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Hypothalamic GHS-R1a-mediated neural-metabolic mechanisms of peripheral brown adipose tissue thermogenesis and prospects for rehabilitation medicine translation

neuroscience
internal-medicine
neurology
obesity
rehabilitation

Abstract

The growth hormone secretagogue receptor 1a (GHS-R1a) serves as a pivotal regulator of brown adipose tissue (BAT) thermogenesis by orchestrating crosstalk between central nervous system (CNS) signaling and peripheral metabolic processes. Activation of the ghrelin-GHS-R1a signaling axis stimulates hypothalamic AgRP/NPY neurons, which project via the nucleus tractus solitarius (NTS) in the brainstem to the intermediolateral column (IML) of the spinal cord. This pathway amplifies norepinephrine release from sympathetic postganglionic fibers, thereby activating BAT lipolysis and thermogenesis through β3-adrenergic receptor (β3-AR)-mediated mechanisms. Concurrently, GHS-R1a dynamically integrates multiple signaling inputs to calibrate thermogenic intensity in response to fluctuating energy demands. Capitalizing on the neuromodulatory properties of GHS-R1a, non-invasive neurostimulation techniques—including transcranial magnetic stimulation (TMS) and transcutaneous vagus nerve stimulation (tVNS)—alongside physical interventions (e.g., cold exposure, infrared therapy) and exercise training and other rehabilitation treatments, synergistically enhance sympathetic-BAT axis output. These modalities potentiate BAT thermogenic activity, offering therapeutic potential to ameliorate insulin resistance and obesity-associated metabolic dysregulation. This review systematically elucidates the mechanistic underpinnings of the GHS-R1a-mediated neuro-BAT regulatory axis, advancing a framework for precision rehabilitation strategies targeting metabolic disorders and establishing a robust theoretical foundation for clinical interventions. This article will serve as a key resource for interdisciplinary scholars and clinicians dedicated to hypothalamic control of energy balance and BAT thermogenesis—and to forging these insights into transformative, non-pharmacological therapeutics for rehabilitation medicine.
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