Acyl-ghrelin administration increases food intake, body weight, and blood glucose. In contrast, mice lacking ghrelin or ghrelin receptors (GHSRs) exhibit life-threatening hypoglycemia during starvation-like conditions, but do not consistently exhibit overt metabolic phenotypes when given ad libitum food access. These results, and findings of ghrelin resistance in obese states, imply nutritional state dependence of ghrelin's metabolic actions. Here, we hypothesized that liver-enriched antimicrobial peptide-2 (LEAP2), a recently characterized endogenous GHSR antagonist, blunts ghrelin action during obese states and postprandially. To test this hypothesis, we determined changes in plasma LEAP2 and acyl-ghrelin due to fasting, eating, obesity, Roux-en-Y gastric bypass (RYGB), vertical sleeve gastrectomy (VSG), oral glucose administration, and type 1 diabetes mellitus (T1DM) using humans and/or mice. Our results suggest that plasma LEAP2 is regulated by metabolic status: its levels increased with body mass and blood glucose and decreased with fasting, RYGB, and in postprandial states following VSG. These changes were mostly opposite of those of acyl-ghrelin. Furthermore, using electrophysiology, we showed that LEAP2 both hyperpolarizes and prevents acyl-ghrelin from activating arcuate NPY neurons. We predict that the plasma LEAP2/acyl-ghrelin molar ratio may be a key determinant modulating acyl-ghrelin activity in response to body mass, feeding status, and blood glucose.

ObjectivesRoux-en-Y gastric bypass (RYGB) has greater efficacy for weight loss in obese patients than gastric banding (BAND) surgery. We hypothesise that this may result from different effects on food hedonics via physiological changes secondary to distinct gut anatomy manipulations.DesignWe used functional MRI, eating behaviour and hormonal phenotyping to compare body mass index (BMI)-matched unoperated controls and patients after RYGB and BAND surgery for obesity.ResultsObese patients after RYGB had lower brain-hedonic responses to food than patients after BAND surgery. RYGB patients had lower activation than BAND patients in brain reward systems, particularly to high-calorie foods, including the orbitofrontal cortex, amygdala, caudate nucleus, nucleus accumbens and hippocampus. This was associated with lower palatability and appeal of high-calorie foods and healthier eating behaviour, including less fat intake, in RYGB compared with BAND patients and/or BMI-matched unoperated controls. These differences were not explicable by differences in hunger or psychological traits between the surgical groups, but anorexigenic plasma gut hormones (GLP-1 and PYY), plasma bile acids and symptoms of dumping syndrome were increased in RYGB patients.ConclusionsThe identification of these differences in food hedonic responses as a result of altered gut anatomy/physiology provides a novel explanation for the more favourable long-term weight loss seen after RYGB than after BAND surgery, highlighting the importance of the gut–brain axis in the control of reward-based eating behaviour.

1. Obstructive sleep apnoea and its variants often provoke hundreds of short arousals that lead to the most important symptom, disabling hypersomnolence. The measurement of sleep in these conditions requires the documentation of these short arousals and this is conventionally done by manual inspection of the sleeping EEG, a laborious procedure. 2. Other markers of 'arousal', that are easier to measure and document, include several cardiovascular signals that change as part of the orienting reflex: pulse rate rise, blood pressure rise, skin vasoconstriction, for example. 3. Pulse transit time (measured as the interval from the ECG R-wave until the arrival of the pulse pressure wave at the periphery, about 250 ms) varies inversely with blood pressure and provides a beat-to-beat estimation of blood pressure changes. 4. In eight normal subjects we have assessed the relationship between transient EEG arousals of different length (provoked by external stimuli) and changes in both pulse transit time and heart rate. 5. Significant falls in pulse transit time occurred in response to external stimuli [15.1 (SEM 1.4) ms], indicating a rise in blood pressure, and were significant even when there was no discernible change in the EEG [9.9 (SEM 2.6) ms]. Significant changes in heart rate also occurred [10.3 (SEM 1.2) beats/min], but were slightly less sensitive than changes in pulse transit time. 6. Changes in pulse transit time (and to a lesser extent pulse rate) are sensitive markers of EEG arousal. As such they should be useful to include when monitoring sleep and its disorders, particularly since pulse transit time recorders can easily be made portable for home use.

Ghrelin administration and fasting have similar acute stimulatory effects on hedonic responses and the activation of corticolimbic reward-cognitive systems during food evaluations. Similar effects of recurrent or chronic hyperghrelinemia on an anticipatory food reward may contribute to the negative impact of skipping breakfast on dietary habits and body weight and the long-term failure of energy restriction for weight loss.