de Kloet, A. | Search bioRxiv

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↗

bioRxiv2018

Arginine to glutamine mutation in olfactomedin-like 3 (OLFML3) is a candidate for severe goniodysgenesis and glaucoma in the Border Collie dog breed.

Goniodysgenesis is a developmental abnormality of the anterior chamber of the eye. It is generally considered to be congenital in dogs (Canis lupus familiaris), and has been associated with glaucoma and blindness. Goniodysgenesis and early-onset glaucoma initially emerged in Border Collies in Australia in the late 1990s and has subsequently been found in Europe and the USA. The objective of the present study was to determine the genetic basis of goniodysgenesis in Border Collies. Clinical diagnosis was based on results of examinations by veterinary ophthalmologists of affected and unaffected dogs from eleven different countries. Genotyping using the Illumina high density canine SNP chip and whole genome sequencing were used to identify candidate genetic regions. Expression profiles and evolutionary conservation of candidate genes were assessed using public databases. Analysis of pedigree information was consistent with an autosomal recessive mode of inheritance for severe goniodysgenesis (potentially leading to glaucoma) in this breed. There was a highly significant peak of association over chromosome 17, with a p-value of 2 x 10-13. Whole genome sequences of three dogs with glaucoma, three severely affected and three unaffected dogs identified a missense variant in the olfactomedin like 3 (OLFML3) gene in all six affected animals. This was homozygous in all nine cases with glaucoma and 12 of 14 other severely affected animals. Of 67 reportedly unaffected animals, only one (offspring of two homozygous affected parents) was homozygous for this variant. The identification of a candidate genetic region and putative causative mutation will aid breeders to reduce the frequency of goniodysgenesis and the risk of glaucoma in the Border Collie population.

genetics↗