The effect of the GLP-1 analogue Exenatide on functional connectivity within an NTS-based network in women with and without obesity.

Objective: The differential effect of GLP-1 agonist Exenatide on functional connectivity of the nucleus tractus solitaries (NTS), a key region associated with homeostasis, and on appetite-related behaviours was investigated in women with normal weight compared with women with obesity. Methods: Following an 8-h fast, 19 female subjects (11 lean, 8 obese) participated in a 2-d double blind crossover study. Subjects underwent functional magnetic resonance imaging at fast and 30-min post subcutaneous injection of 5 µg of Exenatide or placebo. Functional connectivity was examined with the NTS. Drug-induced functional connectivity changes within and between groups and correlations with appetite measures were examined in a region of interest approach focusing on the thalamus and hypothalamus. Results: Women with obesity reported less hunger after drug injection. Exenatide administration increased functional connectivity of the left NTS with the left thalamus and hypothalamus in the obese group only and increased the correlation between NTS functional connectivity and hunger scores in all subjects, but more so in the obese. Conclusions: Obesity can impact the effects of Exenatide on brain connectivity, specifically in the NTS and is linked to changes in appetite control. This has implications for the use of GLP-1 analogues in therapeutic interventions.

Altered functional connectivity within the central reward network in overweight and obese women.

BACKGROUND/OBJECTIVES: Neuroimaging studies in obese subjects have identified abnormal activation of key regions of central reward circuits, including the nucleus accumbens (NAcc), in response to food-related stimuli. We aimed to examine whether women with elevated body mass index (BMI) show structural and resting state (RS) functional connectivity alterations within regions of the reward network. SUBJECTS/METHODS: Fifty healthy, premenopausal women, 19 overweight and obese (high BMI=26-38 kg m(-2)) and 31 lean (BMI=19-25 kg m(-2)) were selected from the University of California Los Angeles' Oppenheimer Center for Neurobiology of Stress database. Structural and RS functional scans were collected. Group differences in grey matter volume (GMV) of the NAcc, oscillation dynamics of intrinsic brain activity and functional connectivity of the NAcc to regions within the reward network were examined. RESULTS: GMV of the left NAcc was significantly greater in the high BMI group than in the lean group (P=0.031). Altered frequency distributions were observed in women with high BMI compared with lean group in the left NAcc (P=0.009) in a medium-frequency (MF) band, and in bilateral anterior cingulate cortex (ACC) (P=0.014, <0.001) and ventro-medial prefrontal cortex (vmPFC) (P=0.034, <0.001) in a high-frequency band. Subjects with high BMI had greater connectivity of the left NAcc with bilateral ACC (P=0.024) and right vmPFC (P=0.032) in a MF band and with the left ACC (P=0.03) in a high frequency band. CONCLUSIONS: Overweight and obese women in the absence of food-related stimuli show significant structural and functional alterations within regions of reward-related brain networks, which may have a role in altered ingestive behaviors.

AT1, AT2, and AT(1-7) receptor expression in the uteroplacental unit of normotensive and hypertensive rats during early and late pregnancy.

INTRODUCTION: We investigated the expression of angiotensin receptors in early pregnancy and established whether normal pregnancy or preeclampsia alters the expression and distribution of the uteroplacental AT1R, AT2R and mas/AT1-7R at late gestation. METHODS: The percentage of each receptor subtype present in tissues from virgin rats and from normotensive and RUPP hypertensive pregnant rats was established by in vitro receptor autoradiography. Receptor mRNA levels were determined by quantitative PCR at early and late pregnancy. RESULTS: AT1R mRNA levels were up-regulated in the interimplantation (IIS) site at day 7 of gestation. AT2R mRNA levels were decreased at day 5 and 7 in the IIS but increased in the implantation site (IS) at day 5 and 7 as compared to the IIS at day 5. Mas/AT1-7R mRNA was increased in early pregnancy. In normal pregnancy and RUPP the mRNA for all angiotensin receptors was reduced in the uterus at late gestation. The AT1R accounted for the majority of binding in the uterus of virgin and the placenta of pregnant and RUPP. In RUPP pregnancy there was a significant competition with d-Ala in the placenta labyrinth. DISCUSSION AND CONCLUSION: The expression of angiotensin receptors suggests their involvement in the maintenance of early stages of pregnancy. During late gestation down-regulation of Ang receptors in the uterus may arise from feedback down-regulation by Ang II. In the placenta the levels of AT1Rs are equivalent in the RUPP model. The increased binding of mas/AT1-7R at late gestation in RUPP may represent a compensatory mechanism to reduce uteroplacental vascular resistance.

Differences in brain responses between lean and obese women to a sweetened drink.

BACKGROUND: Ingestion of sweet food is driven by central reward circuits and restrained by endocrine and neurocrine satiety signals. The specific influence of sucrose intake on central affective and reward circuitry and alterations of these mechanisms in the obese are incompletely understood. For this, we hypothesized that (i) similar brain regions are engaged by the stimulation of sweet taste receptors by sucrose and by non-nutrient sweeteners and (ii) during visual food-related cues, obese subjects show greater brain responses to sucrose compared with lean controls. METHODS: In a double-blind, crossover design, 10 obese and 10 lean healthy females received a sucrose or a non-nutrient sweetened beverage prior to viewing food or neutral images. BOLD signal was measured using a 1.5 Tesla MRI scanner. KEY RESULTS: Viewing food images after ingestion of either drink was associated with engagement of similar brain regions (amygdala, hippocampus, thalamus, anterior insula). Obese differed from lean subjects in behavioral and brain responses rating both beverages as less tasteful and satisfying, yet demonstrating greater brain responses. Obese subjects also showed engagement of an additional brain network (including anterior insula, anterior cingulate, hippocampus, and amygdala) only after sucrose ingestion. CONCLUSIONS & INFERENCES: Obese subjects had a reduced behavioral hedonic response, yet a greater engagement of affective brain networks, particularly after sucrose ingestion, suggesting that in obese subjects, lingual and gut-derived signaling generate less central hedonic effects than food-related memories in response to visual cues, analogous to response patterns implicated in food addiction.