Insulin receptor signaling engages bladder urothelial defenses that limit urinary tract infection.

Urinary tract infections (UTIs) commonly afflict people with diabetes. To better understand the mechanisms that predispose diabetics to UTIs, we employ diabetic mouse models and altered insulin signaling to show that insulin receptor (IR) shapes UTI defenses. Our findings are validated in human biosamples. We report that diabetic mice have suppressed IR expression and are more susceptible to UTIs caused by uropathogenic Escherichia coli (UPEC). Systemic IR inhibition increases UPEC susceptibility, while IR activation reduces UTIs. Localized IR deletion in bladder urothelium promotes UTI by increasing barrier permeability and suppressing antimicrobial peptides. Mechanistically, IR deletion reduces nuclear factor κB (NF-κB)-dependent programming that co-regulates urothelial tight junction integrity and antimicrobial peptides. Exfoliated urothelial cells or urine samples from diabetic youths show suppressed expression of IR, barrier genes, and antimicrobial peptides. These observations demonstrate that urothelial insulin signaling has a role in UTI prevention and link IR to urothelial barrier maintenance and antimicrobial peptide expression.

Development of a Digital Program for Training Community Health Workers in the Detection and Referral of Schizophrenia in Rural India.

This study aimed to develop and assess the acceptability of a digital program for training community health workers (CHWs) in the detection and referral of patients with schizophrenia in community settings in rural India. An iterative design process was employed. First, evidence-based content from existing community programs for schizophrenia care was incorporated into the curriculum, and reviewed by experts to ensure clinical utility and fidelity of the adapted content. Second, CHWs provided feedback on the appropriateness of language, content, and an initial prototype of the digital training program to ensure relevance for the local context. Focus group discussions were then used to understand the acceptability of the digital training prototype and to inform modifications to the design and layout. Qualitative data was analysed using a rapid thematic analysis approach based on predetermined topics pertaining to acceptability of the training content and digital platform. Development of the initial prototype involved content review by 13 subject matter experts with clinical expertise or experience accessing and receiving mental health services, and engagement of 23 CHWs, of which 11 provided feedback for contextualization of the training content and 12 participated in focus group discussions on the acceptability of the prototype. Additionally, 2 service-users with lived experience of schizophrenia contributed to initial testing of the digital training prototype and offered feedback in a focus group discussion. During contextualization of the training content, key feedback pertained to simplifying the language and presentation of the content by removing technical terms and including interactive content and images to enhance interest and engagement with the digital training. During prototype testing, CHWs shared their familiarity with similar symptoms but were unaware of schizophrenia as a treatable illness. They shared that training can help them identify symptoms of schizophrenia and connect patients with specialized care. They were also able to understand misconceptions and discrimination towards people with schizophrenia, and how to address these challenges by supporting others and spreading awareness in their communities. Participants also appreciated the digital training, as it could save them time and could be incorporated within their routine work. This study shows the acceptability of leveraging digital technology for building capacity of CHWs to support early detection and referral of schizophrenia in community settings in rural India. These findings can inform the subsequent evaluation of this digital training program to determine its impact on enhancing the knowledge and skills of CHWs.

How Did the Mental Health Care System in India Respond to COVID 19 Pandemic?

India with a population of 1.3 billion has a unique health care system in its different states. Mental health care varies widely across the country and this became even more apparent after the COVID-19 pandemic set in. This paper examines the various strategies in response to COVID-19 adopted by the Government of India, the health departments of the individual states, and other private players such as on-government organizations and the civil society. The cessation of many services including outpatient and inpatient care and the scarcity of medicines were serious impacts of COVID-19. The prolonged lockdown in many parts of the country impeded access to mental health care services since public transport was unavailable. This led to many relapses in persons with serious mental disorders. The emergence of new cases of psychosis and an increase in suicides were also seen. Tele consultations came to the fore and many helplines were started offering counseling and guidance regarding the availability of mental health care facilities. While these helped the urban dwellers, those in remote and rural areas were unable to use these services effectively. Many mental health wards were used for COVID-19 patients and mental health professionals were deployed for COVID-19 related duty. The severely mentally ill, the homeless mentally ill, and the elderly were especially vulnerable. Based on our experience with COVID-19, we urge a strong call for action, in terms of strengthening the primary care facilities and increasing the manpower resources to deliver mental health care.

Schizophrenia Assessment, Referral and Awareness Training for Health Auxiliaries (SARATHA): Protocol for a Mixed-Methods Pilot Study in Rural India.

BACKGROUND: Workforce shortages pose major obstacles to the timely detection and treatment of schizophrenia, particularly in low-income and middle-income countries. The SARATHA (Schizophrenia Assessment, Referral, and Awareness Training for Health Auxiliaries) project involves the systematic development, iterative refinement, and pilot testing of a digital program for training community health workers in the early detection and referral of schizophrenia in primary care settings in rural India. METHODS: SARATHA is a three-phase study. Phase 1 involves consulting with experts and clinicians, and drawing from existing evidence to inform the development of a curriculum for training community health workers. Phase 2 consists of designing and digitizing the training content for delivery on a smartphone app. Design workshops and focus group discussions will be conducted to seek input from community health workers and service users living with schizophrenia to guide revisions and refinements to the program content. Lastly, Phase 3 entails piloting the training program with a target sample of 20 community health workers to assess feasibility and acceptability. Preliminary effectiveness will be explored, as measured by community health workers' changes in knowledge about schizophrenia and the program content after completing the training. DISCUSSION: If successful, this digital training program will offer a potentially scalable approach for building capacity of frontline community health workers towards reducing delays in early detection of schizophrenia in primary care settings in rural India. This study can inform efforts to improve treatment outcomes for persons living with schizophrenia in low-resource settings.

Reassessing relationships between appetite and adiposity in people at risk of obesity: A twin study using fMRI.

BACKGROUND: Neuroimaging studies suggest that appetitive drive is enhanced in obesity. OBJECTIVE: To test if appetitive drive varies in direct proportion to the level of body adiposity after accounting for genetic factors that contribute to both brain response and obesity risk. SUBJECTS/METHODS: Participants were adult monozygotic (n = 54) and dizygotic (n = 30) twins with at least one member of the pair with obesity. Body composition was assessed by dual-energy X-ray absorptiometry. Hormonal and appetite measures were obtained in response to a standardized meal that provided 20% of estimated daily caloric needs and to an ad libitum buffet meal. Pre- and post-meal functional magnetic resonance imaging (fMRI) assessed brain response to visual food cues in a set of a priori appetite-regulating regions. Exploratory voxelwise analyses outside a priori regions were performed with correction for multiple comparisons. RESULTS: In a group of 84 adults, the majority with obesity (75%), body fat mass was not associated with hormonal responses to a meal (glucose, insulin, glucagon-like peptide-1 and ghrelin, all P>0.40), subjective feelings of hunger (ß=-0.01 mm [95% CI -0.35, 0.34] P = 0.97) and fullness (ß=0.15 mm [-0.15, 0.44] P = 0.33), or buffet meal intake in relation to estimated daily caloric needs (ß=0.28% [-0.05, 0.60] P = 0.10). Body fat mass was also not associated with brain response to high-calorie food cues in appetite-regulating regions (Pre-meal ß=-0.12 [-0.32, 0.09] P = 0.26; Post-meal ß=0.18 [-0.02, 0.37] P = 0.09; Change by a meal ß=0.29 [-0.02, 0.61] P = 0.07). Conversely, lower fat mass was associated with being weight reduced (ß=-0.05% [-0.07, -0.03] P<0.001) and greater pre-meal activation to high-calorie food cues in the dorsolateral prefrontal cortex (Z = 3.63 P = 0.017). CONCLUSIONS: In a large study of adult twins, the majority with overweight or obesity, the level of adiposity was not associated with excess appetitive drive as assessed by behavioral, hormonal, or fMRI measures.

The DEAD-box RNA helicase eIF4A1 interacts with the SWI2/SNF2-related chromatin remodelling ATPase DDM1 in the moss Physcomitrella.

eIF4A is a DEAD box containing RNA helicase that plays crucial roles in regulating translation initiation, growth and abiotic stress tolerance in plants. It also functions as an ATP-dependent RNA binding protein to curb granule formation by limiting RNA-RNA interactions that promote RNA condensation and formation of ribonucleoprotein particles in vivo. Helicase activity of eIF4A is known to be dictated by its binding partners. Proteins interacting with eIF4A have been identified across land plants. In monocots a close link between eIF4A regulated processes and DNA methylation in epigenetic regulation of plant development is inferred from interaction between OseIF4A and the de novo methyltransferase OsDRM2 and loss-of-function studies of these genes in Oryza sativa and Brachypodium distachyon. In the moss Physcomitrella patens, eIF4A1 encoded by Pp3c6_1080V3.1 interacts with the heterogeneous nuclear ribonucleoprotein (hnRNP) PpLIF2L1, homolog of which in Arabidopsis regulates transcription of stress-responsive genes. In this study, using different protein-protein interaction methods, targeted gene knockout strategy and quantitative expression analysis we show genetic interaction between PpeIF4A1 and the putative nucleosome remodeler protein PpDDM1 and between PpDDM1 and PpLIF2L1 in vivo. Stress-induced co-expression of PpeIF4A1, PpDDM1 and PpLIF2L1, their roles in salt stress tolerance and differences in subnuclear distribution of PpLIF2L1 in ppeif4a1 cells in comparison to wild type suggest existence of a regulatory network comprising of RNA helicases, chromatin remodelling proteins and hnRNP active in stress-responsive biological processes in P. patens.

Salience network connectivity is reduced by a meal and influenced by genetic background and hypothalamic gliosis.

BACKGROUND/OBJECTIVES: The salience network (SN) comprises brain regions that evaluate cues in the external environment in light of internal signals. We examined the SN response to meal intake and potential genetic and acquired influences on SN function. SUBJECTS/METHODS: Monozygotic (MZ; 40 pairs) and dizygotic (15 pairs) twins had body composition and plasma metabolic profile evaluated (glucose, insulin, leptin, ghrelin, and GLP-1). Twins underwent resting-state functional magnetic resonance imaging (fMRI) scans before and after a standardized meal. The strength of SN connectivity was analyzed pre- and post-meal and the percentage change elicited by a meal was calculated. A multi-echo T2 MRI scan measured T2 relaxation time, a radiologic index of gliosis, in the mediobasal hypothalamus (MBH) and control regions. Statistical approaches included intraclass correlations (ICC) to investigate genetic influences and within-pair analyses to exclude genetic confounders. RESULTS: SN connectivity was reduced by a meal ingestion (ß = -0.20; P < 0.001). Inherited influences on both pre- and post-meal connectivity were present (ICC MZ twins 26%, P < 0.05 and 47%, P < 0.001, respectively), but not percentage change in response to the meal. SN connectivity in response to a meal did not differ between participants with obesity and of normal weight (χ2(1) = 0.93; P = 0.33). However, when participants were classified as having high or low signs of MBH gliosis, the high MBH gliosis group failed to reduce the connectivity in response to a meal (z = -1.32; P = 0.19). Excluding genetic confounders, the percentage change in SN connectivity by a meal correlated to body fat percentage (r = 0.24; P < 0.01). CONCLUSIONS: SN connectivity was reduced by a meal, indicating potential participation of the SN in control of feeding. The strength of SN connectivity is inherited, but the degree to which SN connectivity is reduced by eating appears to be influenced by adiposity and the presence of hypothalamic gliosis.

The DEAD-box RNA helicase eIF4A regulates plant development and interacts with the hnRNP LIF2L1 in Physcomitrella patens.

eIF4A is a RNA-stimulated ATPase and helicase. Besides its key role in regulating cap-dependent translation initiation in eukaryotes, it also performs specific functions in regulating cell cycle progression, plant growth and abiotic stress tolerance. Flowering plants encode three eIF4A paralogues, eIF4A1, eIF4A2 and eIF4A3 that share conserved sequence motifs but differ in functions. To date, however, no information is available on eIF4A in basal land plants. In this study we report that genome of the moss Physcomitrella patens encodes multiple eIF4A genes. The encoded proteins possess the highly conserved motifs characteristic of the DEAD box helicases. Spatial expression analysis shows these genes to be ubiquitously expressed in all tissue types with Pp3c6_1080V3.1 showing high expression in filamentous protonemata. Targeted deletion of conserved core motifs in Pp3c6_1080V3.1 slowed protonemata growth and resulted in dwarfing of leafy gametophores suggesting a role for Pp3c6_1080V3.1 in regulating cell division/elongation. Rapid and strong induction of Pp3c6_1080V3.1 under salt stress and slow recovery of knockout plants upon exposure to high salt further suggest Pp3c6_1080V3.1 to be involved in stress management in P. patens. Protein-protein interaction studies that show Pp3c6_1080V3.1 to interact with the Physcomitrella heterogenous ribonucleoprotein, LIF2L1, a transcriptional regulator of stress-responsive genes in Arabidopsis. The results presented in this study provide insight into evolutionary conserved functions of eIF4A and shed light on the novel link between eIF4A activities and stress mitigation pathways/RNA metabolic processes in P. patens.

Functional characterization of LIKE HETEROCHROMATIN PROTEIN 1 in the moss Physcomitrella patens: its conserved protein interactions in land plants.

In flowering plants, LIKE HETEROCHROMATIN PROTEIN 1 (LHP1)/TERMINAL FLOWER 2 (TFL2) is known to interact with polycomb group (PcG) and non-PcG proteins and control developmental programs. LHP1/TFL2 is an ancient protein and has been characterized in the early-divergent plant Physcomitrella patens. However, interacting partners of PpLHP1 other than the chromomethylase PpCMT have not been identified to date. Also, while functional polycomb repressive complex 2 (PRC2) is known to exist in P. patens, there is no experimental evidence to support the existence of PRC1-like complexes in these mosses. In this study, using protein-protein interaction methods, transient expression assays and targeted gene knockout strategy, we report the conserved properties of LHP1/TFL2 using the Physcomitrella system. We show that a PRC1-like core complex comprising of PpLHP1 and the putative PRC1 Really Interesting New Gene (RING)-finger proteins can form in vivo. Also, the interaction between PpRING and the PRC2 subunit PpCLF further sheds light on the possible existence of combinatorial interactions between the Polycomb Repressive Complex (PRC) in early land plants. Based on the interaction between PpLHP1 and putative hnRNP PpLIF2-like in planta, we propose that the link between PpLHP1 regulation and RNA metabolic processes was established early in plants. The conserved subnuclear distribution pattern of PpLHP1 in moss protonema further provides insight into the manner in which LHP1/TFL2 are sequestered in the nucleoplasm in discrete foci. The PpLHP1 loss-of-function plants generated in this study share some of the pleiotropic defects with multiple aberrations reported in lhp1/tfl2. Taken together, this work documents an active role for PpLHP1 in epigenetic regulatory network in P. patens.

FTO genotype impacts food intake and corticolimbic activation.

Background: Variants in the first intron of the fat mass and obesity-associated (FTO) gene increase obesity risk. People with "high-risk" FTO genotypes exhibit preference for high-fat foods, reduced satiety responsiveness, and greater food intake consistent with impaired satiety. Objective: We sought central nervous system mechanisms that might underlie impaired satiety perception in people with a higher risk of obesity based on their FTO genotype. Design: We performed a cross-sectional study in a sample that was enriched for obesity and included 20 higher-risk participants with the AA (risk) genotype at the rs9939609 locus of FTO and 94 lower-risk participants with either the AT or TT genotype. We compared subjective appetite, appetite-regulating hormones, caloric intake at a buffet meal, and brain response to visual food cues in an extended satiety network using functional MRI scans acquired before and after a standardized meal. Results: Higher-risk participants reported less subjective fullness (χ2 = 7.48, P < 0.01), rated calorie-dense food as more appealing (χ2 = 3.92, P < 0.05), and consumed ∼350 more kilocalories than lower-risk participants (ß = 348 kcal, P = 0.03), even after adjusting for fat or lean mass. Premeal, the higher-risk group had greater activation by "fattening" food images (compared with objects) in the medial orbital frontal cortex (ß = 11.6; 95% CI: 1.5, 21.7; P < 0.05). Postmeal, the higher-risk subjects had greater activation by fattening (compared with nonfattening) food cues in the ventral tegmental area/substantia nigra (ß = 12.8; 95% CI: 2.7, 23.0; P < 0.05), amygdala (ß = 10.6; 95% CI: 0.7, 20.5; P < 0.05), and ventral striatum (ß = 6.9; 95% CI: 0.2, 13.7; P < 0.05). Moreover, postmeal activation by fattening food cues within the preselected extended satiety network was positively associated with energy intake at the buffet meal (R2 = 0.29, P = 0.04) and this relation was particularly strong in the dorsal striatum (R2 = 0.28, P = 0.01), amygdala (R2 = 0.28, P = 0.03), and ventral tegmental area/substantia nigra (R2 = 0.27, P = 0.01). Conclusion: The findings are consistent with a model in which allelic variants in FTO raise obesity risk through impaired central nervous system satiety processing, thereby increasing food intake. This study is registered at clinicaltrials.gov as NCT02483663.

Resolution of Cognitive Adverse Effects of Electroconvulsive Therapy in Persons with Schizophrenia: A Prospective Study.

BACKGROUND: Cognitive impairments are among the most important adverse effects of electroconvulsive therapy (ECT). Although much is known about them in patients with depression, there is very little information about these in persons with schizophrenia. METHODS: In this study, we examined the persistence of cognitive impairments in a subsample of patients (n = 49) with schizophrenia who had earlier participated in a clinical trial comparing the therapeutic and cognitive efficacy of bifrontal ECT (BFECT; n = 23) and bitemporal ECT (BTECT; n = 29) electrode placements. Total scores on Hindi Mental State Examination, processing speed, working memory, and verbal fluency were assessed in these patients at two points: first, at the end of their respective ECT course and at the follow-up (mean [standard deviation] = 98.7 [38.3] days). The course of cognitive impairments was assessed in all patients (n = 49) as a single group. Further, BFECT and BTECT patients were also compared with one another. RESULTS: ECT-induced acute cognitive impairments in patients with schizophrenia had normalized by the end of 3 months' follow-up post-ECT. All the tested parameters in the realm of Hindi Mental Status Examination, speed of processing, sequencing, spatial and working memory and verbal fluency showed recovery. Further, across all tests, BFECT and BTECT ultimately had similar scores at the follow-up though BFECT performed relatively better with regards to the acute effects. In fact, worst performing BTECT group caught up to recover to comparable levels of performance by the end of follow-up. CONCLUSIONS: In patients with schizophrenia, most of acute ECT-induced cognitive impairments recover by the end of 3 months' post-ECT. Further, different electrode placements do not seem to make any difference regarding ultimate recovery of cognitive deficits. Future prospective studies are needed that could address the limitations of this study.

Effects of Anxiety on Caloric Intake and Satiety-Related Brain Activation in Women and Men.

OBJECTIVE: To test the relationship of anxiety to caloric intake and food cue perception in women and men. METHODS: Fifty-five twins (26 complete, 3 incomplete pairs; 51% women) underwent 2 functional magnetic resonance imaging (fMRI) scans (before and after a standardized meal) and then ate at an ad libitum buffet to objectively assess food intake. State and trait anxiety were assessed using the State-Trait Anxiety Inventory. During the fMRI scans, participants viewed blocks of fattening and nonfattening food images, and nonfood objects. RESULTS: In women, higher trait anxiety was associated with a higher body mass index (BMI) (r = 0.40, p = .010). Trait anxiety was positively associated with kilocalories consumed at the buffet (r = 0.53, p = .005) and percent kilocalories consumed from fat (r = 0.30, p = .006), adjusted for BMI. In within-pair models, which control for shared familial and genetic factors, higher trait anxiety remained associated with kilocalories consumed at the buffet (p = .66, p = .014), but not with BMI. In men, higher state anxiety was related to macronutrient choices, but not to total caloric intake or BMI. FMRI results revealed that women with high trait anxiety did not suppress activation by fattening food cues across brain regions associated with satiety perception after eating a standardized meal (low anxiety, mean difference = -15.4, p < .001; high anxiety, mean difference = -1.53, p = .82, adjusted for BMI). CONCLUSIONS: In women, trait anxiety may promote excess caloric consumption through altered perception of high-calorie environmental food cues, placing women with genetic predispositions toward weight gain at risk of obesity. TRIAL REGISTRATION: Clinicaltrials.govidentifier:NCT02483663.

Brain regulation of appetite in twins.

BACKGROUND: Neural responses to highly energetic food cues are robust and are suppressed by eating. It is not known if neural responsiveness to food cues is an inherited trait and possibly even one that mediates the genetic influences on body weight that have been previously observed. OBJECTIVE: We investigated the inherited influence on brain responses to high-calorie visual food cues before and after a meal. DESIGN: With the use of a monozygotic twin study design, 21 healthy monozygotic twin pairs consumed a standardized breakfast and, 3.5 h later, underwent the first of 2 functional MRI (fMRI) scans with the use of visual food cues. After the first fMRI session, twins consumed a standardized meal, which was followed by the second fMRI. Serial ratings of appetite and food appeal were obtained. An ad libitum buffet was used to measure total caloric and macronutrient intakes. Intraclass correlations (ICCs) were used to test for inherited influences by comparing whether intrapair similarity was greater than interpair similarity. RESULTS: Body mass index was highly correlated within twin pairs (ICC: 0.96; P < 0.0001). ICCs also showed a strong intrapair similarity for the meal-induced change in hunger (ICC: 0.41; P = 0.03), fullness (ICC: 0.39; P = 0.04), and the appeal of fattening food (ICC: 0.57; P < 0.001). Twins ate a similar number of kilocalories at the buffet (ICC: 0.43; P = 0.02). Before the meal, the global brain activation across regions involved in satiety processing was not more similar in twins than in unrelated individuals. However, significant ICCs were present after the meal (ICC: 0.39; P = 0.04) and for the meal-induced change in activation by high-calorie visual food cues (ICC: 0.52; P < 0.01). CONCLUSION: Inherited factors influence both satiety perception and the effect of a meal to alter regional brain responses to images of highly energetic food. This trial was registered at clinicaltrials.gov as NCT02483663.

Radiologic evidence that hypothalamic gliosis is associated with obesity and insulin resistance in humans.

OBJECTIVE: To use quantitative magnetic resonance imaging (MRI) to test whether mediobasal hypothalamic (MBH) gliosis is associated with obesity and insulin resistance in humans. METHODS: Sixty-seven participants underwent a fasting blood draw and MRI. Cases with radiologic evidence of MBH gliosis (N = 22) were identified as the upper tertile of left MBH T2 relaxation time and were compared to controls (N = 23) from the lowest tertile. In a separate postmortem study, brain slices (N = 10) through the MBH were imaged by MRI and stained for glial fibrillary acidic protein (GFAP). RESULTS: In all participants, longer T2 relaxation time in the left MBH was associated with higher BMI (P = 0.01). Compared with controls, cases had longer T2 relaxation times in the right MBH (P < 0.05), as well as higher BMI (P < 0.05), fasting insulin concentrations (P < 0.01), and HOMA-IR values (P < 0.01), adjusted for sex and age. Elevations in insulin and HOMA-IR were also independent of BMI. In the postmortem study, GFAP staining intensity was positively associated with MBH T2 relaxation time (P < 0.05), validating an MRI-based method for the detection of MBH gliosis in humans. CONCLUSIONS: These findings link hypothalamic gliosis to insulin resistance in humans and suggest that the link is independent of the level of adiposity.

In adult twins, visceral fat accumulation depends more on exceeding sex-specific adiposity thresholds than on genetics.

OBJECTIVE: We recently reported sex-specific percent body fat (%BF) thresholds (males=23%, females=38%) above which, visceral adipose tissue (VAT) significantly increases. Using monozygotic (MZ) and dizygotic (DZ) twins, we examined the influence of genetics on regional fat distribution measured by dual-energy X-ray absorptiometry, above and below these sex-specific thresholds for VAT accumulation. METHODS: Fifty-eight twin pairs (44 MZ, 14 DZ) were recruited from the University of Washington Twin Registry. Segmented linear regression was used to assess the threshold between VAT mass and %BF by sex and by zygosity. To assess the effect of genetics on VAT accumulation, Dunnett's T3 compared MZ and DZ pairs whether the twin pairs were both above the adiposity threshold or not. RESULTS: %BF thresholds for VAT accumulation were identified (%BF: M=20.6%, F=39.4%). Zygosity-specific thresholds were not significantly different (p>0.05). If at least one twin was below threshold, DZ twins still exhibited greater within-pair differences than MZ pairs in %BF (p=0.023) but not VAT (p=0.121). CONCLUSIONS: Using a twin study approach, we observed no difference by zygosity for the threshold as which VAT accumulates. Additionally, for the first time we observed that while total BF is influenced by genetics, VAT accumulation may depend more on whether a person's %BF is above their sex-specific adiposity threshold. These results suggest that there may not be a genetic predisposition for VAT accumulation but rather it is a result of a predisposition for total fat accumulation.

Initial evidence that GLP-1 receptor blockade fails to suppress postprandial satiety or promote food intake in humans.

Glucagon-like peptide 1 (GLP-1) has incretin effects that are well-documented, but the independent role of GLP-1 action in human satiety perception is debated. We hypothesized that blockade of GLP-1 receptors would suppress postprandial satiety and increase voluntary food intake. After an overnight fast, eight normal weight participants (seven men, BMI 19-24.7 kg/m(2), age 19-29 year) were enrolled in a double-blind, placebo-controlled, randomized crossover study of the GLP-1 antagonist Exendin-[9-39] (Ex-9) to determine if the satiating effects of a meal are dependent on GLP-1 signaling in humans. Following a fasting blood draw, iv infusion of Ex-9 (600-750 pmol/kg/min) or saline began. Thirty minutes later, subjects consumed a standardized breakfast followed 90 min later (at the predicted time of maximal endogenous circulating GLP-1) by an ad libitum buffet meal to objectively measure satiety. Infusions ended once the buffet meal was complete. Visual analog scale ratings of hunger and fullness and serial assessments of plasma glucose, insulin, and GLP-1 concentrations were done throughout the experiment. Contrary to the hypothesis, during Ex-9 infusion subjects reported a greater decrease in hunger due to consumption of the breakfast (Ex-9 -62 ± 5; placebo -41 ± 9; P=0.01) than during placebo. There were no differences in ad libitum caloric intake between Ex-9 and placebo. Ex-9 increased glucose, insulin, and endogenous GLP-1, which may have counteracted any effects of Ex-9 infusion to block satiety signaling. Blockade of GLP-1 receptors failed to suppress subjective satiety following a standardized meal or increase voluntary food intake in healthy, normal-weight subjects.

Regional brain response to visual food cues is a marker of satiety that predicts food choice.

BACKGROUND: Neuronal processes that underlie the subjective experience of satiety after a meal are not well defined. OBJECTIVE: We investigated how satiety alters the perception of and neural response to visual food cues. DESIGN: Normal-weight participants (10 men, 13 women) underwent 2 fMRI scans while viewing images of high-calorie food that was previously rated as incompatible with weight loss and "fattening" and low-calorie, "nonfattening" food. After a fasting fMRI scan, participants ate a standardized breakfast and underwent reimaging at a randomly assigned time 15-300 min after breakfast to vary the degree of satiety. Measures of subjective appetite, food appeal, and ad libitum food intake (measured after the second fMRI scan) were correlated with activation by "fattening" (compared with "nonfattening") food cues in a priori regions of interest. RESULTS: Greater hunger correlated with higher appeal ratings of "fattening" (r = 0.46, P = 0.03) but not "nonfattening" (r = -0.20, P = 0.37) foods. Fasting amygdalar activation was negatively associated with fullness (left: r = -0.52; right: r = -0.58; both P ≤ 0.01), whereas postbreakfast fullness was positively correlated with activation in the dorsal striatum (right: r = 0.44; left: r = 0.45; both P < 0.05). After breakfast, participants with greater activation in 4 regions-medial orbital frontal cortex (r = 0.49, P < 0.05), left amygdala (r = 0.49, P < 0.05), left insula (r = 0.47, P < 0.05), and nucleus accumbens (right: r = 0.57, P < 0.01; left: r = 0.43, P < 0.05)-chose buffet foods with higher fat content. CONCLUSIONS: Postmeal satiety is shown in regional brain activation by images of high-calorie foods. Regions including the amygdala, nucleus accumbens, and dorsal striatum may alter perception of, and reduce motivation to consume, energy-rich foods, ultimately driving food choice. This trial was registered at clinicaltrials.gov as NCT01631045.