| 1. |
- Massier, Lucas, et al.
(författare)
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An integrated single cell and spatial transcriptomic map of human white adipose tissue
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Single-cell studies of human white adipose tissue (WAT) provide insights into the specialized cell types in the tissue. Here the authors combine publicly available and newly generated high-resolution and bulk transcriptomic results from multiple human datasets to provide a comprehensive cellular map of white adipose tissue. To date, single-cell studies of human white adipose tissue (WAT) have been based on small cohort sizes and no cellular consensus nomenclature exists. Herein, we performed a comprehensive meta-analysis of publicly available and newly generated single-cell, single-nucleus, and spatial transcriptomic results from human subcutaneous, omental, and perivascular WAT. Our high-resolution map is built on data from ten studies and allowed us to robustly identify >60 subpopulations of adipocytes, fibroblast and adipogenic progenitors, vascular, and immune cells. Using these results, we deconvolved spatial and bulk transcriptomic data from nine additional cohorts to provide spatial and clinical dimensions to the map. This identified cell-cell interactions as well as relationships between specific cell subtypes and insulin resistance, dyslipidemia, adipocyte volume, and lipolysis upon long-term weight changes. Altogether, our meta-map provides a rich resource defining the cellular and microarchitectural landscape of human WAT and describes the associations between specific cell types and metabolic states.
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| 2. |
- Negoita, Florentina, et al.
(författare)
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JUP/plakoglobin is regulated by salt-inducible kinase 2, and is required for insulin-induced signalling and glucose uptake in adipocytes
- 2020
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Ingår i: Cellular Signalling. - : Elsevier BV. - 1873-3913 .- 0898-6568. ; 76
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Salt-inducible kinase 2 (SIK2) is abundant in adipocytes, but downregulated in adipose tissue from individuals with obesity and insulin resistance. Moreover, SIK isoforms are required for normal insulin signalling and glucose uptake in adipocytes, but the underlying molecular mechanisms are currently not known. The adherens junction protein JUP, also termed plakoglobin or γ-catenin, has recently been reported to promote insulin signalling in muscle cells.OBJECTIVE: The objective of this study was to analyse if JUP is required for insulin signalling in adipocytes and the underlying molecular mechanisms of this regulation.METHODS: Co-expression of SIK2 and JUP mRNA levels in adipose tissue from a human cohort was analysed. siRNA silencing and/or pharmacological inhibition of SIK2, JUP, class IIa HDACs and CRTC2 was employed in 3T3-L1- and primary rat adipocytes. JUP protein expression was analysed by western blot and mRNA levels by qPCR. Insulin signalling was evaluated by western blot as levels of phosphorylated PKB/Akt and AS160, and by monitoring the uptake of 3H-2-deoxyglucose.RESULTS: mRNA expression of SIK2 correlated with that of JUP in human adipose tissue. SIK2 inhibition or silencing resulted in downregulation of JUP mRNA and protein expression in 3T3-L1- and in primary rat adipocytes. Moreover, JUP silencing reduced the expression of PKB and the downstream substrate AS160, and consequently attenuated activity in the insulin signalling pathway, including insulin-induced glucose uptake. The known SIK2 substrates CRTC2 and class IIa HDACs were found to play a role in the SIK-mediated regulation of JUP expression.CONCLUSIONS: These findings identify JUP as a novel player in the regulation of insulin sensitivity in adipocytes, and suggest that changes in JUP expression could contribute to the effect of SIK2 on insulin signalling in these cells.
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| 3. |
- Vaváková, Magdaléna, et al.
(författare)
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Mechanism of TNFα-induced downregulation of salt-inducible kinase 2 in adipocytes
- 2023
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Ingår i: Scientific Reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Salt-inducible kinase 2 (SIK2) is highly expressed in white adipocytes, but downregulated in individuals with obesity and insulin resistance. These conditions are often associated with a low-grade inflammation in adipose tissue. We and others have previously shown that SIK2 is downregulated by tumor necrosis factor α (TNFα), however, involvement of other pro-inflammatory cytokines, or the mechanisms underlying TNFα-induced SIK2 downregulation, remain to be elucidated. In this study we have shown that TNFα downregulates SIK2 protein expression not only in 3T3L1- but also in human in vitro differentiated adipocytes. Furthermore, monocyte chemoattractant protein-1 and interleukin (IL)-1β, but not IL-6, might also contribute to SIK2 downregulation during inflammation. We observed that TNFα-induced SIK2 downregulation occurred also in the presence of pharmacological inhibitors against several kinases involved in inflammation, namely c-Jun N-terminal kinase, mitogen activated protein kinase kinase 1, p38 mitogen activated protein kinase or inhibitor of nuclear factor kappa-B kinase (IKK). However, IKK may be involved in SIK2 regulation as we detected an increase of SIK2 when inhibiting IKK in the absence of TNFα. Increased knowledge about inflammation-induced downregulation of SIK2 could ultimately be used to develop strategies for the reinstalment of SIK2 expression in insulin resistance.
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