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Agouti-related peptide (AgRP) is a well-established potent orexigenic peptide primarily expressed in hypothalamic neurons. Nevertheless, the expression and functional significance of extrahypothalamic AgRP remain poorly understood. In this study, utilizing histological and molecular biology techniques, we have identified a significant expression of Agrp mRNA and AgRP peptide production in glomus type I cells within the mouse carotid body (CB). Furthermore, we have uncovered evidence supporting the expression of the AgRP receptor melanocortin receptor 3 (Mc3r) in adjacent sympathetic neurons, suggesting a potential local paracrine role for AgRP within the CB. Importantly, AgRP immunoreactivity was also identified in glomus type I cells of the human CB. Given the unexpected abundance of AgRP in glomus type I cells, a chemoreceptor cell specialized i.a. for oxygen sensing, we proceeded to investigate whether Agrp expression in the CB is regulated by hypoxemia and associated oxygen-sensing molecular mechanisms. In vitro luciferase assays reveal that hypoxia stimulates the human and mouse Agrp promoters in a Hypoxia Inducible Factor (HIF1/2)-dependent manner. Our in vivo experiments further demonstrate that exposure to environmental hypoxia (10%) robustly induces Agrp expression in type I glomus cells of mice. Furthermore, these findings collectively highlight the hitherto unknown source of AgRP in murine and human type I glomus cells and underscore the direct control of Agrp transcription by HIF signaling., (Copyright © 2025. Published by Elsevier GmbH.)

Objective: Several groups of neurons in the NTS suppress food intake, including Prlh-expressing neurons (NTS Prlh cells). Not only does the artificial activation of NTS Prlh cells decrease feeding, but also the expression of Prlh (which encodes the neuropeptide PrRP) and neurotransmission by NTS Prlh neurons contributes to the restraint of food intake and body weight, especially in animals fed a high fat diet (HFD). We set out to determine roles for putative PrRP receptors in the response to NTS PrRP and exogenous PrRP-related peptides., Methods: We used animals lacking PrRP receptors GPR10 and/or GPR74 (encoded by Prlhr and Npffr2, respectively) to determine roles for each in the restraint of food intake and body weight by the increased expression of Prlh in NTS Prlh neurons (NTS PrlhOX mice) and in response to the anorectic PrRP analog, p52., Results: Although Prlhr played a crucial role in the restraint of food intake and body weight in HFD-fed control animals, the combined absence of Prlhr and Npffr2 was required to abrogate the restraint of food intake in NTS PrlhOX mice. p52 suppressed feeding independently of both receptors, however., Conclusions: Hence, each receptor can participate in the NTS Prlh -mediated suppression of food intake and body weight gain, while PrRP analog treatment can mediate its effects via distinct systems. While Prlhr plays a crucial role in the physiologic restraint of weight gain, the action of either receptor is capable of ameliorating obesity in response to enhanced NTS Prlh signaling., Competing Interests: Declaration of competing interest MGM and DPO receive research support from AstraZeneca, Eli Lilly, and Novo Nordisk. MGM has served as a paid consultant for Merck and received honoraria from Novo Nordisk. RJS has received research support from Novo Nordisk, Fractyl, Astra Zeneca, Congruence Therapeutics, Eli Lilly, Bullfrog AI, Glycsend Therapeutics and Amgen. RJS has served as a paid consultant for Novo Nordisk, Eli Lilly, CinRx, Fractyl, Structure Therapeutics, Crinetics and Congruence Therapeutics. RJS has received honoraria from AstraZeneca. RJS has equity in Calibrate, Rewind and Levator Therapeutics. SO, JF, EB, DH and CJR are employees of AstraZeneca and hold stock in the company. The authors declare that they have no other conflicts of interest., (Copyright © 2025 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Objectives: Leptin acts via its receptor LepRb on specialized neurons in the brain to modulate food intake, energy expenditure, and body weight. LepRb activates signal transducers and activators of transcription (STATs, including STAT1, STAT3, and STAT5) to control gene expression., Methods: Because STAT3 is crucial for physiologic leptin action, we used TRAP-seq to examine gene expression in LepRb neurons of mice ablated for Stat3 in LepRb neurons (Stat3 LepRb KO mice), revealing the STAT3-dependent transcriptional targets of leptin. To understand roles for STAT proteins in leptin action, we also ablated STAT1 or STAT5 from LepRb neurons and expressed a constitutively-active STAT3 (CASTAT3) in LepRb neurons., Results: While we also found increased Stat1 expression and STAT1-mediated transcription of leptin-regulated genes in Stat3 LepRb KO mice, ablating Stat1 in LepRb neurons failed to alter energy balance (even on the Stat3 LepRb KO background); ablating Stat5 in LepRb neurons also failed to alter energy balance. Importantly, expression of a constitutively-active STAT3 (CASTAT3) in LepRb neurons decreased food intake and body weight and improved metabolic parameters in leptin-deficient (ob/ob) mice, as well as in wild-type animals., Conclusions: Thus, STAT3 represents the unique STAT protein required for leptin action and STAT3 suffices to mediate important components of leptin action in the absence of other LepRb signals., (Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Objective: To date, early developmental ablation of leptin receptor (LepRb) expression from circumscribed populations of hypothalamic neurons (e.g., arcuate nucleus (ARC) Pomc- or Agrp-expressing cells) has only minimally affected energy balance. In contrast, removal of LepRb from at least two large populations (expressing vGat or Nos1) spanning multiple hypothalamic regions produced profound obesity and metabolic dysfunction. Thus, we tested the notion that the total number of leptin-responsive hypothalamic neurons (rather than specific subsets of cells with a particular molecular or anatomical signature) subjected to early LepRb deletion might determine energy balance., Methods: We generated new mouse lines deleted for LepRb in ARC Ghrh Cre neurons or in Htr2c Cre neurons (representing roughly half of all hypothalamic LepRb neurons, distributed across many nuclei). We compared the phenotypes of these mice to previously-reported models lacking LepRb in Pomc, Agrp, vGat or Nos1 cells., Results: The early developmental deletion of LepRb from vGat or Nos1 neurons produced dramatic obesity, but deletion of LepRb from Pomc, Agrp, Ghrh, or Htr2c neurons minimally altered energy balance., Conclusions: Although early developmental deletion of LepRb from known populations of ARC neurons fails to substantially alter body weight, the minimal phenotype of mice lacking LepRb in Htr2c cells suggests that the phenotype that results from early developmental LepRb deficiency depends not simply upon the total number of leptin-responsive hypothalamic LepRb cells. Rather, specific populations of LepRb neurons must play particularly important roles in body energy homeostasis; these as yet unidentified LepRb cells likely reside in the DMH., (Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Objective: Leptin acts via its receptor (LepRb) on multiple subpopulations of LepRb neurons in the brain, each of which controls specific aspects of energy balance. Despite the importance of LepRb-containing neurons, the transcriptome and molecular identity of many LepRb subpopulations remain undefined due to the difficulty of studying the small fraction of total cells represented by LepRb neurons in heterogeneous brain regions. Here we sought to examine the transcriptome of LepRb neurons directly and identify markers for functionally relevant LepRb subsets., Methods: We isolated mRNA from mouse hypothalamic and brainstem LepRb cells by Translating Ribosome Affinity Purification (TRAP) and analyzed it by RNA-seq (TRAP-seq)., Results: TRAP mRNA from LepRb cells was enriched for markers of peptidergic neurons, while TRAP-depleted mRNA from non-LepRb cells was enriched for markers of glial and immune cells. Genes encoding secreted proteins that were enriched in hypothalamic and brainstem TRAP mRNA revealed subpopulations of LepRb neurons that contained neuropeptide-encoding genes (including prodynorphin, Pdyn) not previously used as functional markers for LepRb neurons. Furthermore, Pdyn (cre) -mediated ablation of Lepr (flox) in Pdyn-expressing neurons (LepRb (Pdyn) KO mice) blunted energy expenditure to promote obesity during high-fat feeding., Conclusions: TRAP-seq of CNS LepRb neurons defines the LepRb neuron transcriptome and reveals novel markers for previously unrecognized subpopulations of LepRb neurons.

Melanocortins and their receptors are critical components of energy homeostasis and the paraventricular nucleus of the hypothalamus (PVH) is an important site of melanocortin action. Although best known for its role in osmoregulation, arginine vasopressin (AVP) has been implicated in feeding and is robustly expressed in the PVH. Since the anorectic melanocortin agonist MTII activates PVH-AVP neurons, we hypothesized that PVH-AVP neurons contribute to PVH-mediated anorexia. To test this, we used an AVP-specific Cre-driver mouse in combination with viral vectors to acutely manipulate PVH-AVP neuron function. Using designer receptors exclusively activated by designer drugs (DREADDs) to control PVH-AVP neuron activity, we show that activation of PVH-AVP neurons acutely inhibits food intake, whereas their inhibition partially reverses melanocortin-induced anorexia. We further show that MTII fails to fully suppress feeding in mice with virally-induced PVH-AVP neuron ablation. Thus PVH-AVP neurons contribute to feeding behaviors, including the acute anorectic response to MTII.