Mechanisms of activation of mouse and human enteroendocrine cells by nutrients

AstraZeneca, Wellcome Trust, Bowel and Cancer Research, Barts and the London Charity

Spatial distribution and abundance of Common Sharp-tailed Snakes (Contia tenuis) on Observatory Hill, Vancouver Island, British Columbia

Similar to many small, secretive snakes, the natural history and population biology of Sharp-tailed Snakes are poorly known. Information on habitat use and patterns of abundance are particularly important for management and recovery of this species listed as endangered in Canada. We surveyed for snakes from October 2010 to March 2019 using a microhabitat-based array of 162 artificial cover-object stations. The surveys (236 array checks) resulted in 177 detections of Sharp-tailed Snakes, representing 106 individuals identified through pattern mapping. Body size (snout-vent length) of the snakes ranged from 82 mm to 261 mm, and most (65.1%) were adults >180 mm. The dispersion of snakes among sampling stations was aggregated over time with 42 stations used by one to 15 individuals over the course of the study, including three “hot spots” used by over ten individuals; these sites represented hibernation and possibly also egg-laying sites. Most detections were on the warmer west and south slopes of the hill and were correlated with the presence of talus but not with other habitat attributes examined. The population sampled by the array was estimated to consist of a mean of 128 snakes (6.04/ha) in 2011 and 80 (3.80/ha) in 2018 with mean annual survival rate of 52.9%. We suggest focusing survey efforts on stable talus patches with south- and west-facing aspects both to locate the species at new sites and to identify important habitats at known sites

The Rumsfeld Paradigm: Knowns and Unknowns in Characterizing Habitats Used by the Endangered Sharp-tailed Snake, Contia tenuis, in Southwestern British Columbia

The Sharp-tailed Snake, Contia tenuis, has a small and highly fragmented range in British Columbia, where it is considered endangered. Known sites are few in number and generally small in spatial extent; numbers of snakes apparently are correspondingly low. Furthermore, most known sites for the species are on private lands in areas that are fairly heavily developed or being developed. Thus, the species is under serious threat of habitat alteration or loss. Although land stewardship has been a valuable conservation tool in this case, we also need to identify the key habitat requirements of Sharp-tailed Snakes to identify potential new sites, modify former or potential ones, or even create new ones. In this study, we compared sites known to harbour Sharp-tailed Snakes with those that seemed subjectively similar and therefore potentially suitable. We also compared these known and potential sites with randomly chosen nearby locations. Variability of most measured features was high, both within and among site/location categories. Nonetheless, we found significant differences between known and potential sites and between those locations and random ones. Overall, locations known to be used by snakes had a more southerly aspect, more rock cover, shallower soil and litter, and less shrub cover than other sites. This study was constrained by the small number of known sites for Sharp-tailed Snakes in southwestern British Columbia, making our conclusions suggestive rather than definitive. Future work should incorporate additional variables. It also might be useful to undertake comparative habitat studies elsewhere in the range of the Sharp-tailed Snake where it is more common

Ghrelin

This work was supported by grants from the NIH (DP2DK105570-01 and 2P30DK046200 to MLA, DK21397 to HJG, K01DK098319 to KMH, K01MH091222 to LH, DK093848 to RJS, R01DK082590 to LS, R01DK097550 to JT, RO1 DK 076037 to MOT, R01DA024680 and R01MH085298 to JMZ, R01AG019230 and R01AG029740 to RGS) The Wellcome Trust (MK), Science Foundation Ireland (12/YI/B2480 to CWL), the Alexander von Humboldt Foundation (MHT), the Deutsches Zentrum für Diabetesforschung (MHT), the Helmholtz Alliance ICEMED e Imaging and Curing Environmental Metabolic Diseases, through the Initiative and Networking Fund of the Helmholtz Association (MHT), and the Helmholtz cross-program topic “Metabolic Dysfunction” (MHT). Allan Geliebter was sponsored by NIH grants R01DK80153; R01DK074046; R03DK068603; P30DK26687

Ageing compromises mouse thymus function and remodels epithelial cell differentiation.

Ageing is characterised by cellular senescence, leading to imbalanced tissue maintenance, cell death and compromised organ function. This is first observed in the thymus, the primary lymphoid organ that generates and selects T cells. However, the molecular and cellular mechanisms underpinning these ageing processes remain unclear. Here, we show that mouse ageing leads to less efficient T cell selection, decreased self-antigen representation and increased T cell receptor repertoire diversity. Using a combination of single-cell RNA-seq and lineage-tracing, we find that progenitor cells are the principal targets of ageing, whereas the function of individual mature thymic epithelial cells is compromised only modestly. Specifically, an early-life precursor cell population, retained in the mouse cortex postnatally, is virtually extinguished at puberty. Concomitantly, a medullary precursor cell quiesces, thereby impairing maintenance of the medullary epithelium. Thus, ageing disrupts thymic progenitor differentiation and impairs the core immunological functions of the thymus

Increased Oral Detection, but Decreased Intestinal Signaling for Fats in Mice Lacking Gut Microbiota

Germ-free (GF) mice lacking intestinal microbiota are significantly leaner than normal (NORM) control mice despite consuming more calories. The contribution of microbiota on the recognition and intake of fats is not known. Thus, we investigated the preference for, and acceptance of, fat emulsions in GF and NORM mice, and associated changes in lingual and intestinal fatty acid receptors, intestinal peptide content, and plasma levels of gut peptides. GF and NORM C57Bl/6J mice were given 48-h two-bottle access to water and increasing concentrations of intralipid emulsions. Gene expression of the lingual fatty acid translocase CD36 and protein expression of intestinal satiety peptides and fatty-acid receptors from isolated intestinal epithelial cells were determined. Differences in intestinal enteroendocrine cells along the length of the GI tract were quantified. Circulating plasma satiety peptides reflecting adiposity and biochemical parameters of fat metabolism were also examined. GF mice had an increased preference and intake of intralipid relative to NORM mice. This was associated with increased lingual CD36 (P<0.05) and decreased intestinal expression of fatty acid receptors GPR40 (P<0.0001), GPR41 (P<0.0001), GPR43 (P<0.05), and GPR120 (P<0.0001) and satiety peptides CCK (P<0.0001), PYY (P<0.001), and GLP-1 (P<0.001). GF mice had fewer enteroendocrine cells in the ileum (P<0.05), and more in the colon (P<0.05), relative to NORM controls. Finally, GF mice had lower levels of circulating leptin and ghrelin (P<0.001), and altered plasma lipid metabolic markers indicative of energy deficits. Increased preference and caloric intake from fats in GF mice are associated with increased oral receptors for fats coupled with broad and marked decreases in expression of intestinal satiety peptides and fatty-acid receptors

Current and Future Drug Targets in Weight Management

Obesity will continue to be one of the leading causes of chronic disease unless the ongoing rise in the prevalence of this condition is reversed. Accumulating morbidity figures and a shortage of effective drugs have generated substantial research activity with several molecular targets being investigated. However, pharmacological modulation of body weight is extremely complex, since it is essentially a battle against one of the strongest human instincts and highly efficient mechanisms of energy uptake and storage. This review provides an overview of the different molecular strategies intended to lower body weight or adipose tissue mass. Weight-loss drugs in development include molecules intended to reduce the absorption of lipids from the GI tract, various ways to limit food intake, and compounds that increase energy expenditure or reduce adipose tissue size. A number of new preparations, including combinations of the existing drugs topiramate plus phentermine, bupropion plus naltrexone, and the selective 5-HT2C agonist lorcaserin have recently been filed for approval. Behind these leading candidates are several other potentially promising compounds and combinations currently undergoing phase II and III testing. Some interesting targets further on the horizon are also discussed