Biology subjects

Shiao, R.

Publications and source records attributed to Shiao, R..

5 recordsLinked to original sources

bioRxiv2026

Single-cell multi-omics identify OTP and NOVA1 as regulators of leptin action in hypothalamic feeding circuits

Leptin acts directly and indirectly on multiple neuronal populations to regulate feeding and numerous other physiologic functions. However, our understanding of how a single circulating signal coordinates diverse neuronal populations across multiple circuits is limited. To further elucidate how leptin reshapes molecular states in its direct and indirect neural targets, we combined time-resolved single-nucleus transcriptomics and chromatin accessibility profiling to map leptin-induced transcriptional and chromatin state changes across individual neurons in two key hypothalamic nuclei: the arcuate nucleus (ARC), which contains the majority of leptin receptor (LepR) neurons, and the paraventricular hypothalamic nucleus (PVH), an established downstream target of ARC LepR neurons. We found that leptin treatment of leptin-deficient ob/ob mice does not alter neuronal identity, but instead induces coordinated, cell-type-specific transcriptional and regulatory state changes that propagate hierarchically from the ARC to downstream PVH neurons. Integrating RNA velocity, cis-regulatory analysis, and cell-cell communication inference revealed that leptin modulates hypothalamic circuit architecture by selectively strengthening specific interactions while pruning broadly distributed, low-specificity signaling. Although leptin broadly activated STAT3 signaling across LepR neuronal subtypes, integrated multi-omic analyses revealed that activation of STAT3 engages distinct downstream regulatory programs in different neuronal populations, often with opposing physiological functions. Functional analyses identified the homeobox transcription factor OTP, a leptin-responsive regulator selectively induced in AGRP neurons, as a critical mediator of leptin-mediated inhibition of hunger-promoting AGRP neuronal activity and feeding. In parallel, unbiased analysis of PVH neuronal state transitions shows that NOVA1, an RNA-binding protein primarily expressed in inhibitory neurons, is regulated by leptin and alterations of NOVA1 expression bidirectionally control food intake and body weight. Together, these findings define a multi-layered regulatory framework through which leptin regulates hypothalamic feeding circuits to control energy balance.

neuroscience↗

bioRxiv2026

Lipid mobilization establishes metabolic tolerance and prevents autonomic collapse in infection

Survival during infection depends on both pathogen clearance and the ability to tolerate infection-induced physiological changes. Metabolic adaptations are a central component of this tolerance, but the mechanisms underlying these responses remain incompletely defined. Here, we identify white adipose tissue (WAT) lipolysis as a central regulator of metabolic tolerance to infection. In patients with sepsis, higher circulating non-esterified fatty acid (NEFA) levels were associated with reduced mortality. In mouse models of polymicrobial sepsis, infection induced robust adipose lipolysis and increased circulating NEFAs. Genetic ablation of adipose triglyceride lipase (ATGL) in adipose tissue impaired lipolysis, leading to hypothermia, bradycardia, and increased mortality without altering immune cell populations or pathogen burden, consistent with a defect in tolerance rather than resistance. Mechanistically, lipolysis-derived NEFAs, but not glycerol, were required for protection, as restoring circulating NEFAs rescued autonomic stability and survival in adipose tissue ATGL-deficient mice. Infection-induced lipolysis was redundantly regulated and did not depend on any single upstream signaling pathway. Both pharmacologic activation of lipolysis using a {beta}3-adrenergic agonist and exogenous fatty acid supplementation increased circulating NEFAs, improved survival, and promoted tolerance in mice. Consistent with these findings, analysis of real-world electronic health record data demonstrated that septic patients receiving FDA-approved {beta}3-adrenergic agonists had reduced mortality or hospice discharge in a propensity-matched cohort. Together, these results identify WAT lipolysis and circulating fatty acids as key mediators of tolerance to infection and support a therapeutic strategy based on repurposing clinically available {beta}3-adrenergic agonists to improve outcomes in sepsis. One Sentence SummaryWhite adipose tissue lipolysis promotes metabolic tolerance to infection through circulating fatty acids and is associated with improved survival in sepsis

physiology↗

bioRxiv2022

Corticothalamic Neurons in Motor Cortex Have a Permissive Role in Motor Execution

The primary motor cortex (M1) is a central hub for motor learning and execution. M1 is composed of heterogeneous cell types, many exhibiting varying relationships to movement. Here, we employed an unbiased screen to tag active neurons at different stages of performance of a motor task. We characterized the relative cell type composition of active neurons across training and identified one cell type consistently enriched as training progressed: corticothalamic neurons (M1CT). Using two-photon calcium imaging, we found that M1CT activity is largely suppressed during movement, and this negative correlation with movement scales with movement vigor and augments with training. Closed-loop optogenetic manipulation of this population revealed that increasing M1CT activity during forelimb movement significantly hinders execution, an effect that became stronger with training. Similar optogenetic manipulations, however, had little effect on locomotion. In contrast to M1CT neurons, we observed that M1 corticospinal neurons positively correlate with movement, and that this positive correlation increases with learning. Finally, by examining the connectivity between M1CT and corticospinal neurons, we uncovered that M1CT neurons can suppress M1 corticospinal activity via feedforward inhibition, and that this inhibition scales with training. These results identify a novel permissive role of corticothalamic neurons in movement execution through suppression of inhibition of corticospinal neurons.

neuroscience↗

bioRxiv2022

Microbiota-stimulated Interleukin-22 regulates brain neurons and protects against stress-induced anxiety

Psychological stress and its sequelae are a major public health problem. While the immune system has been implicated in the development of stress-related disorders, how the immune signals modulate neural responses to stress is poorly understood. Contrary to our expectations, we found that the immune cytokine Interleukin (IL)-22 is the key mediator of an immune-to-brain pathway that diminishes, rather than amplifies, stress-induced anxiety. We showed that stress induced TH17 differentiation and IL-22 production in the intestine following barrier dysfunction and microbiota stimulation. IL-22 then directly signaled to septal neurons in the brain to mitigate anxiety-like behavior. Accordingly, mice treated with exogenous IL-22 showed resilience to chronic stress-induced anxiety disorders. Our study thus reveals a previously-unappreciated immune-to-brain axis that defends against psychological stress, suggesting a potential intervention strategy for stress-related mental diseases.

immunology↗

bioRxiv2020

Targeted millisecond-scale activation of cells using non-invasive Sonogenetics

Ultrasound has been used to non-invasively manipulate neuronal functions in humans and other animals1-4. However, this approach is limited as it has been challenging to target specific cells within the brain or body5-8. Here, we identify human Transient Receptor Potential A1 (hsTRPA1) as a candidate that confers ultrasound sensitivity to mammalian cells. Ultrasound-evoked gating of hsTRPA1 specifically requires its N-terminal tip region and cholesterol interactions; and target cells with an intact actin cytoskeleton, revealing elements of the sonogenetic mechanism. Next, we use calcium imaging and electrophysiology to show that hsTRPA1 potentiates ultrasound-evoked responses in primary neurons. Furthermore, unilateral expression of hsTRPA1 in mouse layer V motor cortical neurons leads to c-fos expression and contralateral limb responses in response to ultrasound delivered through an intact skull. Collectively, we demonstrate that hsTRPA1-based sonogenetics can effectively manipulate neurons within the intact mammalian brain, a method that could be used across species.

neuroscience↗