bims-adipim 2023-06-25 papers

Issue of 2023–06–25
five papers selected by
Matthew C. Sinton, University of Glasgow

Nat Metab. 2023 Jun 19.

Adipogenic and SWAT cells separate from a common progenitor in human brown and white adipose depots.

Nagendra P Palani, Carla Horvath, Pascal N Timshel, Pytrik Folkertsma, Alexander G B Grønning, Tora I Henriksen, Lone Peijs, Verena H Jensen, Wenfei Sun, Naja Z Jespersen, Christian Wolfrum, Tune H Pers, Søren Nielsen, Camilla Scheele.

Adipocyte function is a major determinant of metabolic disease, warranting investigations of regulating mechanisms. We show at single-cell resolution that progenitor cells from four human brown and white adipose depots separate into two main cell fates, an adipogenic and a structural branch, developing from a common progenitor. The adipogenic gene signature contains mitochondrial activity genes, and associates with genome-wide association study traits for fat distribution. Based on an extracellular matrix and developmental gene signature, we name the structural branch of cells structural Wnt-regulated adipose tissue-resident (SWAT) cells. When stripped from adipogenic cells, SWAT cells display a multipotent phenotype by reverting towards progenitor state or differentiating into new adipogenic cells, dependent on media. Label transfer algorithms recapitulate the cell types in human adipose tissue datasets. In conclusion, we provide a differentiation map of human adipocytes and define the multipotent SWAT cell, providing a new perspective on adipose tissue regulation.

DOI: https://doi.org/10.1038/s42255-023-00820-z

Nat Metab. 2023 Jun 19.

Wnt signaling preserves progenitor cell multipotency during adipose tissue development.

Zinger Yang Loureiro, Shannon Joyce, Tiffany DeSouza, Javier Solivan-Rivera, Anand Desai, Pantos Skritakis, Qin Yang, Rachel Ziegler, Denise Zhong, Tammy T Nguyen, Ormond A MacDougald, Silvia Corvera.

Mesenchymal stem/progenitor cells are essential for tissue development and repair throughout life, but how they are maintained under chronic differentiation pressure is not known. Using single-cell transcriptomics of human progenitor cells we find that adipose differentiation stimuli elicit two cellular trajectories: one toward mature adipocytes and another toward a pool of non-differentiated cells that maintain progenitor characteristics. These cells are induced by transient Wnt pathway activation and express numerous extracellular matrix genes and are therefore named structural Wnt-regulated adipose tissue cells. We find that the genetic signature of structural Wnt-regulated adipose tissue cells is present in adult human adipose tissue and adipose tissue developed from human progenitor cells in mice. Our results suggest a mechanism whereby adipose differentiation occurs concurrently with the maintenance of a mesenchymal progenitor cell pool, ensuring tissue development, repair and appropriate metabolic control over the lifetime.

DOI: https://doi.org/10.1038/s42255-023-00813-y

Cell Rep. 2023 Jun 13. pii: S2211-1247(23)00638-1. [Epub ahead of print] 112627

Inhibition of high-fat diet-induced inflammatory responses in adipose tissue by SF1-expressing neurons of the ventromedial hypothalamus.

Misbah Rashid, Kunio Kondoh, Gergo Palfalvi, Ken-Ichiro Nakajima, Yasuhiko Minokoshi.

Inflammation and thermogenesis in white adipose tissue (WAT) at different sites influence the overall effects of obesity on metabolic health. In mice fed a high-fat diet (HFD), inflammatory responses are less pronounced in inguinal WAT (ingWAT) than in epididymal WAT (epiWAT). Here we show that ablation and activation of steroidogenic factor 1 (SF1)-expressing neurons in the ventromedial hypothalamus (VMH) oppositely affect the expression of inflammation-related genes and the formation of crown-like structures by infiltrating macrophages in ingWAT, but not in epiWAT, of HFD-fed mice, with these effects being mediated by sympathetic nerves innervating ingWAT. In contrast, SF1 neurons of the VMH preferentially regulated the expression of thermogenesis-related genes in interscapular brown adipose tissue (BAT) of HFD-fed mice. These results suggest that SF1 neurons of the VMH differentially regulate inflammatory responses and thermogenesis among various adipose tissue depots and restrain inflammation associated with diet-induced obesity specifically in ingWAT.

Keywords: CP: Metabolism; CP: Neuroscience; adipose tissue; diet-induced obesity; inflammation; macrophage; steroidogenic factor 1; sympathetic nerve; ventromedial hypothalamus

DOI: https://doi.org/10.1016/j.celrep.2023.112627

FASEB J. 2023 Jul;37(7): e23033

KLF7 promotes adipocyte inflammation and glucose metabolism disorder by activating the PKCζ/NF-κB pathway.

Xin Yang, Maodi Liang, Yihan Tang, Dingling Ma, Menghuan Li, Chenggang Yuan, Yanting Hou, Chaoyue Sun, Jie Liu, Qianqian Wei, Yongsheng Chang, Cuizhe Wang, Jun Zhang.

In the obesity context, inflammatory cytokines secreted by adipocytes lead to insulin resistance and are key to metabolic syndrome development. In our previous study, we found that the transcription factor KLF7 promoted the expression of p-p65 and IL-6 in adipocytes. However, the specific molecular mechanism remained unclear. In the present study, we found that the expression of KLF7, PKCζ, p-IκB, p-p65, and IL-6 in epididymal white adipose tissue (Epi WAT) in mice fed a high-fat diet (HFD) was significantly increased. In contrast, the expression of PKCζ, p-IκB, p-p65, and IL-6 was significantly decreased in Epi WAT of KLF7 fat conditional knockout mice. In 3T3-L1 adipocytes, KLF7 promoted the expression of IL-6 via the PKCζ/NF-κB pathway. In addition, we performed luciferase reporter and chromatin immunoprecipitation assays, which confirmed that KLF7 upregulated the expression of PKCζ transcripts in HEK-293T cells. Collectively, our results show that KLF7 promotes the expression of IL-6 by upregulating PKCζ expression and activating the NF-κB signaling pathway in adipocytes.

Keywords: IL-6; KLF7; NF-κB; PKCζ; obesity

DOI: https://doi.org/10.1096/fj.202300005R

bioRxiv. 2023 Jun 11. pii: 2023.06.09.544407. [Epub ahead of print]

13 C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 + T cells.

Eric H Ma, Michael S Dahabieh, Lisa M DeCamp, Irem Kaymak, Susan M Kitchen-Goosen, Dominic G Roy, Mark J Verway, Radia M Johnson, Bozena Samborska, Catherine A Scullion, Mya Steadman, Matthew Vos, Thomas P Roddy, Connie M Krawczyk, Kelsey S Williams, Ryan D Sheldon, Russell G Jones.

Infusion of 13C-labeled metabolites provides a gold-standard for understanding the metabolic processes used by T cells during immune responses in vivo . Through infusion of 13C-labeled metabolites (glucose, glutamine, acetate) in Listeria monocytogenes ( Lm )-infected mice, we demonstrate that CD8+ T effector (Teff) cells utilize metabolites for specific pathways during specific phases of activation. Highly proliferative early Teff cells in vivo shunt glucose primarily towards nucleotide synthesis and leverage glutamine anaplerosis in the tricarboxylic acid (TCA) cycle to support ATP and de novo pyrimidine synthesis. Additionally, early Teff cells rely on glutamic-oxaloacetic transaminase 1 (Got1)-which regulates de novo aspartate synthesis-for effector cell expansion in vivo . Importantly, Teff cells change fuel preference over the course of infection, switching from glutamine-to acetate-dependent TCA cycle metabolism late in infection. This study provides insights into the dynamics of Teff metabolism, illuminating distinct pathways of fuel consumption associated with Teff cell function in vivo .
Teaser: Interrogating dynamics of fuel utilization by CD8 + T cells in vivo reveals new metabolic checkpoints for immune function in vivo .

DOI: https://doi.org/10.1101/2023.06.09.544407