bims-mimead 2024-12-08 papers

Issue of 2024–12–08
four papers selected by
Rachel M. Handy, University of Guelph

NPJ Metab Health Dis. 2024 ;2(1): 34

Human adipose depots' diverse functions and dysregulations during cardiometabolic disease.

Adipose tissue depots develop specific functions in a location dependent manner. In humans, this for example includes thermogenic capacity in the brown adipose supraclavicular, deep neck and perirenal depots, healthy lipid storage primarily in the gluteofemoral subcutaneous depot, and immunogenic support in the visceral omental depot. These distinct functions are at some point programmed into adipose progenitor cells, which retain some of the phenotype from the depot they originated from upon isolation and differentiation in vitro. Cardiometabolic diseases associate with body fat distribution, with an accumulation of lipids in the visceral depot accompanied by low grade inflammation and insulin resistance as a typical phenotype. However, well-functioning subcutaneous adipose tissue and brown adipose tissue contribute to a metabolically healthy phenotype, and it is therefore worth understanding the function and regulation of these adipocytes. In this review, we will discuss the dysregulations in distinct human adipose tissue depots associated with cardiometabolic disease, some of the consequences this has on whole body metabolism, and how depot-specific dysregulations might affect other adipose depots to progress a cardiometabolic disease condition.

Keywords: Cell biology; Fat metabolism; Metabolic diseases; Physiology

DOI: https://doi.org/10.1038/s44324-024-00036-z

BMC Med. 2024 12 02. 22(1): 572

Multiomics profiling of DNA methylation, microRNA, and mRNA in skeletal muscle from monozygotic twin pairs discordant for type 2 diabetes identifies dysregulated genes controlling metabolism.

Charlotte Ling, Magdalena Vavakova, Bilal Ahmad Mir, Johanna Säll, Alexander Perfilyev, Melina Martin, Per-Anders Jansson, Cajsa Davegårdh, Olof Asplund, Ola Hansson, Allan Vaag, Emma Nilsson.

BACKGROUND: A large proportion of skeletal muscle insulin resistance in type 2 diabetes (T2D) is caused by environmental factors.
METHODS: By applying multiomics mRNA, microRNA (miRNA), and DNA methylation platforms in biopsies from 20 monozygotic twin pairs discordant for T2D, we aimed to delineate the epigenetic and transcriptional machinery underlying non-genetic muscle insulin resistance in T2D.
RESULTS: Using gene set enrichment analysis (GSEA), we found decreased mRNA expression of genes involved in extracellular matrix organization, branched-chain amino acid catabolism, metabolism of vitamins and cofactors, lipid metabolism, muscle contraction, signaling by receptor tyrosine kinases pathways, and translocation of glucose transporter 4 (GLUT4) to the plasma membrane in muscle from twins with T2D. Differential expression levels of one or more predicted target relevant miRNA(s) were identified for approximately 35% of the dysregulated GSEA pathways. These include miRNAs with a significant overrepresentation of targets involved in GLUT4 translocation (miR-4643 and miR-548z), signaling by receptor tyrosine kinases pathways (miR-607), and muscle contraction (miR-4658). Acquired DNA methylation changes in skeletal muscle were quantitatively small in twins with T2D compared with the co-twins without T2D. Key methylation and expression results were validated in muscle, myotubes, and/or myoblasts from unrelated subjects with T2D and controls. Finally, mimicking T2D-associated changes by overexpressing miR-548 and miR-607 in cultured myotubes decreased expression of target genes, GLUT4 and FGFR4, respectively, and impaired insulin-stimulated phosphorylation of Akt (Ser473) and TBC1D4.
CONCLUSIONS: Together, we show that T2D is associated with non- and epigenetically determined differential transcriptional regulation of pathways regulating skeletal muscle metabolism and contraction.

Keywords: DNA methylation; Discordant monozygotic twins; Epigenetics; Gene expression; MicroRNA (miRNA); Skeletal muscle; Type 2 diabetes (T2D)

DOI: https://doi.org/10.1186/s12916-024-03789-y

Circ Res. 2024 Dec 04.

GSK3β Deficiency Expands Obese Adipose Vasculature to Mitigate Metabolic Disorders.

Li Wang, Jiajia Li, Ping Tang, Dongliang Zhu, Lixin Tai, Yuan Wang, Tsukiko Miyata, James R Woodgett, Lijun Di.

BACKGROUND: Maintaining a well-developed vascular system alongside adipose tissue (AT) expansion significantly reduces the risk of metabolic complications. Although GSK3β (glycogen synthase kinase-3 beta) is known for its role in various cellular processes, its specific functions in AT and regulation of body homeostasis have not been reported.
METHODS: GSK3β-floxed and GSK3α-floxed mice were crossed with adiponectin-Cre mice to generate GSK3β or GSK3α adipocyte-specific knockout mice (GSK3βADKO and GSK3αADKO). A comprehensive whole-body metabolism analysis was performed on obese GSK3βADKO mice induced by a high-fat diet. RNA sequencing was conducted on AT of both obese GSK3βADKO and GSK3αADKO mice. Various analyses, including vessel perfusion studies, lipolysis analysis, multiplex protein assays, in vitro protein phosphorylation assays, and whole-mount histology staining, were performed on AT of obese GSK3βADKO mice. Tube-formation experiments were performed using 3B-11 endothelial cells cultured in the conditional medium of matured adipocytes under hypoxic conditions. Chromatin precipitation and immunofluorescence studies were conducted using cultured adipocytes with GSK3 inhibition.
RESULTS: Our findings provide the first evidence that adipocyte-specific knockout of GSK3β expands AT vascularization and mitigates obesity-related metabolic disorders. GSK3β deficiency, but not GSK3α, in adipocytes activates AMPK (AMP-activated protein kinase), leading to increased phosphorylation and nuclear accumulation of HIF-2α, resulting in enhanced transcriptional regulation. Consequently, adipocytes increased VEGF (vascular endothelial growth factor) expression, which engages VEGFR2 on endothelial cells, promoting angiogenesis, expanding the vasculature, and improving vessel perfusion within obese AT. GSK3β deficiency promotes AT remodeling, shifting unhealthy adipocyte function toward a healthier state by increasing insulin-sensitizing hormone adiponectin and preserving healthy adipocyte function. These effects lead to reduced fibrosis, reactive oxygen species, and ER stress in obese AT and improve metabolic disorders associated with obesity.
CONCLUSIONS: Deletion of GSK3β in adipocytes activates the AMPK/HIF-2α/VEGF/VEGFR2 axis, promoting vasculature expansion within obese AT. This results in a significantly improved local microenvironment, reducing inflammation and effectively ameliorating metabolic disorders associated with obesity.

Keywords: AMP-activated protein kinases; basic helix-loop-helix transcription factors; glycogen synthase kinase 3; metabolic diseases; obesity; vascular endothelial growth factor A

DOI: https://doi.org/10.1161/CIRCRESAHA.124.325187

Neuroscience. 2024 Nov 29. pii: S0306-4522(24)00691-2. [Epub ahead of print]

Reduced 17β-estradiol following ovariectomy induces mitochondrial dysfunction and degradation of synaptic proteins in the entorhinal cortex.

Olayemi Joseph Olajide, Ariel A Batallán Burrowes, Igor Ferraz da Silva, Andreas Bergdahl, Clifton Andrew Chapman.

Reductions in circulating estrogens can contribute to cognitive decline, in part by impairing mitochondrial function within the hippocampal region. The entorhinal cortex provides the hippocampus with its main cortical input and, to assess the impact of estrogen deficiency on mitochondrial respiration and synaptic proteins in the entorhinal cortex, wildtype rats received either sham surgery, bilateral ovariectomy, or ovariectomy with implantation of a subdermal capsule to maintain low levels of 17β-estradiol (E2). Mitochondrial respiration in the entorhinal cortex was not significantly affected two weeks following ovariectomy, but there was a reduction in oxygen consumption four weeks after ovariectomy that was prevented by E2 supplementation. The expression of mitochondrial membrane integrity element voltage-dependent anion channel protein (VDAC1) was also reduced four weeks after ovariectomy, suggesting that respiration was reduced due to a decline in mitochondrial density. Ovariectomy also increased mitochondrial and cytoplasmic cytochrome c and upregulated superoxide dismutase 2 (SOD2) both two and four weeks after ovariectomy, reflecting mitochondrial electron leakage and oxidative redox imbalance. Further, the ovariectomy-induced changes in mitochondrial proteins were associated with reductions in postsynaptic density protein 95 (PSD95) and the presynaptic protein synaptophysin. There were no changes in mitochondrial or synaptic proteins in ovariectomized animals that received E2 supplementation. Our findings indicate that reductions in circulating 17β-estradiol induced by ovariectomy disrupt mitochondrial functions in the entorhinal cortex, and suggest that a resulting increase in oxidative stress contributes to the degradation in synaptic proteins that may affect cognitive functions mediated by the hippocampal region.

Keywords: Estrogens; Mitochondria; Ovariectomy; Oxidative stress; Rat; Respirometry

DOI: https://doi.org/10.1016/j.neuroscience.2024.11.071