Biology subjects

Heyward, F. D.

Publications and source records attributed to Heyward, F. D..

3 recordsLinked to original sources

bioRxiv2025

Single-nucleus transcriptional and chromatin accessibility profiling of mouse hypothalamic LepRb neurons reveals cell type-specific cis-regulatory elements linked to human obesity

Leptin receptor-expressing hypothalamic neurons (LepRHypo) are key regulators of energy balance, yet a comprehensive, cell type-resolved, chromatin accessibility map of these neurons is lacking. We profiled [~]20,000 LepRHypo nuclei using single-nucleus multiome (snRNA-seq/snATAC-seq), identifying 39 transcriptionally and epigenetically distinct clusters, including AgRP (two subtypes), Pomc (two subtypes), Foxb1, Irx5/3 (three subtypes), Nts, PNOC (two subtypes), Kiss1/Pdyn (KNDy, two subtypes), Ghrh, Tcf7l2, and Sf1/Nr5a1 (three subtypes) populations. We also identified three Glp1r-expressing clusters with the highest Lepr enrichment, each marked by distinct molecular signatures. Cluster-specific open chromatin regions (OCRs) delineated putative cis-regulatory elements unique to each LepRHypo subtype. Mouse cell-type specific OCRs conserved in the human genome were identified; a subset were proximal to genes with high Human Genetic Evidence (HuGE) scores for obesity-related traits, overlapped obesity-associated GWAS loci, and/or coincided with eQTLs, including variants with the potential to influence human energy balance. Together, these data provide cell type-specific cis-regulatory atlas of LepRHypo neuronal subtypes, including Glp1r/Lepr-enriched populations, and highlight evolutionarily conserved, subtype-specific regulatory elements, associated candidate genes, and putative functional variants that may modulate LepRHypo subtype function and influence energy homeostasis and obesity susceptibility in humans.

neuroscience↗

bioRxiv2024

Evidence of persistent hyperphagia following a dietary weight-loss intervention in mice

ObjectiveThis study sought to determine whether the drive to regain weight following weight loss was truly long-lived in mice. MethodsWe generated a model of reduced dietary obesity (ReDO) whereby male mice with diet-induced obesity (DIO) mice were calorically restricted until weight matched to control mice, and then after a 24-hour food assessment period were pair-fed relative to control mice. We subsequently generated ReDO mice that, after CR were pair-fed relative to control mice for 0, 8, or 28 days, or chronically. Body weight, food intake, and select metabolic parameters were measured, along with whole hypothalamic Pomc gene expression. ResultsReDO mice in both experiments exhibited hyperphagia following CR, while a persistent form of hyperphagia was detected in ReDO_8d and ReDO_28d mice relative to control and chronically pair-fed mice. 4-week initial weight gain was predictive of the degree of weight regain across ReDO_8 and ReDO_28 mice. ConclusionsReDO mice exhibit a long-lived form of hyperphagia and an apparent drive to reclaim an upwardly shifted body weight set point. There was considerable variability with regard to ReDO_8 and ReDO_28 body weight regain which was correlated with the of initial degree of 4-week body-weight gain when first exposed to a high-fat diet. This study showcases the perdurance of weight loss-associated hyperphagia and introduces a prognostic tool for identifying mice that are prone towards weight regain, while setting the stage for future inquiries into the neurobiological basis of persistent hunger following weight loss owed to a dietary intervention in mice.

physiology↗

bioRxiv2022

Integrated genomic analysis of AgRP neurons reveals that IRF3 regulates leptin's hunger-suppressing effects

AgRP neurons in the arcuate nucleus of the hypothalamus (ARC) coordinate homeostatic changes in appetite associated with fluctuations in food availability and leptin signaling. Identifying the relevant transcriptional regulatory pathways in these neurons has been a priority, yet such attempts have been stymied due to their low abundance and the rich cellular diversity of the ARC. Here we generated AgRP neuron-specific transcriptomic and chromatin accessibility profiles during opposing states of fasting-induced hunger and leptin-induced hunger suppression. Cis-regulatory analysis of these integrated datasets enabled the identification of 28 putative hunger-promoting and 29 putative hunger-suppressing transcriptional regulators in AgRP neurons, 16 of which were predicted to be transcriptional effectors of leptin. Within our dataset, Interferon regulatory factor 3 (IRF3) emerged as a leading candidate mediator of leptin-induced hunger-suppression. Gain- and loss-of-function experiments in vivo confirm the role of IRF3 in mediating the acute satiety-evoking effects of leptin in AgRP neurons, while live-cell imaging in vitro indicate that leptin can activate neuronal IRF3 in a cell autonomous manner. Finally, we employ CUT&RUN to uncover direct transcriptional targets of IRF3 in AgRP neurons in vivo. Thus, our findings identify AgRP neuron-expressed IRF3 as a key transcriptional effector of the hunger-suppressing effects of leptin.

neuroscience↗