The intestinal epithelium is scattered with enteroendocrine cells (EECs), which, although only accounting for less than 1% of this tissue, can be considered the biggest endocrine organ in the body. Some of the peptides secreted have important regulatory roles for metabolism; glucagon-like peptide-1 (GLP-1) for example boosts postprandial insulin secretion and is the basis for mimetics with improved plasma half-life now widely used in the treatment of diabetes and obesity. GLP-1 and the co-secreted polypeptide YY also reduce food intake, and elevated plasma levels of these hormones correlate with the positive effects of gastric bypass surgery for the treatment of obesity.
Our lab, which works in close collaboration with Fiona Gribble’s group, has made a number of transgenic mice in which cells expressing specific hormones are tagged by fluorescent reporters or Cre-recombinase, allowing identification and/or manipulation of EEC-subsets. We have established intestinal organoids – intestinal epithelial stem cells giving rise to all derived cells including EECs in vitro – from different intestinal sections from these mice and similar organoids derived from human intestinal tissue have been edited by CRISPR/Cas9 to express fluorescent indicators for Ca2+ or cAMP in specific EE-subsets. We use electrophysiological and live-cell imaging techniques to identify the mechanisms underlying the secretion of GLP-1, glucose-dependent insulinotropic peptide (GIP) and other hormones, with the aim eventually to manipulate their release therapeutically for the treatment of diabetes and obesity. We are developing LC-MS/MS based methods for simultaneous and sensitive detection of gut hormones in biological matrices, which we hope will extend our understanding of integrated EEC-responses to different nutrient challenges and changes associated with disease. To better understand the targets recruited by these gut hormones we have made mice expressing Cre-recombinase under control of the promoters of the receptors for some of the secreted peptides, e.g. GLP1R, GIPR and Rxfp4, the receptor for insulin-like peptide-5 (Insl5), which is co-secreted with GLP-1 in the distal colon.
One arm of the lab focuses on the expression of these receptors in several different nuclei of the central nervous system regulating food intake behaviour and energy homeostasis. We use chemogenetic/optogenetic activity modulation of receptor expressing cells combined with operant chamber or calorimetric assessment. Viral tracing is used to map the neuronal circuitry engaged by enteroendocrine hormones, often also released from specific subsets of neurons, and in vivo assessment is complemented by live cell imaging in acute brain slices.
Foreman RE, Miedzybrodzka EL, Eiriksson FF, Thorsteinsdottir M, Bannon C, Wheller R, *Reimann F, * Gribble FM, *Kay RG (2023) An optimised LC-MS/MS method for the detection of ppCCK(21-44) – a surrogate to monitor human cholecystokinin secretion. J Proteome Res. 2023 Aug 17. doi 10.1021/acs.jproteome.3c00272. Online ahead of print. PMID: 37591880 (*joint corresponding)
*Adriaenssens A, Broichhagen J, de Bray A, Ast J, Hasib A, Jones B, Tomas A, Figueredo Burgos N, Woodward O, Lewis J, O’Flaherty Rottenberger E, El K, Cui C, Harad N, Inagaki N, Campbell J, Brierley D, Hodson D, Samms R, *Gribble F, *Reimann F (2023) Glucose-dependent insulinotropic polypeptide receptor (GIPR)-expressing nuerons in the hypothalamus and the dorsal vagal complex employ distinct mechanisms to affect feeding behaviour. JCI Insight. 2023;8(10):e164921. https://doi.org/10.1172/jci.insight.164921. PMID: 37212283 PMCID: PMC10322681 (*joint corresponding)
*Lewis JE, Woodward ORM, Nuzzaci D, Smith CA, Adriaenssens AE, Billing L, Brighton C, Phillips BU, Tadross JA, Kinston SJ, Ciabatti E, Göttgens B, Tripodi M, Hornigold D, David Baker D, *Gribble FM, *Reimann F (2022) Relaxin/insulin-like family peptide receptor 4 (Rxfp4) expressing hypothalamic neurons modulate food intake and preference in mice. Mol Metab 2022 Sep 30;66:101604. doi: 10.1016/j.molmet.2022.101604. Online ahead of print. PMID: 36184065 PMCID: PMC9579047 (* joint corresponding)
Miedzybrodzka EL, Foreman RE, Lu VB, George AL, Smith CA, Larraufie P, Kay RG, Goldspink DA, *Reimann F, *Gribble FM (2021) Stimulation of motilin secretion by bile, free fatty acids and acidification in human duodenal organoids. Mol Metab. 2021 Oct 15;54:101356. doi: 10.1016/j.molmet.2021.101356. Online ahead of print. PMID: 34662713 PMCID: PMC8590067 (* joint corresponding)
Goldspink DA, Lu VB, Miedzybrodzka EL, Smith CA, Foreman RE, Billing LJ, Kay RG, *Reimann F, *Gribble FM (2020) Labelling and characterization of human GLP-1 secreting L-cells in primary ileal organoid culture. Cell Rep. 2020 Jun 30;31(13):107833. doi: 10.1016/j.celrep.2020.107833. PMID: 32610134 PMCID: PMC7342002 (* joint corresponding)
Billing JL, Larraufie P, Lewis J, Leiter A, Li J, Lam B, Yeo GSH, Goldspink DA, Kay RG, Gribble FM*, Reimann F* (2019) Single cell transcriptomic profiling of large intestinal enteroendocrine cells in mice – identification of selective stimuli for Insulin-like peptide-5 and Glucagon-like peptide-1 co-expressing cells. Mol Metab. 2019 Nov;29:158-169. PMID: 31668387. PMCID: PMC6812004 (* joint corresponding)
Adriaenssens AE, Biggs EK, Darwish T, Tadross J, Sukthankar T, Girish M, Polex-Wolf J, Lam BY, Zvetkova I, Pan W, Chiarugi D, Yeo GSH, Blouet C, Gribble FM*, Reimann F* (2019) Glucose-dependent insulinotropic polypeptide receptor-expressing cells in the hypothalamus regulate food intake. Cell Metab. 30(5):987-996 PMID:31447324, PMCID: PMC6838660 (* joint corresponding)
Lu VB, Rievaj J, O’Flaherty EA, Smith CA, Pais R, Pattison LA, Tolhurst G, Leiter AB, Bulmer DC, *Gribble FM, *Reimann F (2019) Adenosine triphosphate is co-secreted with glucagon-like peptide-1 to modulate intestinal enterocytes and afferent neurons. Nat Commun. 2019 Mar 4;10(1):1029. doi: 10.1038/s41467-019-09045-9.PMID: 30833673 PMCID: PMC6399286 (* joint corresponding)
Larraufie P, Roberts GP, McGavigan A, Kay RG, Li J, Leiter A, Melvin A, Biggs EK, Ravn P, Davy K, Hornigold D, Yeo G, Hardwick RH, Reimann F*, Gribble FM* (2019) Important role of the GLP-1 axis for glucose homeostasis after bariatric surgery. Cell Rep. 2019 Feb 5;26(6):1399-1408 PMID:30726726 PMCID: PMC6367566 (* joint corresponding)
* Roberts GP, Larraufie P, Richards P, G Kay RG, Galvin SG, Miedzybrodzka EL, Leiter A, Li HJ, Glass LL, Ma MKL, Lam B, Yeo GSH, Scharfmann R, Chiarugi D, Hardwick RH, *Reimann F, *Gribble FM (2019) Comparison of human and murine enteroendocrine cells by transcriptomic and peptidomic profiling. 2019 May;68(5):1062-1072. PMID: 30733330 PMCID:PMC6477899 (* joint corresponding)
Richards P, Parker H, Adriaenssens A, Hodgson J, Cork S, Trapp S, Gribble FM, Reimann F (2014) Identification and characterisation of glucagon-like peptide-1 receptor expressing cells using a new transgenic mouse model. Diabetes 63(4):1224-33. PMID:24296712; PMCID:4092212
Parker HE, Habib AM, Rogers GJ, Gribble FM and Reimann F (2009) Nutrient-dependent secretion of glucose-dependent insulinotropic polypeptide from primary murine K-cells. Diabetologia 52:289-298. PMID:19082577; PMCID: 4308617