bims-adipim 2023-10-08 papers

Issue of 2023–10–08
seven papers selected by
Matthew C. Sinton, University of Glasgow

Endocrinology. 2023 Oct 03. pii: bqad147. [Epub ahead of print]

LncRNA Hnscr regulates lipid metabolism by mediating adipocyte lipolysis.

Yi-Fan Guo, Jing-Yi Sun, Ya Liu, Zhe-Yu Liu, Yan Huang, Tian Su, Yuan Xiao.

Obesity is a process of fat accumulation due to the imbalance between energy intake and consumption. Long non-coding RNA (lncRNA) Hnscr is crucial for metabolic regulation, but its roles in lipid metabolism during obesity are still unknown. In this article, we found that the expression of Hnscr gradually decreased in adipose tissues of diet-induced obese (DIO) mice. Furthermore, the deletion of Hnscr promoted an increase in body weight and adipose tissue weight by upregulating the expression of lipogenesis genes and downregulating lipolysis genes in inguinal white adipose tissue (iWAT) and brown adipose tissue (BAT). In vitro, knockdown of Hnscr in adipocytes resulted in reduced lipolysis of adipocytes. Overexpression of Hnscr by adenovirus or drug mimics showed the opposite. Mechanistically, Hnscr regulated adipose lipid metabolism by mediating the cAMP/PKA signaling pathway. This study identifies the initial characterization of Hnscr as a critical modifier that regulates lipid metabolism, suggesting that LncRNA Hnscr is a potential target for treating obesity.

Keywords: Hnscr ; adipocyte; lipid metabolism; lipolysis; obesity

DOI: https://doi.org/10.1210/endocr/bqad147

Front Cardiovasc Med. 2023 ;10 1264479

Obesity accelerates endothelial-to-mesenchymal transition in adipose tissues of mice and humans.

Nicholas W Chavkin, Tanvi Vippa, Changhee Jung, Stephanie McDonnell, Karen K Hirschi, Noyan Gokce, Kenneth Walsh.

Introduction: Vascular dysfunction and chronic inflammation are characteristics of obesity-induced adipose tissue dysfunction. Proinflammatory cytokines can drive an endothelial-to-mesenchymal transition (EndoMT), where endothelial cells undergo a phenotypic switch to mesenchymal-like cells that are pro-inflammatory and pro-fibrotic. In this study, we sought to determine whether obesity can promote EndoMT in adipose tissue.
Methods: Mice in which endothelial cells are lineage-traced with eYFP were fed a high-fat/high-sucrose (HF/HS) or Control diet for 13, 26, and 52 weeks, and EndoMT was assessed in adipose tissue depots as percentage of CD45-CD31-Acta2+ mesenchymal-like cells that were eYFP +. EndoMT was also assessed in human adipose endothelial cells through cell culture assays and by the analysis of single cell RNA sequencing datasets obtained from the visceral adipose tissues of obese individuals.
Results: Quantification by flow cytometry showed that mice fed a HF/HS diet display a time-dependent increase in EndoMT over Control diet in subcutaneous adipose tissue (+3.0%, +2.6-fold at 13 weeks; +10.6%, +3.2-fold at 26 weeks; +11.8%, +2.9-fold at 52 weeks) and visceral adipose tissue (+5.5%, +2.3-fold at 13 weeks; +20.7%, +4.3-fold at 26 weeks; +25.7%, +4.8-fold at 52 weeks). Transcriptomic analysis revealed that EndoMT cells in visceral adipose tissue have enriched expression of genes associated with inflammatory and TGFβ signaling pathways. Human adipose-derived microvascular endothelial cells cultured with TGF-β1, IFN-γ, and TNF-α exhibited a similar upregulation of EndoMT markers and induction of inflammatory response pathways. Analysis of single cell RNA sequencing datasets from visceral adipose tissue of obese patients revealed a nascent EndoMT sub-cluster of endothelial cells with reduced PECAM1 and increased ACTA2 expression, which was also enriched for inflammatory signaling genes and other genes associated with EndoMT.
Discussion: These experimental and clinical findings show that chronic obesity can accelerate EndoMT in adipose tissue. We speculate that EndoMT is a feature of adipose tissue dysfunction that contributes to local inflammation and the systemic metabolic effects of obesity..

Keywords: adipose; aging; endothelial-to-mesenchymal transition; endothelium; obesity; vascular biology

DOI: https://doi.org/10.3389/fcvm.2023.1264479

Mucosal Immunol. 2023 Sep 30. pii: S1933-0219(23)00072-7. [Epub ahead of print]

The IL-17A-neutrophil axis promotes epithelial cell IL-33 production during nematode lung migration.

Jesuthas Ajendra, Pedro H Papotto, James E Parkinson, Rebecca J Dodd, André L Bombeiro, Stella Pearson, Brian H K Chan, Julie C Ribot, Henry J McSorley, Tara E Sutherland, Judith E Allen.

The early migratory phase of pulmonary helminth infections is characterized by tissue injury leading to the release of the alarmin IL-33 and subsequent induction of type 2 immune responses. We recently described a role for IL-17A, through suppression of IFNγ, as an important inducer of type 2 responses during infection with the lung-migrating rodent nematode Nippostrongylus brasiliensis. Here, we aimed to investigate the interaction between IL-17A and IL-33 during the early lung migratory stages of N. brasiliensis infection. In this brief report, we demonstrate that deficiency of IL-17A leads to impaired IL-33 expression and secretion early in infection, independent of IL-17A suppression of IFNγ. Neutrophil-depletion experiments, which dramatically reduce lung injury, revealed that neutrophils are primarily responsible for the IL-17A-dependent release of IL-33 into the airways. Taken together, our results reveal an IL-17A-neutrophil-axis that can drive IL-33 during helminth infection, highlighting an additional pathway by which IL-17A regulates pulmonary type 2 immunity.

DOI: https://doi.org/10.1016/j.mucimm.2023.09.006

Cell Metab. 2023 Sep 27. pii: S1550-4131(23)00337-6. [Epub ahead of print]

Comprehensive quantification of metabolic flux during acute cold stress in mice.

Marc R Bornstein, Michael D Neinast, Xianfeng Zeng, Qingwei Chu, Jessie Axsom, Chelsea Thorsheim, Kristina Li, Megan C Blair, Joshua D Rabinowitz, Zoltan Arany.

Cold-induced thermogenesis (CIT) is widely studied as a potential avenue to treat obesity, but a thorough understanding of the metabolic changes driving CIT is lacking. Here, we present a comprehensive and quantitative analysis of the metabolic response to acute cold exposure, leveraging metabolomic profiling and minimally perturbative isotope tracing studies in unanesthetized mice. During cold exposure, brown adipose tissue (BAT) primarily fueled the tricarboxylic acid (TCA) cycle with fat in fasted mice and glucose in fed mice, underscoring BAT's metabolic flexibility. BAT minimally used branched-chain amino acids or ketones, which were instead avidly consumed by muscle during cold exposure. Surprisingly, isotopic labeling analyses revealed that BAT uses glucose largely for TCA anaplerosis via pyruvate carboxylation. Finally, we find that cold-induced hepatic gluconeogenesis is critical for CIT during fasting, demonstrating a key functional role for glucose metabolism. Together, these findings provide a detailed map of the metabolic rewiring driving acute CIT.

Keywords: FBP1; brown adipose tissue; cold exposure; flux; gluconeogenesis; glucose; metabolomics; pyruvate carboxylase; thermogenesis

DOI: https://doi.org/10.1016/j.cmet.2023.09.002

Elife. 2023 10 02. pii: RP88049. [Epub ahead of print]12

Mice lacking triglyceride synthesis enzymes in adipose tissue are resistant to diet-induced obesity.

Chandramohan Chitraju, Alexander W Fischer, Yohannes A Ambaw, Kun Wang, Bo Yuan, Sheng Hui, Tobias C Walther, Robert V Farese.

Triglycerides (TGs) in adipocytes provide the major stores of metabolic energy in the body. Optimal amounts of TG stores are desirable as insufficient capacity to store TG, as in lipodystrophy, or exceeding the capacity for storage, as in obesity, results in metabolic disease. We hypothesized that mice lacking TG storage in adipocytes would result in excess TG storage in cell types other than adipocytes and severe lipotoxicity accompanied by metabolic disease. To test this hypothesis, we selectively deleted both TG synthesis enzymes, DGAT1 and DGAT2, in adipocytes (ADGAT DKO mice). As expected with depleted energy stores, ADGAT DKO mice did not tolerate fasting well and, with prolonged fasting, entered torpor. However, ADGAT DKO mice were unexpectedly otherwise metabolically healthy and did not accumulate TGs ectopically or develop associated metabolic perturbations, even when fed a high-fat diet. The favorable metabolic phenotype resulted from activation of energy expenditure, in part via BAT (brown adipose tissue) activation and beiging of white adipose tissue. Thus, the ADGAT DKO mice provide a fascinating new model to study the coupling of metabolic energy storage to energy expenditure.

Keywords: adipose tissue; fat; glucose metabolism; lipodystrophy; medicine; metabolism; mouse; triglyceride

DOI: https://doi.org/10.7554/eLife.88049

Front Immunol. 2023 ;14 1238664

Fat and inflammation: adipocyte-myeloid cell crosstalk in atherosclerosis.

Aleksandra M Mazitova, Ana Cristina Márquez-Sánchez, Ekaterina K Koltsova.

Adipose tissue inflammation has been implicated in various chronic inflammatory diseases and cancer. Perivascular adipose tissue (PVAT) surrounds the aorta as an extra layer and was suggested to contribute to atherosclerosis development. PVAT regulates the function of endothelial and vascular smooth muscle cells in the aorta and represent a reservoir for various immune cells which may participate in aortic inflammation. Recent studies demonstrate that adipocytes also express various cytokine receptors and, therefore, may directly respond to inflammatory stimuli. Here we will summarize current knowledge on immune mechanisms regulating adipocyte activation and the crosstalk between myeloid cells and adipocytes in pathogenesis of atherosclerosis.

Keywords: adipocytes; atherosclerosis; cytokines; inflammation; perivascular adipose tissue

DOI: https://doi.org/10.3389/fimmu.2023.1238664

Sci Rep. 2023 10 03. 13(1): 16628

Inhibition of IL-17 ameliorates keratinocyte-borne cytokine responses in an in vitro model for house-dust-mite triggered atopic dermatitis.

Juliane Haertlé, Petra Kienlin, Gabriele Begemann, Thomas Werfel, Lennart M Roesner.

A subgroup of patients suffering from atopic dermatitis (AD) does not respond to biologics therapy targeting the key players of type-2 inflammation, and it is an ongoing discussion whether skin-infiltrating Th17 cells may underlie this phenomenon. This study aimed to investigate the potential of allergen-induced, immune-cell derived IL-17 on the induction of inflammatory processes in keratinocytes. Peripheral blood mononuclear cells derived from respectively sensitized AD patients were stimulated with house dust mite (HDM) extract and cell culture supernatants were applied subsequently in absence or presence of secukinumab to primary human keratinocytes. Hereby we confirm that the immune response of sensitized AD patients to HDM contains aside from type-2 cytokines significant amounts of IL-17. Blocking IL-17 efficiently reduced the stimulation-induced changes in keratinocyte gene expression. IL-17-dependent transcriptional changes included increased expression of the cytokines IL-20 and IL-24 as well as Suppressor of Cytokine Siganling 3 (SOCS3), a negative feedback-regulator of the STAT3/IL-17/IL-24 immune response. We conclude that the immune response to HDM can induce pro-inflammatory cytokines from keratinocytes in AD, which in part is mediated via IL-17. Targeting IL-17 may turn out to be a reasonable alternative therapy in a subgroup of patients with moderate to severe AD and HDM sensitization.

DOI: https://doi.org/10.1038/s41598-023-42595-z