Biology subjects

Murphy, K. G.

Publications and source records attributed to Murphy, K. G..

5 recordsLinked to original sources

bioRxiv2025

The microbial tryptophan metabolite indole acts on the gastrointestinal tract to improve glucose homeostasis by enhancing GLP-1 secretion and L-cell differentiation

Aims/hypothesisGrowing evidence implicates gut microbiota-derived metabolites in metabolic homeostasis. Indole, a microbial tryptophan metabolite, has been reported to enhance Glucagon-like peptide-1 (GLP-1) secretion in vitro, and its derivatives have been inversely associated with risk of type 2 diabetes (T2D). We hypothesised that indole acts via the gastrointestinal tract to modulate glucose homeostasis, and aimed to test this hypothesis using in vitro and in vivo models. MethodsThe acute effects of indole on GLP-1 secretion in vitro, and on glucose tolerance and hormone secretion in mice, were determined. Subsequently, the effects of indole on intestinal epithelial cell fate and L-cell differentiation in murine ileal organoids and in vivo were studied. Finally, the utility of chronic indole administration in a murine model of T2D was explored. ResultsIndole stimulated in vitro GLP-1 secretion in a concentration-dependent manner, and improved acute glucose control in vivo. Additionally, we demonstrate that indole drives enteroendocrine L-cell differentiation in murine ileal organoids, resulting in increased L-cell density and longer-term glucoregulatory benefits in vivo. Finally, sub-chronic indole administration improved glucose tolerance and insulin sensitivity in diabetic mice. Conclusions/interpretationOur findings identify indole as an anti-diabetic molecule that acts on the gut, and raise the possibility of incorporating indole into nutraceutical supplements to aid in the treatment or prevention of T2D. This highlights the importance of gut microbiota-derived metabolites in metabolic health and opens new avenues for developing novel strategies to combat T2D. Research in ContextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIGut microbiota-derived metabolites play a role in metabolic homeostasis. C_LIO_LIIndole, a microbial tryptophan metabolite, enhances GLP-1 secretion in vitro. C_LIO_LIIndole derivatives are inversely associated with type 2 diabetes (T2D) risk. C_LI What is the key question?O_LIDoes indole act on the gut to modulate glucose homeostasis? C_LI What are the new findings?O_LIIndole stimulates GLP-1 secretion and improves acute glucose control in vivo. C_LIO_LIIndole drives enteroendocrine L-cell differentiation in murine ileal organoids, increasing L-cell density and long-term glucoregulatory benefits. C_LIO_LISub-chronic indole administration improves glucose tolerance and insulin sensitivity in mice with type 2 diabetes, showing the potential of gut microbiota-derived metabolites as therapeutic targets. C_LI How might this impact clinical practice in the foreseeable future?O_LIIndole could be incorporated into nutraceutical supplements for T2D prevention or treatment. C_LI

physiology↗

bioRxiv2025

Extracellular Ca2+-Sensing Receptor (CaSR) Regulates Hypothalamic Function to Control Energy and Skeletal Metabolism in Mice

Introductory paragraphThe extracellular Calcium-sensing receptor (CaSR) regulates cellular responsiveness to physiological changes in ionized calcium (Ca2+) concentrations. The CaSR is expressed in the brain, including in hypothalamic growth hormone stimulating GHRH and anorectic POMC neurons that control growth and energy homeostasis. We embryonically deleted the Casr gene in neurons to create NeuronCaSR-/- mice to delineate the role of this receptor in regulating growth, skeletal development, and energy metabolism. NeuronCaSR-/- mice had reduced size, weight and bone mass compared to littermate controls, with a dysregulated growth hormone axis. They also showed increased adiposity and circulating leptin levels, leptin resistance, and decreased glucose tolerance, along with reduced expression of the anorectic precursor peptide POMC and secondary increases in the expression of the anorectic peptide AgRP in the hypothalamus of NeuronCaSR-/- mice. Knockdown of CaSR in adult mice specifically in the hypothalamic arcuate nucleus, where GHRH, POMC and AgRP neurons reside, also resulted in increased body weight, adiposity, leptin resistance, and glucose intolerance, and reduced bone mass. Together these data suggest that neuronal CaSR critically regulates energy and skeletal metabolism and body growth by modulating hypothalamic function, representing a new paradigm for central integration of calcaemic activities with body function.

physiology↗

bioRxiv2025

Enteropancreatic neurons drive the glucoregulatory response to ingested lipid

Enteropancreatic neurons project from the small intestinal wall to the pancreas. Though well positioned to mediate the effects of ingested nutrients on pancreatic function, the metabolic role of these neurons is unclear. Diets rich in olive oil promote weight loss and improve remission rates in patients with T2DM. Here, we show that olive oil improves acute glucose tolerance by stimulating insulin release via neurotensin receptor type 1 (NTSR1)-expressing enteropancreatic neurons. These neurons are necessary for the effects of olive and neurotensin on glucose tolerance, and their activation is sufficient to improve glucose tolerance. These findings suggest a mechanism by which dietary olive oil regulates blood glucose levels and present a novel functional role for enteropancreatic neurons in regulating glucose homeostasis.

physiology↗

bioRxiv2024

Mapping the druggable targets displayed by human colonic enteroendocrine cells

Enteroendocrine cells (EECs) are specialized intestinal hormone-secreting cells that play critical roles in metabolic homeostasis, digestion, and gut-brain communication. They detect diverse stimuli including endocrine, immune, neuronal, microbial, and dietary signals, through a complex array of receptors, ion channels, and transporters, to modulate the release of over 20 hormones. These molecular sensors serve as potential drug targets to modulate hormone secretion, but until recently, catalogues of such targets in human colonic EECs have not been produced. To address this gap, we performed bulk and single-cell RNA sequencing on fluorescently labelled EECs isolated from human colonic organoids, identifying and cataloguing potential druggable targets. This catalogue includes receptors, orphan GPCRs, transporters, and hormones not previously reported in human colonic EECs. Comparison with murine EECs highlighted interspecies similarities and differences, key data to facilitate the design and optimise the predictive accuracy of pre-clinical models. We also functionally validated two receptors not previously identified in human EECs: IL-13R1, was expressed in both peptide-producing EECs and serotonin producing Enterochromaffin cells (ECs), and its ligand IL-13 stimulated the secretion of glucagon-like peptide-1 (GLP-1) and serotonin measured in real-time, and GPR173, which was selectively expressed in ECs and, when activated by its agonist Phoenixin-20, also promoted serotonin release. These analyses provide a valuable resource for therapeutic interventions aimed at modulating gut hormone secretion, with potential applications in treating gastrointestinal, metabolic, and other related disorders.

cell biology↗

bioRxiv2019

Interpreting, forecasting, and controlling feeding behaviour using high-resolution data

Better understanding of feeding behaviour will be vital in reducing obesity and metabolic syndrome, but we lack a standard model that captures the complexity of feeding behaviour. We construct an accurate stochastic model of rodent feeding at the bout level in order to perform quantitative behavioural analysis. Analysing the different effects on feeding behaviour of PYY3-36, lithium chloride, GLP-1 and leptin shows the precise behavioural changes caused by each anorectic agent. Our analysis demonstrates that the changes in feeding behaviour evoked by the anorectic agents investigated not mimic satiety. In the ad libitum fed state during the light period, meal initiation is governed by complete stomach emptying, whereas in all other conditions there is a graduated response. We show how robust homeostatic control of feeding thwarts attempts to reduce food intake, and how this might be overcome. In silico experiments suggest that introducing a minimum intermeal interval or modulating gastric emptying can be as effective as anorectic drug administration.

animal behavior and cognition↗