Biology subjects

Klemm, P.

Publications and source records attributed to Klemm, P..

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↗

bioRxiv2022

Cold-induced expression of a truncated Adenylyl Cyclase 3 acts as rheostat to brown fat function.

Promoting brown adipose tissue (BAT) activity has been recognized as innovative therapeutic approach to improve obesity and metabolic disease. Whilst the molecular circuitry underlying thermogenic activation of BAT is well understood, the processes underlying rheostatic regulation of BAT to maintain homeostasis and avoid excessive energy dissipation remain ill-defined. Increasing cyclic AMP (cAMP) biosynthesis is key for BAT activation. Here, we demonstrate that ADCY3, an adenylyl cyclase whose expression is induced during cold exposure and regulates cAMP homeostasis in thermogenic fat, is dispensable for BAT function in lean mice, but becomes critical during obesity. Furthermore, by combining RNA-seq with epigenomic H3K4me3 profiling, we detected a novel, cold-inducible promoter that generates a 5 truncated Adcy3-at mRNA isoform, Adcy3-at. Mice lacking only Adcy3-at, but not full-length Adcy3, displayed increased energy expenditure already under lean conditions and were protected against obesity and ensuing metabolic imbalances. Subcellularly, translated ADCY3-AT proteins are retained in the endoplasmic reticulum (ER), did not translocate to the cell membrane, and lacked enzymatic activity. By interacting with ADCY3, ADCY3-AT retained ADCY3 in the ER and, thereby, reduced the plasma membrane pool of ADCYs available for G-protein mediated cAMP synthesis. Thereby, ADCY3-AT acts as a signaling rheostat in BAT, limiting adverse consequences of uncurbed cAMP activity after long-term BAT activation. Adcy3-at induction was driven by a cold-induced, truncated isoform of the transcriptional cofactor PPARGC1A (PPARG Coactivator 1 Alpha, PPARGC1A-AT). Expression of Ppargc1a-at and Adcy3-at are evolutionary conserved, indicating that transcriptional rewiring by commissioning of alternative promoters is key for thermogenic fat function.

cell biology↗

bioRxiv2021

P2Y6 receptor signaling in natural killer cells impairs insulin sensitivity in obesity

Natural killer (NK) cells contribute to the development of obesity-associated insulin resistance and have previously been shown to up-regulate the expression of the P2Y purinoreceptor 6 (P2Y6R) upon high fat diet (HFD)-induced obesity. Here, we reveal that NK cell-specific inactivation of the P2Y6R gene improves insulin sensitivity in obese mice and reduces the expression of chemokines in adipose tissue infiltrating NK-cells. Obese mice lacking P2Y6R specifically in NK cells exhibited a reduction in adipose tissue inflammation, exhibited improved insulin-stimulated suppression of lipolysis in adipose tissue and a reduction in hepatic glucose production, leading to an overall improvement of systemic insulin sensitivity. In contrast, myeloid lineage specific P2Y6R inactivation does not affect energy or glucose homeostasis in obesity. Collectively, we show that P2Y6R signaling in NK cells contributes to the development of obesity-associated insulin resistance and thus might be a future target for the treatment of obesity-associated insulin resistance and type 2 diabetes.

immunology↗