surgery suggest that these elevations are not static but undergo coordinated regulation throughout the postoperative time course. The studies described here test the hypothesis that incretin secretion, islet function, and peripheral insulin sensitivity undergo temporal regulation following bariatric surgery as a means to regulate glucose homeostasis. Methods Incretin secretion, islet function, and insulin sensitivity in mice with vertical sleeve gastrectomy (VSG) were compared to sham-operated controls that were pair-fed for 90d, matching food consumption and body-weight between groups. Results Glucose clearance and insulin secretion were enhanced in VSG mice compared to controls during mixed-meal tolerance tests (MMTT) at 12 and 80 days postoperatively, as were prandial GLP-1, GIP, and glucagon levels. Insulin sensitivity was comparable between groups 14d after surgery, but significantly greater in the VSG group at day 75, despite similar body-weight gain between groups. Glucose stimulated insulin secretion was greater in VSG mice compared to controls in vivo (I.P. glucose injection) and ex vivo (islet perifusion) indicating a rapid and sustained enhancement of β-cell function after surgery. Notably, glycemia following a MMTT was progressively higher over time in the control animals but improved in the VSG mice at 80d despite weight regain. However, meal-stimulated incretin secretion decreased in VSG mice from 10 to 80 days postoperative, as did meal-stimulated and I.P. glucose-stimulated insulin secretion. This occurred over the same time period that insulin sensitivity was enhanced in VSG mice, suggesting postoperative islet output is tightly regulated by insulin demand. Conclusions These data demonstrate a dynamic, multifactorial physiology for improved glucose control after VSG, whereby rapidly elevated insulin secretion is complimented by later enhancements in insulin sensitivity. Critically, the glucose lowering effect of VSG is demonstrably larger than that of caloric-restriction, suggesting these adaptations are mediated by surgical modification of gastrointestinal anatomy and not weight-loss per se., Highlights • β-cell glucose sensitivity is enhanced 90d after VSG compared to controls, coincident with improved glucose tolerance. • Prandial GLP-1 and GIP are elevated 12d following VSG but return to preoperative levels 80d after VSG. • Insulin sensitivity is enhanced 75d after surgery, but not 14d after surgery, in mice with VSG compared to controls. • Mixed-meal glucose control is improved from 12d to 80d in VSG mice, but worsens in controls despite similar body-weight.

Objective The blood–brain barrier (BBB) regulates the entry of substrates and peptides into the brain. Ghrelin is mainly produced in the stomach but exerts its actions in the central nervous system (CNS) by crossing the BBB. Once present in the CNS, ghrelin can act in the hypothalamus to regulate food intake, in the hippocampus to regulate neurogenesis, and in the olfactory bulb to regulate food-seeking behavior. The goal of this study was to determine whether the primary signaling receptor for ghrelin, the growth hormone secretagogue receptor (GHSR), mediates the transport of ghrelin from blood to brain. Methods We utilized the sensitive and quantitative multiple-time regression analysis technique to determine the transport rate of mouse and human acyl ghrelin (AG) and desacyl ghrelin (DAG) in wildtype and Ghsr null mice. We also measured the regional distribution of these ghrelin peptides throughout the brain. Lastly, we characterized the transport characteristics of human DAG by measuring the stability in serum and brain, saturability of transport, and the complete transfer across the brain endothelial cell. Results We found the transport rate across the BBB of both forms of ghrelin, AG, and DAG, were not affected by the loss of GHSR. We did find differences in the transport rate between the two isoforms, with DAG being faster than AG; this was dependent on the species of ghrelin, human being faster than mouse. Lastly, based on the ubiquitous properties of ghrelin throughout the CNS, we looked at regional distribution of ghrelin uptake and found the highest levels of uptake in the olfactory bulb. Conclusions The data presented here suggest that ghrelin transport can occur independently of the GHSR, and ghrelin uptake varies regionally throughout the brain. These findings better our understanding of the gut-brain communication and may lead to new understandings of ghrelin physiology., Highlights • Ghrelin is transported across the BBB in the absence of GHSR. • Human DAG is transported the fastest compared to mDAG > hAG > mAG. • The olfactory bulb contained the greatest amount of ghrelin.

Restrictive eating disorders (ED) are increasing and represent a serious risk to the health of adolescent females. Restrictive ED in youth are often treated through aggressive short-term refeeding. Although evidence supports that this intervention is the “gold standard” for improving ED outcomes in youth, little research has specifically probed appetite and meal-related responses to this type of intensive, short-term refeeding in newly diagnosed individuals. Information about appetite and meal-related dysfunction could provide valuable insights regarding treatment-interfering features of ED in both acute inpatient and longer-term outpatient treatment. The purpose of this study was to evaluate the hunger, fullness, olfactory, and gustatory responses of adolescents with newly-diagnosed restrictive ED and to probe how and when these responses are altered by refeeding. Using a quasi-experimental ecologically valid methodology, this study described and compared profiles of hunger, fullness, olfactory, and gustatory responses in adolescent females (n = 15) with newly diagnosed restrictive ED at hospital admission (i.e., severe malnutrition) and after medical refeeding, in comparison to healthy controls (n = 15). Results showed that newly diagnosed (i.e., malnourished) adolescents with ED showed significantly different meal-related experiences than controls. Refeeding improved some of these differences, but not all. Following refeeding, females with ED continued to show lower hunger, greater fullness, and lower pleasantness of smell ratings compared to controls. Unpleasantness of taste ratings maladaptively increased, such that females who were re-fed reported more aversive scents than pre-treatment. Profiles of meal-related responses were also identified and compared between groups. The applicability of these findings are discussed within the context of critical periods of change during refeeding treatment and potentially promising intervention targets that might enhance treatment outcomes for adolescents with newly onset, restrictive ED.

Reductions in calorie intake contribute significantly to the positive outcome of bariatric surgeries. However, the physiological mechanisms linking the rerouting of the gastrointestinal tract to reductions in sugar cravings remain uncertain. We show that a duodenal-jejunal bypass (DJB) intervention inhibits maladaptive sweet appetite by acting on dopamine-responsive striatal circuitries. DJB disrupted the ability of recurrent sugar exposure to promote sweet appetite in sated animals, thereby revealing a link between recurrent duodenal sugar influx and maladaptive sweet intake. Unlike ingestion of a low-calorie sweetener, ingestion of sugar was associated with significant dopamine effluxes in the dorsal striatum, with glucose infusions into the duodenum inducing greater striatal dopamine release than equivalent jejunal infusions. Consistently, optogenetic activation of dopamine-excitable cells of the dorsal striatum was sufficient to restore maladaptive sweet appetite in sated DJB mice. Our findings point to a causal link between striatal dopamine signaling and the outcomes of bariatric interventions.

Ghrelin increases food intake and decreases energy expenditure, promoting a positive energy balance. We observed a single case of serious hypothermia during sustained ghrelin treatment in a male subject, suggesting that ghrelin may play a role in the regulation of body temperature. We therefore investigated the effect of ghrelin treatment on body temperature in rodents and humans under controlled conditions. Intriguingly, we could demonstrate ghrelin binding in axon terminals of the medial preoptic area of the hypothalamus located in the vicinity of cold-sensitive neurons. This localization of ghrelin receptors provides a potential anatomical basis for the regulation of body temperature by ghrelin. However, our follow-up studies also indicated that neither a chronic i.c.v. application of ghrelin in rats, nor a single s.c. injection under cold exposure in mice resulted in a relevant decrease in body core temperature. In addition, a four-hour intravenous ghrelin infusion did not decrease body surface temperature in healthy humans. We concluded that while there is a theoretical molecular basis for ghrelin to modify body temperature in mammals, its magnitude is irrelevant under physiologic circumstances. Hypothermia is not likely to represent a serious risk associated with this agent and pathway.

DECREASES THE RISK OF METABOLIC SYNDROME BETTINA PAEK, KATHERINE EASTWOOD, KRISTINA UTZSCHNEIDER, JENNY TONG, FERNANDO GERCHMAN, DREW ROBILIO, WILFRED FUJIMOTO, STEVEN KAHN, DARCY CARR, University of Washington, Obstetrics and Gynecology, Seattle, Washington, University of Washington, Medicine, Seattle, Washington OBJECTIVE: Having a low weight at birth (LBW) or macrosomic weight (MBW) have been linked to cardiovascular risk factors and type 2 diabetes (T2D) later in life. We hypothesized that the risk of obesity, hypertension (HTN), the metabolic syndrome (MS), and T2D would be increased in subjects who weighed !2500g (LBW) or 4000g (MBW) at birth and had a first-degree relative with T2D. STUDY DESIGN: We performed a cross sectional analysis on 1148 motherchild pairs who participated in the GENetics of Non-Insulin dependent Diabetes (GENNID) to compare the frequencies of the MS and T2D in adult offspring with reported LBW (n=120) or MBW (n=122) compared to normal BW (NBW: n=906). The MS was defined by the revised National Cholesterol Education Program Adult Treatment Panel III. T2D was determined by medical history or fasting and 2 hour glucose values. RESULTS: The groups had similar age (meanGSE: LBW 45.2G1.12 vs NBW 44.2G0.39 vs MBW 43.4G1.07 years,p=0.5), sex distribution (female: 63 vs 59 vs 56%, p=0.6) and smoking status (48 vs 49 vs 57%, p=0.1). LBW subjects were more likely to be African American (25 vs 14 vs 9%, p=0.001). Adjusting for age, sex, smoking, and race, LBW were less obese than NBW (BMI 28.4G0.64 vs 31.3G0.28 kg/m, p!0.0001 and had lower waist circumference 92G2 cm vs 101G1 cm, p!0.0001), whereas MBW had higher BMI (33.6G0.87 vs 31.4G0.28 kg/m, p=0.02) and a trend to higher waist circumference (105G2 vs 101G1 cm, p=0.09). LBW also had lower blood pressures (systolic 119G2 vs. 123G1 mmHg, p=0.006) and insulin levels (13.9G1.3 vs 17.6G0.7 iU/ml, p=0.007). Consistent with this, LBW had a decreased risk of the MS (LBW 58 vs NBW 70%, OR .54, 95% CI .30-.95, p=0.03). However, the risk of T2D was not different (LBW 61 vs NBW 60 vs MBW 60%, p=0.9). CONCLUSION: Among individuals with a family history of T2D, having LBW decreased the risk of obesity, central adiposity, HTN, and the MS later in life. Thus, in this high-risk population, LBW appears protective for future metabolic risk; whereas MBW did not confer additional risk of MS or T2D over NBW.