Research in real supermarkets can be challenging due to competing health and business agendas. This study used a 2-dimensional (2D) simulated supermarket to investigate whether visual attention to, and intended purchase of, products in prominent store locations (checkout, end-of-aisle, store entrance) differed for healthy, unhealthy or non-food items. The study also explored if these findings were modified by participants’ level of educational attainment. Women from Wessex, UK, took part in one of two trials. Phase 1: 201 women completed an online questionnaire in which all participants viewed simulated supermarket journeys depicting healthy, unhealthy and non-food product routes, starting at the store entrance and ending at the checkout, in a random order. Participants clicked on items (i) that they were interested in and then (ii) that they wished to purchase. Phase 2: 71 women participated in an eye-tracking study in which all participants again viewed all journey types, followed by a series of side-by-side preferential looking scenes to allow comparison of attention between the three product types, presented in a random order. Twelve participants took part in semi-structured interviews to better understand their views on what influences product attention; data were analysed using thematic analysis. Phase 1: Participants demonstrated higher attention to food items compared to non-food items but their intention to purchase was higher for healthy foods than both unhealthy and non-food items. Phase 2: there was no difference in attention across product types during the journey task. In the preferential looking task, participants spent more time viewing healthy products than unhealthy or non-food products. Participants also exhibited higher intention to purchase healthy products than unhealthy or non-food items. Interview participants used shopping lists and avoided certain aisles to prevent unhealthy purchases. They wanted to see healthy foods or essential non-food options at prominent store locations. Women intend to make more healthy purchases than unhealthy purchases when they shop but supermarket strategies to promote less healthy foods in prominent locations in stores may undermine this intent. These findings support the use of prominent positioning of healthier items in stores as a useful strategy to increase healthy sales and support current and planned food policies. This was a quasi-experimental study of participants’ attention in an online questionnaire (phase 1) and an eye-tracking study (phase 2) and trial registration was not required. Participants did not receive an intervention.

This paper reports an expansion of the English as a second language (L2) component of the Multilingual Eye Movement Corpus (MECO L2), an international database of eye movements during text reading. While the previous Wave 1 of the MECO project (Kuperman et al., 2023) contained English as a L2 reading data from readers with 12 different first language (L1) backgrounds, the newly collected dataset adds eye-tracking data on English text reading from 13 distinct L1 backgrounds ( N = 660) as well as participants’ scores on component skills of English proficiency and information about their demographics and language background and use. The paper reports reliability estimates, descriptive statistics, and correlational analyses as means to validate the expansion dataset. Consistent with prior literature and the MECO Wave 1, trends in the MECO Wave 2 data include a weak correlation between reading comprehension and oculomotor measures of reading fluency and a greater L1-L2 contrast in reading fluency than reading comprehension. Jointly with Wave 1, the MECO project includes English reading data from more than 1,200 readers representing a diversity of native writing systems (logographic, abjad, abugida, and alphabetic) and 19 distinct L1 backgrounds. We provide multiple pointers to new venues of how L2 reading researchers can mine this rich publicly available dataset.

Variation in eye movement patterns can be considerable even within skilled readers. Here, individual differences and eye movements of 88 average-to-very-skilled readers were assessed to examine the reliability of previous observations of a reduced word frequency effect associated with skilled reading. Shorter fixation durations and higher skipping rates were observed for high frequency compared to low-frequency words. High scores on reading ability tests and vocabulary knowledge tests predicted reduced frequency effects in gaze duration in models with single individual differences predictors, demonstrated by faster reading of low-frequency words compared to low scorers. A principal components analysis grouped individual differences tests based on shared variance. High "lexical proficiency" predicted shorter gaze durations, reading times, and increased word skipping. "Lexical proficiency" and the Wechsler Individual Achievement Test-II comprehension test predicted a reduced frequency effect in go past times, and all tests apart from the Nelson Denny Reading Test comprehension test predicted a reduced frequency effect in sentence reading times. Data revealed surprising discrepancies in findings based on two subtests supposedly measuring comprehension (Nelson Denny Reading Test and Wechsler Individual Achievement Test-II), constituting an example of the jingle fallacy: the false assumption that two measures that share a name actually measure the same construct. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

When a preview contains substituted letters (SL; markey) word identification is more disrupted for a target word (monkey), compared to when the preview contains transposed letters (TL; mnokey). The transposed letter effect demonstrates that letter positions are encoded more flexibly than letter identities, and is a robust finding in adults. However, letter position encoding has been shown to gradually become more flexible as reading skills develop. It is unclear whether letter position encoding flexibility reaches maturation in skilled adult readers, or whether some differences in the magnitude of the TL effect remain in relation to individual differences in cognitive skills. We examined 100 skilled adult readers who read sentences containing a correct, TL or SL preview. Previews were replaced by the correct target word when the reader’s gaze triggered an invisible boundary. Cognitive skills were assessed and grouped based on overlapping variance via Principal Components Analysis (PCA) and subsequently used to predict eye movement measures for each condition. Consistent with previous literature, adult readers were found to generally encode letter position more flexibly than letter identity. Very few differences were found in the magnitude of TL effects between adults based on individual differences in cognitive skills. The flexibility of letter position encoding appears to reach maturation (or near maturation) in skilled adult readers.

Attentional biases to negative information are often observed in emotional disorders such as anxiety and depression. Recently, Fergus et al. (Cognitive Therapy and Research 37:735-741, 2013) demonstrated that participants scoring high in Intolerance of Uncertainty (IU), a transdiagnostic risk factor for emotional disorders, were faster at identifying targets with uncertainty-based information (e.g., word stimuli such as ‘maybe’), relative to neutral information (e.g. word stimuli related to household items). Moreover, this effect was specific to IU over other anxious traits such as worry. This report aimed to conceptually replicate the results of Fergus et al. (Cognitive Therapy and Research 37:735-741, 2013). The current experiment was conducted with a student sample (n = 126). As in the original study, a visual search task with uncertainty-based and neutral information (e.g., word stimuli) was used. Reaction times were collected. IU and trait anxiety was measured via self-report. We partially replicated the results of Fergus et al. (Cognitive Therapy and Research 37:735-741, 2013). We found that higher IU was significantly associated with faster identification of uncertainty-based information, relative to neutral information. However, we also observed a similar pattern of results for trait anxiety. Additionally, we observed no specificity of IU or trait anxiety in predicting faster identification of uncertainty-based information, relative to neutral information. Despite the lack of specificity of IU or trait anxiety in predicting attentional bias to uncertainty-based information, these findings highlight that negative emotionality may be generally associated with attentional biases to uncertainty-based information in the absence of direct threat.

This article presents the ENglish Reading Online (ENRO) project that offers data on English reading and listening comprehension from 7,338 university-level advanced learners and native speakers of English representing 19 countries. The database also includes estimates of reading rate and seven component skills of English, including vocabulary, spelling, and grammar, as well as rich demographic and language background data. We first demonstrate high reliability for ENRO tests and their convergent validity with existing meta-analyses. We then provide a bird's-eye view of first (L1) and second (L2) language comparisons and examine the relative role of various predictors of reading and listening comprehension and reading speed. Across analyses, we found substantially more overlap than differences between L1 and L2 speakers, suggesting that English reading proficiency is best considered across a continuum of skill, ability, and experiences spanning L1 and L2 speakers alike. We end by providing pointers for how researchers can mine ENRO data for future studies.

PAQR4 is an orphan receptor in the PAQR family with an unknown function in metabolism. Here, we identify a critical role of PAQR4 in maintaining adipose tissue function and whole-body metabolic health. We demonstrate that expression of Paqr4 specifically in adipocytes, in an inducible and reversible fashion, leads to partial lipodystrophy, hyperglycaemia and hyperinsulinaemia, which is ameliorated by wild-type adipose tissue transplants or leptin treatment. By contrast, deletion of Paqr4 in adipocytes improves healthy adipose remodelling and glucose homoeostasis in diet-induced obesity. Mechanistically, PAQR4 regulates ceramide levels by mediating the stability of ceramide synthases (CERS2 and CERS5) and, thus, their activities. Overactivation of the PQAR4-CERS axis causes ceramide accumulation and impairs adipose tissue function through suppressing adipogenesis and triggering adipocyte de-differentiation. Blocking de novo ceramide biosynthesis rescues PAQR4-induced metabolic defects. Collectively, our findings suggest a critical function of PAQR4 in regulating cellular ceramide homoeostasis and targeting PAQR4 offers an approach for the treatment of metabolic disorders. PAQR4 regulates cellular ceramide synthesis and accumulation to mediate adipose tissue function, glucose homoeostasis and, thus, systemic metabolic health.

The Jingle fallacy is the false assumption that instruments which share the same name measure the same underlying construct. In this experiment, we focus on the comprehension subtests of the Nelson Denny Reading Test (NDRT) and the Wechsler Individual Achievement Test (WIAT-II). 91 university students read passages for comprehension whilst their eye movements were recorded. Participants took part in two experimental blocks of which the order was counterbalanced, one with higher comprehension demands and one with lower comprehension demands. We assumed that tests measuring comprehension would be able to predict differences observed in eye movement patterns as a function of varying comprehension demands. Overall, readers were able to adapt their reading strategy to read more slowly, making more and longer fixations, coupled with shorter saccades when comprehension demands were higher. Within an experimental block, high scorers on the NDRT were able to consistently increase their pace of reading over time for both higher and lower comprehension demands, whereas low scorers approached a threshold where they could not continue to increase their reading speed or further reduce the number of fixations to read a text, even when comprehension demands were low. Individual differences based on the WIAT-II did not explain similar patterns. The NDRT comprehension test was therefore more predictive of differences in the reading patterns of skilled adult readers in response to comprehension demands than the WIAT-II (which also suffered from low reliability). Our results revealed that these different comprehension measures should not be used interchangeably, and researchers should be cautious when choosing reading comprehension tests for research.

Adiponectin is a secretory protein, primarily produced in adipocytes. However, low but detectable expression of adiponectin can be observed in cell types beyond adipocytes, particularly in kidney tubular cells, but its local renal role is unknown. We assessed the impact of renal adiponectin by utilizing male inducible kidney tubular cell-specific adiponectin overexpression or knockout mice. Kidney-specific adiponectin overexpression induces a doubling of phosphoenolpyruvate carboxylase expression and enhanced pyruvate-mediated glucose production, tricarboxylic acid cycle intermediates and an upregulation of fatty acid oxidation (FAO). Inhibition of FAO reduces the adiponectin-induced enhancement of glucose production, highlighting the role of FAO in the induction of renal gluconeogenesis. In contrast, mice lacking adiponectin in the kidney exhibit enhanced glucose tolerance, lower utilization and greater accumulation of lipid species. Hence, renal adiponectin is an inducer of gluconeogenesis by driving enhanced local FAO and further underlines the important systemic contribution of renal gluconeogenesis.

The disease progression of the metabolic syndrome is associated with prolonged hyperlipidemia and insulin resistance, eventually giving rise to impaired insulin secretion, often concomitant with hypoadiponectinemia. As an adipose tissue derived hormone, adiponectin is beneficial for insulin secretion and β cell health and differentiation. However, the down-stream pathway of adiponectin in the pancreatic islets has not been studied extensively. Here, along with the overall reduction of endocrine pancreatic function in islets from adiponectin KO mice, we examine PPARα and HNF4α as additional down-regulated transcription factors during a prolonged metabolic challenge. To elucidate the function of β cell-specific PPARα and HNF4α expression, we developed doxycycline inducible pancreatic β cell-specific PPARα (β-PPARα) and HNF4α (β-HNF4α) overexpression mice. β-PPARα mice exhibited improved protection from lipotoxicity, but elevated β-oxidative damage in the islets, and also displayed lowered phospholipid levels and impaired glucose-stimulated insulin secretion. β-HNF4α mice showed a more severe phenotype when compared to β-PPARα mice, characterized by lower body weight, small islet mass and impaired insulin secretion. RNA-sequencing of the islets of these models highlights overlapping yet unique roles of β-PPARα and β-HNF4α. Given that β-HNF4α potently induces PPARα expression, we define a novel adiponectin-HNF4α-PPARα cascade. We further analyzed downstream genes consistently regulated by this axis. Among them, the islet amyloid polypeptide (IAPP) gene is an important target and accumulates in adiponectin KO mice. We propose a new mechanism of IAPP aggregation in type 2 diabetes through reduced adiponectin action.

Abstract Background Circulating sex hormones exert unique effects on metabolism, leading to sexual dimorphism in white adipose tissue distribution and function. The gender affirming hormone therapy (GAHT) or cross-sex hormone therapy (CSHT) for transgender patients lower the endogenous sex hormones while raising the opposite sex hormones. Sex hormones are known to have a significant impact on white adipose tissue and metabolism. However, long-term metabolic changes with GAHT in transgender individuals have not been studied, nor are the underlying mechanisms properly elucidated. Hypothesis We test the hypothesis that GAHT will result in sexual dimorphic changes in morphology and function of white adipose tissue according to the type of sex hormones used and the native sex of the patients. Aim 1 To study the effect of cross-sex hormones on clinical parameters such as blood pressure, weight, waist-hip circumference ratio, serum lipids, insulin sensitivity Aim 2 To study the changes in human subcutaneous white adipose tissue (SWAT) distribution and expansion with GAHT Aim 3 To study changes in circulating metabolites and adipokines, and pro-inflammatory and pro-fibrotic gene expression in SWAT with GAHT. Methodology 31 hormone-naive patients (19 Male-to-Female; MtF and 12 Female-to-Male; FtM) were enrolled in the longitudinal study and followed up for 3 years. Clinical parameters and blood samples were gathered at baseline and at 6 month intervals. DXA scans and fat biopsies (peri-umbilical SWAT) were performed at baseline and at 1 year intervals. Results The results presented here compare baseline and at 1 year of GAHT. There was an increase in total cholesterol in the MtF group. HOMA-IR, total fat mass and visceral fat mass increased in MtF group, while they decreased in the FtM group. In MtF group, lean mass and bone mineral content (BMC) decreased at 1 year, but no change was observed in the FtM group. On histological assessment, fat cell size increased in MtF group, while it decreased in the FtM group. Conclusion In MtF transgender patients, androgen deprivation and estrogen treatment resulted in reduced insulin sensitivity together with a rise in total cholesterol possibly via a decrease in lean mass and adipose tissue expansion through significant adipocyte hypertrophy. In FtM transgender patients, testosterone treatment caused improved insulin sensitivity possibly via a decrease in total and visceral fat mass. The greatest strengths of our project include its longitudinal nature over 3 years to capture long-term effects in the same patients as well as deeper mechanistic insights into the underlying metabolite, adipokine and gene expression changes. The limitations of our study include the small sample size with heterogeneity of study population in terms of demographics and lifestyles. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

The anorexigenic effect of serotonergic compounds has largely been attributed to activation of serotonin 2C receptors (Htr2cs). Using mouse genetic models in which Htr2c can be selectively deleted or restored (in Htr2c-null mice), we investigate the role of Htr2c in forebrain Sim1 neurons. Unexpectedly, we find that Htr2c acts in these neurons to promote food intake and counteract the anorectic effect of serotonergic appetite suppressants. Furthermore, Htr2c marks a subset of Sim1 neurons in the paraventricular nucleus of the hypothalamus (PVH). Chemogenetic activation of these neurons in adult mice suppresses hunger, whereas their silencing promotes feeding. In support of an orexigenic role of PVH Htr2c, whole-cell patch-clamp experiments demonstrate that activation of Htr2c inhibits PVH neurons. Intriguingly, this inhibition is due to Gαi/o-dependent activation of ATP-sensitive K+ conductance, a mechanism of action not identified previously in the mammalian nervous system.

Cannabinoid 1 receptor (CB1R) inverse agonists reduce body weight and improve several parameters of glucose homeostasis. However, these drugs have also been associated with deleterious side effects. CB1R expression is widespread in the brain and in peripheral tissues, but whether specific sites of expression can mediate the beneficial metabolic effects of CB1R drugs, while avoiding the untoward side effects, remains unclear. Evidence suggests inverse agonists may act on key sites within the central nervous system to improve metabolism. The ventromedial hypothalamus (VMH) is a critical node regulating energy balance and glucose homeostasis. To determine the contributions of CB1Rs expressed in VMH neurons in regulating metabolic homeostasis, we generated mice lacking CB1Rs in the VMH. We found that the deletion of CB1Rs in the VMH did not affect body weight in chow- and high-fat diet-fed male and female mice. We also found that deletion of CB1Rs in the VMH did not alter weight loss responses induced by the CB1R inverse agonist SR141716. However, we did find that CB1Rs of the VMH regulate parameters of glucose homeostasis independent of body weight in diet-induced obese male mice. NEW & NOTEWORTHY Cannabinoid 1 receptors (CB1Rs) regulate metabolic homeostasis, and CB1R inverse agonists reduce body weight and improve parameters of glucose metabolism. However, the cell populations expressing CB1Rs that regulate metabolic homeostasis remain unclear. CB1Rs are highly expressed in the ventromedial hypothalamic nucleus (VMH), which is a crucial node that regulates metabolism. With CRISPR/Cas9, we generated mice lacking CB1Rs specifically in VMH neurons and found that CB1Rs in VMH neurons are essential for the regulation of glucose metabolism independent of body weight regulation.

Iron overload is positively associated with diabetes risk. However, the role of iron in adipose tissue remains incompletely understood. Here, we report that transferrin-receptor-1-mediated iron uptake is differentially required for distinct subtypes of adipocytes. Notably, adipocyte-specific transferrin receptor 1 deficiency substantially protects mice from high-fat-diet-induced metabolic disorders. Mechanistically, low cellular iron levels have a positive impact on the health of the white adipose tissue and can restrict lipid absorption from the intestine through modulation of vesicular transport in enterocytes following high-fat diet feeding. Specific reduction of adipocyte iron by AAV-mediated overexpression of the iron exporter Ferroportin1 in adult mice effectively mimics these protective effects. In summary, our studies highlight an important role of adipocyte iron in the maintenance of systemic metabolism through an adipocyte-enterocyte axis, offering an additional level of control over caloric influx into the system after feeding by regulating intestinal lipid absorption.

Objective: Histaminergic neurons of the tuberomammillary nucleus (TMN) are wake-promoting and contribute to the regulation of energy homeostasis. Evidence indicates that melanocortin 4 receptors (MC4R) are expressed within the TMN. However, whether the melanocortin system influences the activity and function of TMN neurons expressing histidine decarboxylase (HDC), the enzyme required for histamine synthesis, remains undefined. Methods: We utilized Hdc-Cre mice in combination with whole-cell patch-clamp electrophysiology and in vivo chemogenetic techniques to determine whether HDC neurons receive metabolically relevant information via the melanocortin system. Results: We found that subsets of HDC-expressing neurons were excited by melanotan II (MTII), a non-selective melanocortin receptor agonist. Use of melanocortin receptor selective agonists (THIQ, [D-Trp8]- gamma-MSH) and inhibitors of synaptic transmission (TTX, CNQX, AP5) indicated that the effect was mediated specifically by MC4Rs and involved a glutamatergic dependent presynaptic mechanism. MTII enhanced evoked excitatory post-synaptic currents (EPSCs) originating from electrical stimulation of the perifornical lateral hypothalamic area (PeFLH), supportive of melanocortin effects on the glutamatergic PeFLH projection to the TMN. Finally, in vivo chemogenetic inhibition of HDC neurons strikingly enhanced the anorexigenic effects of intracerebroventricular administration of MTII, suggesting that MC4R activation of histaminergic neurons may restrain the anorexigenic effects of melanocortin system activation. Conclusions: These experiments identify a functional interaction between the melanocortin and histaminergic systems and suggest that HDC neurons act naturally to restrain the anorexigenic effect of melanocortin system activation. These findings may have implications for the control of arousal and metabolic homeostasis, especially in the context of obesity, in which both processes are subjected to alterations. (C) 2020 The Author(s). Published by Elsevier GmbH.

The physiological role of leptin is thought to be a driving force to reduce food intake and increase energy expenditure. However, leptin therapies in the clinic have failed to effectively treat obesity, predominantly due to a phenomenon referred to as leptin resistance. The mechanisms linking obesity and the associated leptin resistance remain largely unclear. With various mouse models and a leptin neutralizing antibody, we demonstrated that hyperleptinemia is a driving force for metabolic disorders. A partial reduction of plasma leptin levels in the context of obesity restores hypothalamic leptin sensitivity and effectively reduces weight gain and enhances insulin sensitivity. These results highlight that a partial reduction in plasma leptin levels leads to improved leptin sensitivity, while pointing to a new avenue for therapeutic interventions in the treatment of obesity and its associated comorbidities.

Objective: The sympathetic nervous system (SNS) is a key regulator of the metabolic and endocrine functions of adipose tissue. Increased SNS outflow promotes fat mobilization, stimulates non-shivering thermogenesis, promotes browning, and inhibits leptin production. Most of these effects are attributed to norepinephrine activation of the Gs-coupled beta adrenergic receptors located on the surface of the adipocytes. Evidence suggests that other adrenergic receptor subtypes, including the Gi-coupled alpha 2 adrenergic receptors might also mediate the SNS effects on adipose tissue. However, the impact of acute stimulation of adipocyte Gs and Gi has never been reported. Methods: We harness the power of chemogenetics to develop unique mouse models allowing the specific and spatiotemporal stimulation of adipose tissue Gi and Gs signaling. We evaluated the impact of chemogenetic stimulation of these pathways on glucose homeostasis, lipolysis, leptin production, and gene expression. Results: Stimulation of Gs signaling in adipocytes induced rapid and sustained hypoglycemia. These hypoglycemic effects were secondary to increased insulin release, likely consequent to increased lipolysis. Notably, we also observed differences in gene regulation and ex vivo lipolysis in different adipose depots. In contrast, acute stimulation of Gi signaling in adipose tissue did not affect glucose metabolism or lipolysis, but regulated leptin production. Conclusion: Our data highlight the significance of adipose Gs signaling in regulating systemic glucose homeostasis. We also found previously unappreciated heterogeneity across adipose depots following acute stimulation. Together, these results highlight the complex interactions of GPCR signaling in adipose tissue and demonstrate the usefulness of chemogenetic technology to better understand adipocyte function. (C) 2019 The Authors. Published by Elsevier GmbH.

Phosphoinositide 3-kinase (PI3K) signaling in hypothalamic neurons integrates peripheral metabolic cues, including leptin and insulin, to coordinate systemic glucose and energy homeostasis. PI3K is composed of different subunits, each of which has several unique isoforms. However, the role of the PI3K subunits and isoforms in the ventromedial hypothalamus (VMH), a prominent site for the regulation of glucose and energy homeostasis, is unclear. Here we investigated the role of subunit p110β in steroidogenic factor-1 (SF-1) neurons of the VMH in the regulation of metabolism. Our data demonstrate that the deletion of p110β in SF-1 neurons disrupts glucose metabolism, rendering the mice insulin resistant. In addition, the deletion of p110β in SF-1 neurons leads to the whitening of brown adipose tissues and increased susceptibility to diet-induced obesity due to blunted energy expenditure. These results highlight a critical role for p110β in the regulation of glucose and energy homeostasis via VMH neurons.

Ghrelin administration increases food intake, body weight (BW), adiposity, and blood glucose. In contrast, although mouse models lacking ghrelin or its receptor (Growth Hormone Secretagogue Receptor (GHSR)) exhibit life-threatening hypoglycemia in starvation-like states, they do not exhibit appreciable reductions in food intake, BW, adiposity, blood glucose, or survival when food availability is unrestricted. This suggests the existence of a parallel neuromodulatory system that can compensate for disruptions in the ghrelin system in certain settings. Here, we hypothesized that the cannabinoid CB1 receptor (CB1R) may encode this putative redundancy, and as such, that genetic deletion of both GHSR and CB1R would exaggerate the metabolic deficits associated with deletion of GHSR alone. To test this hypothesis, we assessed food intake, BW, blood glucose, survival, and plasma acyl-ghrelin in ad libitum-fed male wild-type mice and those that genetically lack GHSR (GHSR-nulls), CB1R (CB1R-nulls), or both GHSR and CB1R (double-nulls). BW, fat mass, and lean mass were similar in GHSR-nulls and wild-types, lower in CB1R-nulls, but not further reduced in double-nulls. Food intake, plasma acyl-ghrelin, and blood glucose were similar among genotypes. Deletion of either GHSR or CB1R alone did not have a statistically-significant effect on survival, but double-nulls demonstrated a statistical trend towards decreased survival (p = 0.07). We conclude that CB1R is not responsible for the normal BW, adiposity, food intake, and blood glucose observed in GHSR-null mice in the setting of unrestricted food availability. Nor is CB1R required for plasma acyl-ghrelin secretion in that setting. However, GHSR may be protective against exaggerated mortality associated with CB1R deletion.

Leptin is critical for energy balance, glucose homeostasis, and for metabolic and neuroendocrine adaptations to starvation. A prevalent model predicts that leptin's actions are mediated through pro-opiomelanocortin (POMC) neurons that express leptin receptors (LEPRs). However, previous studies have used prenatal genetic manipulations, which may be subject to developmental compensation. Here, we tested the direct contribution of POMC neurons expressing LEPRs in regulating energy balance, glucose homeostasis and leptin secretion during fasting using a spatiotemporally controlled Lepr expression mouse model. We report a dissociation between leptin's effects on glucose homeostasis versus energy balance in POMC neurons. We show that these neurons are dispensable for regulating food intake, but are required for coordinating hepatic glucose production and for the fasting-induced fall in leptin levels, independent of changes in fat mass. We also identify a role for sympathetic nervous system regulation of the inhibitory adrenergic receptor (ADRA2A) in regulating leptin production. Collectively, our findings highlight a previously unrecognized role of POMC neurons in regulating leptin levels.