Biology subjects

Holt, M. K.

Publications and source records attributed to Holt, M. K..

4 recordsLinked to original sources

bioRxiv2025

Brainstem GLP-1 neurons modulate physiological satiation and drive sustained weight loss in obese mice

Glucagon-like peptide-1 receptor (GLP-1R) activation in the brain strongly reduces appetite, but most brain GLP-1Rs are not accessible for systemically administered GLP-1R agonists. Acute activation of nucleus tractus solitarius (NTS) GLP-1 neurons, targeting brain GLP-1Rs, strongly suppresses food intake separate from GLP-1R agonists. However, it is unknown if their chronic stimulation is a viable strategy for appetite suppression, or if obesity disrupts their function. Here we demonstrate that GLP-1 neurons, distributed through NTS and IRT, determine meal size and their number is inversely correlated with bodyweight gain. GLP-1 neurons in IRT and NTS differ in their inputs but generate outputs in largely overlapping areas. Higher body weight and fat mass predicts a higher percentage of active GLP-1 neurons. Their chemogenetic activation is an efficient means of reducing food intake, and in obese mice chronic activation elicits sustained weight loss. In conclusion, GLP-1 neurons are a feasible target for obesity treatment.

neuroscience↗

bioRxiv2023

A neuronal circuit driven by GLP-1 in the olfactory bulb regulates insulin secretion

Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We demonstrate that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an 2-adrenergic receptor agonist, highlighting the functional implication of the sympathetic nervous system (SNS). Inhibiting GABAA receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. These findings identify a novel top-down neural mechanism engaged by OB GLP-1 signaling to control insulin secretion via the SNS.

physiology↗

bioRxiv2022

Modulation of stress-related behaviour by hypothalamic engagement of preproglucagon neurons in the nucleus of the solitary tract

Stress-induced behaviours are driven by complex neural circuits and some neuronal populations concurrently modulate diverse behavioural and physiological responses to stress. Glucagon-like peptide-1 (GLP1)-producing preproglucagon (PPG) neurons within the lower brainstem caudal nucleus of the solitary tract (cNTS) are particularly sensitive to stressful stimuli and are implicated in multiple physiological and behavioural responses to interoceptive and psychogenic threats. However, the afferent inputs driving stress-induced activation of PPG neurons are largely unknown, and the role of PPG neurons in anxiety-like behaviour is controversial. Through chemogenetic manipulations we reveal that cNTS PPG neurons have the ability to moderately increase anxiety-like behaviours in mice in a sex-dependent manner. Using an intersectional approach, we show that a corticotropin-releasing hormone (CRH)-rich input from the paraventricular nucleus of the hypothalamus (PVN) drives activation of both the cNTS as a whole and PPG neurons in particular in response to acute stress. Finally, we demonstrate that NTS-projecting PVN neurons are necessary for the ability of acute stress to suppress food intake. Our findings reveal sex differences in behavioural responses to PPG neural activation and highlight a hypothalamic-brainstem pathway in stress-induced hypophagia.

neuroscience↗

bioRxiv2020

Central and peripheral GLP-1 systems independently and additively suppress eating

The anorexigenic peptide glucagon-like peptide-1 (GLP-1) is secreted from gut enteroendocrine cells and brain preproglucagon (PPG) neurons, which respectively define the peripheral and central GLP-1 systems. As peripheral satiation signals are integrated in the nucleus tractus solitarius (NTS), PPGNTS neurons are assumed to link the peripheral and central GLP-1 systems, forming a unified GLP-1 gut-brain satiation circuit. This hypothesis, however, remains unsubstantiated. We report that PPGNTS neurons encode satiation in mice, consistent with vagal gastrointestinal distension signalling. However, PPGNTS neurons predominantly receive vagal input from oxytocin receptor-expressing vagal neurons, rather than those expressing GLP-1 receptors. Furthermore, PPGNTS neurons are not necessary for eating suppression induced by the GLP-1 receptor agonists liraglutide or semaglutide, and semaglutide and PPGNTS neuron activation additively suppress eating. Central and peripheral GLP-1 systems thus suppress eating via independent gut-brain circuits, hence PPGNTS neurons represent a rational pharmacological target for anti-obesity combination therapy with GLP-1 receptor agonists. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/234427v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1c7643aorg.highwire.dtl.DTLVardef@18520daorg.highwire.dtl.DTLVardef@12fc8fdorg.highwire.dtl.DTLVardef@34809b_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract: C_FIG

neuroscience↗