Biology subjects

Knudsen, L. B.

Publications and source records attributed to Knudsen, L. B..

3 recordsLinked to original sources

bioRxiv2023

Human HYPOMAP: A comprehensive spatio-cellular map of the human hypothalamus

The hypothalamus is a brain region that plays a key role in coordinating fundamental biological functions. However, our understanding of the underlying cellular components and circuitry, have, until recently, emerged primarily from rodent studies. Here, we combine a single-nucleus sequencing database of 433,369 human hypothalamic cells, with spatial transcriptomics, to present a comprehensive spatio-cellular transcriptional map of the human hypothalamus, the HYPOMAP. Analysing hypothalamic leptin melanocortin pathway neuronal populations that play a role in appetite control, we identify spatially distinct populations of arcuate nucleus POMC and AGRP neurons, and their receptors MC3R and MC4R. Next, we map the cells expressing incretin receptors, targets of the new generation of anti-obesity medications, and uncover transcriptionally distinct GLP1R and GIPR-expressing cellular populations. Finally, out of the 458 hypothalamic cell types in HYPOMAP, we find 182 neuronal clusters are significantly enriched in expression of BMI GWAS genes. This enrichment is driven by 375 effector genes, with rare deleterious variants in 6 of these; MC4R, PCSK1, POMC, CALCR, BSN and CORO1A, the last of which has previously not been linked to obesity; being significantly associated with changes in BMI at the population level. Thus, the HYPOMAP provides a detailed atlas of the human hypothalamus in a spatial context, and serves as an important resource to identify novel druggable targets for treating a wide range of conditions, including reproductive, circadian, and metabolic disorders.

neuroscience↗

bioRxiv2021

Leptin-mediated suppression of food intake by conserved Glp1r-expressing neurons prevents obesity

The adipose-derived hormone leptin acts via its receptor (LepRb) in the brain to control energy balance. A previously unidentified population of GABAergic hypothalamic LepRb neurons plays key roles in the restraint of food intake and body weight by leptin. To identify markers for candidate populations of LepRb neurons in an unbiased manner, we performed single-nucleus RNA-sequencing of enriched mouse hypothalamic LepRb cells, as well as with total hypothalamic cells from multiple mammalian species. In addition to identifying known LepRb neuron types, this analysis identified several previously unrecognized populations of hypothalamic LepRb neurons. Many of these populations display strong conservation across species, including GABAergic Glp1r-expressing LepRb (LepRbGlp1r) neurons that express more Lepr and respond more robustly to exogenous leptin than other LepRb populations. Ablating LepRb from these cells provoked hyperphagic obesity without impairing energy expenditure. Conversely, reactivating LepRb in Glp1r-expressing cells decreased food intake and body weight in otherwise LepRb-null mice. Furthermore, LepRb reactivation in GABA neurons improved energy balance in LepRb-null mice, and this effect required the expression of LepRb in GABAergic Glp1r-expressing neurons. Thus, the conserved GABAergic LepRbGlp1r neuron population plays crucial roles in the control of food intake and body weight by leptin.

neuroscience↗

bioRxiv2021

A survey of the mouse hindbrain in the fed and fasted state using single-nucleus RNA sequencing

ObjectiveThe area postrema (AP) and the nucleus tractus solitaris (NTS), located in the hindbrain, are key nuclei that sense and integrate peripheral nutritional signals and, consequently, regulate feeding behaviour. While single cell transcriptomics have been used in mice to reveal the gene expression profile and heterogeneity of key hypothalamic populations, similar in-depth studies have not yet been performed in the hindbrain. MethodsUsing single-nucleus RNA sequencing, we provide a detailed survey of 16,034 cells within the AP and NTS of the mouse, in the fed and fasted state. ResultsOf these, 8910 are neurons that group into 30 clusters, with 4289 coming from mice fed ad libitum and 4621 from overnight fasted mice. 7124 nuclei are from non-neuronal cells, including oligodendrocytes, astrocytes and microglia. Interestingly, we identified that the oligodendrocyte population was particularly transcriptionally sensitive to an overnight fast. The receptors GLP1R, GIPR, GFRAL and CALCR, which bind GLP1, GIP, GDF15 and amylin respectively, are all expressed in the hindbrain and are major targets for anti-obesity therapeutics. We characterise the transcriptomes of these four populations and show that their gene expression profiles are not dramatically altered by an overnight fast. Notably, we find that roughly half of cells that express GIPR are oligodendrocytes. Additionally, we profile POMC expressing neurons within the hindbrain and demonstrate that 84% of POMC neurons express either PCSK1, PSCK2 or both, implying that melanocortin peptides are likely produced by these neurons. ConclusionWe provide a detailed single-cell level characterisation of AP and NTS cells expressing receptors for key anti-obesity drugs that are either already approved for human use or are in clinical trials. This resource will help delineate the mechanisms underlying the effectiveness of these compounds, and also prove useful in the continued search for other novel therapeutic targets.

neuroscience↗