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A Treadmill-Based Mouse Model for Investigating Hot Flashes with Continuous Skin Temperature Monitoring

Hot flashes significantly impair the quality of life in menopausal women, yet the underlying neural mechanisms and effective therapies remain poorly ...

Fudan University

The 5-hydroxytryptamine 2C receptor (5-HTR2C) is a class G protein-coupled receptor (GPCR) enriched in the hypothalamus and the brain stem, where it has been shown to regulate energy homeostasis, including feeding and glucose metabolism. Accordingly, 5-HTR2C has been the target of several anti-obesity drugs, though the associated side effects greatly curbed their clinical applications. Dissecting the specific neural circuits of 5-HTR2C-expressing neurons and the detailed molecular pathways of 5-HTR2C signaling in metabolic regulation will help to develop better therapeutic strategies towards metabolic disorders. In this review, we introduced the regulatory role of 5-HTR2C in feeding behavior and glucose metabolism, with particular focus on the molecular pathways, neural network, and its interaction with other metabolic hormones, such as leptin, ghrelin, insulin, and estrogens. Moreover, the latest progress in the clinical research on 5-HTR2C agonists was also discussed.

Central 5-HTR2C in the Control of Metabolic Homeostasis.

Calorie restriction (CR) and exercise training (EX) are two critical lifestyle interventions for the prevention and treatment of metabolic diseases, such as obesity and diabetes. Brown adipose tissue (BAT) and skeletal muscle are two important organs for the generation of heat. Here, we undertook detailed transcriptional profiling of these two thermogenic tissues from mice treated subjected to CR and/or EX. We found transcriptional reprogramming of BAT and skeletal muscle as a result of CR but little from EX. Consistent with this, CR induced alterations in the expression of genes encoding adipokines and myokines in BAT and skeletal muscle, respectively. Deconvolution analysis showed differences in the subpopulations of myogenic cells, mesothelial cells and endogenic cells in BAT and in the subpopulations of satellite cells, immune cells and endothelial cells in skeletal muscle as a result of CR or EX. NicheNet analysis, exploring potential inter-organ communication, indicated that BAT and skeletal muscle could mutually regulate their fatty acid metabolism and thermogenesis through ligands and receptors. These data comprise an extensive resource for the study of thermogenic tissue molecular responses to CR and/or EX in a healthy state.

Transcriptomics Dissection of Calorie Restriction and Exercise Training in Brown Adipose Tissue and Skeletal Muscle.

β cells are defined by the ability to produce and secret insulin. Recent studies have evaluated that human pancreatic β cells are heterogeneous and demonstrated the transcript alterations of β cell subpopulation in diabetes. Single-cell RNA sequence (scRNA-seq) analysis helps us to refine the cell types signatures and understand the role of the β cells during metabolic challenges and diseases. Here, we construct the pseudotime trajectory of β cells from publicly available scRNA-seq data in health and type 2 diabetes (T2D) based on highly dispersed and highly expressed genes using Monocle2. We identified three major states including 1) Normal branch, 2) Obesity-like branch and 3) T2D-like branch based on biomarker genes and genes that give rise to bifurcation in the trajectory. β cell function-maintain-related genes, insulin expression-related genes, and T2D-related genes enriched in three branches, respectively. Continuous pseudotime spectrum might suggest that β cells transition among different states. The application of pseudotime analysis is conducted to clarify the different cell states, providing novel insights into the pathology of β cells in T2D.

Pseudotime Ordering Single-Cell Transcriptomic of β Cells Pancreatic Islets in Health and Type 2 Diabetes.

General anesthesia (GA) is an unconscious state produced by anesthetic drugs, which act on neurons to cause overall suppression of neuronal activity in the brain. Recent studies have revealed that GA also substantially enhances the dynamics of microglia, the primary brain immune cells, with increased process motility and territory surveillance. However, whether microglia are actively involved in GA modulation remains unknown. Here, we report a previously unrecognized role for microglia engaging in multiple GA processes. We found that microglial ablation reduced the sensitivity of mice to anesthetics and substantially shortened duration of loss of righting reflex (LORR) or unconsciousness induced by multiple anesthetics, thereby promoting earlier emergence from GA. Microglial repopulation restored the regular anesthetic recovery, and chemogenetic activation of microglia prolonged the duration of LORR. In addition, anesthesia-accompanying analgesia and hypothermia were also attenuated after microglial depletion. Single-cell RNA sequencing analyses showed that anesthesia prominently affected the transcriptional levels of chemotaxis and migration-related genes in microglia. By pharmacologically targeting different microglial motility pathways, we found that blocking P2Y receptor (P2YR) reduced the duration of LORR of mice. Moreover, genetic ablation of P2YR in microglia also promoted quicker recovery in mice from anesthesia, verifying the importance of microglial P2YR in anesthetic regulation. Our work presents the first evidence that microglia actively participate in multiple processes of GA through P2YR-mediated signaling and expands the non-immune roles of microglia in the brain.

Microglia modulate general anesthesia through P2Y receptor.

Periodontitis, a prevalent chronic inflammatory disease, profoundly impacts both quality of life and overall health. Clinical studies have suggested a correlation between periodontitis and sleep deficiency, but the underlying mechanisms involved remain elusive. Here, we observed an elevated risk of periodontitis in individuals with sleep deficiency, as demonstrated in both clinical subjects and mouse models. Retrograde tracing from the periodontium revealed a neural connection from trigeminal TRPV1 neurons, which may mediate the aggravating effects of sleep deficiency on periodontitis. The ablation of TRPV1 neurons effectively mitigated the aggravating effects of sleep deficiency on periodontitis. Under periodontitis, sleep restriction increased the secretion of substance P from trigeminal neurons in the periodontium, enhancing vasodilation and vascular permeability, which in turn promoted the infiltration of proinflammatory immune cells. Blocking substance P signaling via a Neurokinin-1 receptor antagonist or knocking down Tacr1 in vascular endothelial cells alleviated these detrimental effects. Our findings unveil a critical neuron-vessel-immune axis that exacerbates periodontitis during sleep deficiency and suggest potential therapeutic strategies targeting this axis for managing periodontitis in individuals suffering from sleep deficiency.

Article	Year
Central 5-HTR2C in the Control of Metabolic Homeostasis. Frontiers in endocrinology\| PubMed ID: 34367066	2021
Transcriptomics Dissection of Calorie Restriction and Exercise Training in Brown Adipose Tissue and Skeletal Muscle. Nutrients\| PubMed ID: 36839405	2023
Pseudotime Ordering Single-Cell Transcriptomic of β Cells Pancreatic Islets in Health and Type 2 Diabetes. Phenomics (Cham, Switzerland)\| PubMed ID: 36939754	2021
Microglia modulate general anesthesia through P2Y receptor. Current biology : CB\| PubMed ID: 37167975	2023
Sleep deficiency exacerbates periodontal inflammation via trigeminal TRPV1 neurons. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 40489620	2025

Zhicheng Cui

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