bims-aditis 2021-12-19 papers

Issue of 2021–12–19
six papers selected by
Matthew C. Sinton, University of Glasgow

Cell Rep. 2021 Dec 14. pii: S2211-1247(21)01598-9. [Epub ahead of print]37(11): 110104

Defective brown adipose tissue thermogenesis and impaired glucose metabolism in mice lacking Letmd1.

Kyung-Mi Choi, Jung Hak Kim, Xiangmudong Kong, Meltem Isik, Jin Zhang, Hee-Woong Lim, John C Yoon.

Manipulation of energy-dissipating adipocytes has the potential to produce metabolic benefits. To this end, it is valuable to understand the mechanisms controlling the generation and function of thermogenic fat. Here, we identify Letm1 domain containing 1 (Letmd1) as a regulator of brown fat formation and function. The expression of Letmd1 is induced in brown fat by cold exposure and by β-adrenergic activation. Letmd1-deficient mice exhibit severe cold intolerance concomitant with abnormal brown fat morphology, reduced thermogenic gene expression, and low mitochondrial content. The null mice exhibit impaired β3-adrenoreceptor-dependent thermogenesis and are prone to diet-induced obesity and defective glucose disposal. Letmd1 was previously described as a mitochondrial protein, and we find that it also localizes to the nucleus and interacts with the transcriptional coregulator and chromatin remodeler Brg1/Smarca4, thus providing a way to impact thermogenic gene expression. Our study uncovers a role for Letmd1 as a key regulatory component of adaptive thermogenesis.

Keywords: Letmd1; brown fat; thermogenesis

DOI: https://doi.org/10.1016/j.celrep.2021.110104

Mol Cell Endocrinol. 2021 Dec 12. pii: S0303-7207(21)00375-0. [Epub ahead of print] 111531

Interleukins in adipose tissue: Keeping the balance.

Barbara Antuna-Puente, Soraya Fellahi, Chloé McAvoy, Bruno Fève, Jean-Philippe Bastard.

The role of the immune system is to defend the host and preserve the functionality in response to stress. This function is not limited to infection or injury as it also plays a role in the response to overnutrition. Indeed, low-grade chronic activation of the immune system associated with overnutrition may be deleterious, contributing importantly to diabetes and long-term complications, such as cardiovascular disorders. Increasing evidence shows that adipose tissue participates in the obesity-related inflammatory response and that interleukins are one of the key players, either as a pro-inflammatory response to the metabolic dysregulation or to restore homeostasis. The crosstalk between adipocytes and immune cells through some important interleukins and their role in metabolic disruption is the topic of this review.

Keywords: Adipose tissue; Cytokine; Insulin resistance; Interleukins; Obesity

DOI: https://doi.org/10.1016/j.mce.2021.111531

J Intern Med. 2021 Dec 16.

Human white adipose tissue-a highly dynamic metabolic organ.

Peter Arner, Mikael Rydén.

Recent technological developments have allowed determination of the age of fat cells and their lipids in adult humans. In contrast to prior views, this has demonstrated a high turnover rate of the fat cells (10%/year) and their unilocular lipid droplets (six times/10 years). Fat cell turnover is increased in obesity and when adipose tissue is composed of many but small adipocytes (hyperplasia, a benign adipose phenotype). While fat mass gain increases adipocyte number and size, only the latter is altered (decreased) after weight loss which may facilitate weight regain. Fat cell lipid turnover is attenuated in subjects with excess body fat. In the subcutaneous region, this dysregulation occurs already in the overweight state while in the visceral depot, it is only observed in severe obesity. This may explain why the latter depot is particularly pernicious in the overweight/obese state as it allows for more rapid lipid fluxes between visceral fat and the liver. Adipose lipid turnover decreases during ageing due to impaired breakdown (lipolysis) of stored triglycerides. If this decline is not compensated by reduced adipocyte lipid uptake, bodyweight will increase over time. In concordance with this, low lipolysis rates are a risk factor for future weight gain and glucose intolerance. Adipose lipid turnover is also decreased in insulin resistance and certain forms of dyslipidemia. Altogether, adult human adipose tissue is in a highly dynamic state. Alterations in the turnover of fat cells and their lipids are therefore novel factors to consider in the pathophysiology of common metabolic disorders. This article is protected by copyright. All rights reserved.

Keywords: adipocyte; dyslipidemia; fatty acids; obesity; type 2 diabetes mellitus

DOI: https://doi.org/10.1111/joim.13435

Cardiovasc Res. 2021 Dec 13. pii: cvab359. [Epub ahead of print]

Interleukin-23 receptor expressing γδ T cells locally promote early atherosclerotic lesion formation and plaque necrosis in mice.

Jesus Gil-Pulido, Núria Amézaga, Ivana Jorgacevic, Helga D Manthey, Melanie Rösch, Theresa Brand, Peter Cidlinsky, Sarah Schäfer, Andreas Beilhack, Antoine-Emmanuel Saliba, Kristina Lorenz, Louis Boon, Immo Prinz, Ari Waisman, Thomas Korn, Clément Cochain, Alma Zernecke.

AIMS: Atherosclerosis is a chronic inflammatory disease of the vessel wall controlled by local and systemic immune responses. The role of interleukin-23 receptor (IL-23R), expressed in adaptive immune cells (mainly T helper 17 cells) and γδ T cells, in atherosclerosis is only incompletely understood. Here we investigated the vascular cell types expressing IL-23R and addressed the function of IL-23R and γδ T cells in atherosclerosis.
METHOD AND RESULTS: IL-23R+ cells were frequently found in the aortic root in contrast to the aorta in low density lipoprotein receptor deficient IL-23R reporter mice (Ldlr-/-Il23rgfp/+), and mostly identified as γδ T cells that express IL-17 and GM-CSF. scRNA-seq confirmed γδ T cells as the main cell type expressing Il23r and Il17a in the aorta. Ldlr-/-Il23rgfp/gfp mice deficient in IL-23R showed a loss of IL-23R+ cells in the vasculature, and had reduced atherosclerotic lesion formation in the aortic root compared to Ldlr-/- controls after 6 weeks of high fat diet feeding. In contrast, Ldlr-/-Tcrδ-/- mice lacking all γδ T cells displayed unaltered early atherosclerotic lesion formation compared to Ldlr-/- mice. In both HFD-fed Ldlr-/-Il23rgfp/gfp and Ldlr-/-Tcrδ-/- mice a reduction in the plaque necrotic core area was noted as well as an expansion of splenic regulatory T cells. In vitro, exposure of bone marrow-derived macrophages to both IL-17A and GM-CSF induced cell necrosis, and necroptotic RIP3K and MLKL expression, as well as inflammatory mediators.
CONCLUSIONS: IL-23R+ γδ T cells are predominantly found in the aortic root rather than the aorta and promote early atherosclerotic lesion formation, plaque necrosis and inflammation at this site. Targeting IL-23R may thus be explored as a therapeutic approach to mitigate atherosclerotic lesion development.
TRANSLATIONAL PERSPECTIVE: The mechanisms and cell types contributing to early inflammation and lesion formation are incompletely understood. Here we demonstrate that the aortic root harbors a population of IL23R-dependent γδ T cells that can release IL-17 and GM-CSF, and both cytokines together induce macrophage inflammation and necroptosis. IL-23R+ γδ T cells locally promote early lesion formation in the aortic root and contribute to the expansion of the necrotic core, a hallmark of vulnerable atherosclerotic lesions. Targeting IL-23R or IL-23 itself could thus be further explored as a therapeutic option in early atherosclerosis.

DOI: https://doi.org/10.1093/cvr/cvab359

Nat Metab. 2021 Dec 13.

Peroxisomal β-oxidation acts as a sensor for intracellular fatty acids and regulates lipolysis.

Lianggong Ding, Wenfei Sun, Miroslav Balaz, Anyuan He, Manuel Klug, Stefan Wieland, Robert Caiazzo, Violeta Raverdy, Francois Pattou, Philippe Lefebvre, Irfan J Lodhi, Bart Staels, Markus Heim, Christian Wolfrum.

To liberate fatty acids (FAs) from intracellular stores, lipolysis is regulated by the activity of the lipases adipose triglyceride lipase (ATGL), hormone-sensitive lipase and monoacylglycerol lipase. Excessive FA release as a result of uncontrolled lipolysis results in lipotoxicity, which can in turn promote the progression of metabolic disorders. However, whether cells can directly sense FAs to maintain cellular lipid homeostasis is unknown. Here we report a sensing mechanism for cellular FAs based on peroxisomal degradation of FAs and coupled with reactive oxygen species (ROS) production, which in turn regulates FA release by modulating lipolysis. Changes in ROS levels are sensed by PEX2, which modulates ATGL levels through post-translational ubiquitination. We demonstrate the importance of this pathway for non-alcoholic fatty liver disease progression using genetic and pharmacological approaches to alter ROS levels in vivo, which can be utilized to increase hepatic ATGL levels and ameliorate hepatic steatosis. The discovery of this peroxisomal β-oxidation-mediated feedback mechanism, which is conserved in multiple organs, couples the functions of peroxisomes and lipid droplets and might serve as a new way to manipulate lipolysis to treat metabolic disorders.

DOI: https://doi.org/10.1038/s42255-021-00489-2

World J Stem Cells. 2021 Nov 26. 13(11): 1696-1713

Regulation of the mesenchymal stem cell fate by interleukin-17: Implications in osteogenic differentiation.

Jelena Krstić, Slavko Mojsilović, Sonja S Mojsilović, Juan F Santibanez.

Bone regeneration is a tightly regulated process that ensures proper repair and functionality after injury. The delicate balance between bone formation and resorption is governed by cytokines and signaling molecules released during the inflammatory response. Interleukin (IL)-17A, produced in the early phase of inflammation, influences the fate of osteoprogenitors. Due to their inherent capacity to differentiate into osteoblasts, mesenchymal stem/stromal cells (MSCs) contribute to bone healing and regeneration. This review presents an overview of IL-17A signaling and the leading cellular and molecular mechanisms by which it regulates the osteogenic differentiation of MSCs. The main findings demonstrating IL-17A's influence on osteoblastogenesis are described. To this end, divergent information exists about the capacity of IL-17A to regulate MSCs' osteogenic fate, depending on the tissue context and target cell type, along with contradictory findings in the same cell types. Therefore, we summarize the data showing both the pro-osteogenic and anti-osteogenic roles of IL-17, which may help in the understanding of IL-17A function in bone repair and regeneration.

Keywords: Bone; Inflammation; Interleukin-17; Mesenchymal stem cells; Osteoblast; Osteogenesis

DOI: https://doi.org/10.4252/wjsc.v13.i11.1696