bims-obesme 2024-07-14 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2024‒07‒14
eleven papers selected by
Xiong Weng, University of Edinburgh

Diet induced insulin resistance is due to induction of PTEN expression.
Short-Term Statin Therapy Induces Hepatic Insulin Resistance Through HNF4α/PAQR9/PPM1α Axis Regulated AKT Phosphorylation.
M6A modification and T cells in adipose tissue inflammation.
Novel perspectives on autophagy-oxidative stress-inflammation axis in the orchestration of adipogenesis.
tRNA m1A modification regulate HSC maintenance and self-renewal via mTORC1 signaling.
Ceramides in the central control of metabolism.
The caspase-activated DNase promotes cellular senescence.
Quantification of cell cycle re-entry during dedifferentiation of primary adipocytes in vitro.
KAP1 negatively regulates RNA polymerase II elongation kinetics to activate signal-induced transcription.
Dynamics of single-nuclei transcriptomic profiling of adipose tissue from diverse anatomical locations during mouse aging process.
PKM2 aggregation drives metabolism reprograming during aging process.

Res Sq. 2024 Jun 27. pii: rs.3.rs-4021885. [Epub ahead of print]

Diet induced insulin resistance is due to induction of PTEN expression.

Neal Rosen, Radha Mukherjee, Priya Pancholi, Malvika Sharma, Hilla Solomon, Merna Timaul, Claire Thant, Rory McGriskin, Omar Hayatt, Vladimir Markov, John D'Allara, Simona Bekker, Jacqueline Candelier, Sebastian Carrasco, Elisa de Stanchina, Kiran Vanaja.

Type 2 Diabetes (T2D) is a condition that is often associated with obesity and defined by reduced sensitivity of PI3K signaling to insulin (insulin resistance), hyperinsulinemia and hyperglycemia. Molecular causes and early signaling events underlying insulin resistance are not well understood. Insulin activation of PI3K signaling causes mTOR dependent induction of PTEN translation, a negative regulator of PI3K signaling. We speculated that insulin resistance is due to insulin dependent induction of PTEN protein that prevent further increases in PI3K signaling. Here we show that in a diet induced model of obesity and insulin resistance, PTEN levels are increased in fat, muscle and liver tissues. Onset of hyperinsulinemia and PTEN induction in tissue is followed by hyperglycemia, hepatic steatosis and severe glucose intolerance. Treatment with a PTEN phosphatase inhibitor prevents and reverses these phenotypes, whereas an mTORC1 kinase inhibitor reverses all but the hepatic steatosis. These data suggest that induction of PTEN by increasing levels of insulin elevates feedback inhibition of the pathway to a point where downstream PI3K signaling is reduced and hyperglycemia ensues. PTEN induction is thus necessary for insulin resistance and the type 2 diabetes phenotype and a potential therapeutic target.

DOI: https://doi.org/10.21203/rs.3.rs-4021885/v1
Adv Sci (Weinh). 2024 Jul 05. e2403451

Short-Term Statin Therapy Induces Hepatic Insulin Resistance Through HNF4α/PAQR9/PPM1α Axis Regulated AKT Phosphorylation.

Yijun Lin, Shuying Wang, Zixuan Li, Yuling Zhou, Ruiying Wang, Yan Wang, Yan Chen.

  Statins, the first-line medication for dyslipidemia, are linked to an increased risk of type 2 diabetes. But exactly how statins cause diabetes is yet unknown. In this study, a developed short-term statin therapy on hyperlipidemia mice show that hepatic insulin resistance is a cause of statin-induced diabetes. Statin medication raises the expression of progesterone and adiponectin receptor 9 (PAQR9) in liver, which inhibits insulin signaling through degradation of protein phosphatase, Mg2+/Mn2+ dependent 1 (PPM1α) to activate ERK pathway. STIP1 homology and U-box containing protein 1 (STUB1) is found to mediate ubiquitination of PPM1α promoted by PAQR9. On the other hand, decreased activity of hepatocyte nuclear factor 4 alpha (HNF4α) seems to be the cause of PAQR9 expression under statin therapy. The interventions on PAQR9, including deletion of PAQR9, caloric restriction and HNF4α activation, are all effective treatments for statin-induced diabetes, while liver specific over-expression of PPM1α is another possible tactic. The results reveal the importance of HNF4α-PAQR9-STUB1-PPM1α axis in controlling the statin-induced hepatic insulin resistance, offering a fresh insight into the molecular mechanisms underlying statin therapy.

Keywords:  AKT phosphorylation; hepatic insulin resistance; progesterone and adiponectin receptor 9 (PAQR9); statins; type 2 diabetes

DOI:  https://doi.org/10.1002/advs.202403451
Cell Biochem Funct. 2024 Jul;42(5): e4089

M6A modification and T cells in adipose tissue inflammation.

Xiaoting Yang, Haojun Tang, Xuan Sun, Qingjun Gui.

  Adipose tissue in the obese state can lead to low-grade chronic inflammation while inducing or exacerbating obesity-related metabolic diseases and impairing overall health.T cells, which are essential immune cells similar to macrophages, are widely distributed in adipose tissue and perform their immunomodulatory function; they also cross-talk with other cells in the vascular stromal fraction. Based on a large number of studies, it has been found that N6 methyl adenine (m6A) is one of the most representative of epigenetic modifications, which affects the crosstalk between T cells, as well as other immune cells, in several ways and plays an important role in the development of adipose tissue inflammation and related metabolic diseases. In this review, we first provide an overview of the widespread presence of T cells in adipose tissue and summarize the key role of T cells in adipose tissue inflammation. Next, we explored the effects of m6A modifications on T cells in adipose tissue from the perspective of adipose tissue inflammation. Finally, we discuss the impact of m6a-regulated crosstalk between T cells and immune cells on the prospects for improving adipose tissue inflammation research, providing additional new ideas for the treatment of obesity.

Keywords:  T cells; adipose tissue; cell crosstalk; inflammation; m6A

DOI:  https://doi.org/10.1002/cbf.4089
Front Endocrinol (Lausanne). 2024 ;15 1404697

Novel perspectives on autophagy-oxidative stress-inflammation axis in the orchestration of adipogenesis.

Chun Hong, Xinming Li, Kunli Zhang, Qiuyan Huang, Baohong Li, Haiyun Xin, Bin Hu, Fanming Meng, Xiangxing Zhu, Dongsheng Tang, Chuanhuo Hu, Chenyu Tao, Jianhao Li, Yang Cao, Hai Wang, Bo Deng, Sutian Wang.

  Adipose tissue, an indispensable organ, fulfils the pivotal role of energy storage and metabolism and is instrumental in maintaining the dynamic equilibrium of energy and health of the organism. Adipocyte hypertrophy and adipocyte hyperplasia (adipogenesis) are the two primary mechanisms of fat deposition. Mature adipocytes are obtained by differentiating mesenchymal stem cells into preadipocytes and redifferentiation. However, the mechanisms orchestrating adipogenesis remain unclear. Autophagy, an alternative cell death pathway that sustains intracellular energy homeostasis through the degradation of cellular components, is implicated in regulating adipogenesis. Furthermore, adipose tissue functions as an endocrine organ, producing various cytokines, and certain inflammatory factors, in turn, modulate autophagy and adipogenesis. Additionally, autophagy influences intracellular redox homeostasis by regulating reactive oxygen species, which play pivotal roles in adipogenesis. There is a growing interest in exploring the involvement of autophagy, inflammation, and oxidative stress in adipogenesis. The present manuscript reviews the impact of autophagy, oxidative stress, and inflammation on the regulation of adipogenesis and, for the first time, discusses their interactions during adipogenesis. An integrated analysis of the role of autophagy, inflammation and oxidative stress will contribute to elucidating the mechanisms of adipogenesis and expediting the exploration of molecular targets for treating obesity-related metabolic disorders.

Keywords:  adipogenesis; autophagy; immune responses; inflammation; oxidative stress

DOI:  https://doi.org/10.3389/fendo.2024.1404697
Nat Commun. 2024 Jul 08. 15(1): 5706

tRNA m1A modification regulate HSC maintenance and self-renewal via mTORC1 signaling.

Hongna Zuo, Aiwei Wu, Mingwei Wang, Liquan Hong, Hu Wang.

Haematopoietic stem cells (HSCs) possess unique physiological adaptations to sustain blood cell production and cope with stress responses throughout life. To maintain these adaptations, HSCs rely on maintaining a tightly controlled protein translation rate. However, the mechanism of how HSCs regulate protein translation remains to be fully elucidated. In this study, we investigate the role of transfer RNA (tRNA) m1A58 'writer' proteins TRMT6 and TRMT61A in regulating HSCs function. Trmt6 deletion promoted HSC proliferation through aberrant activation of mTORC1 signaling. TRMT6-deficient HSCs exhibited an impaired self-renewal ability in competitive transplantation assay. Mechanistically, single cell RNA-seq analysis reveals that the mTORC1 signaling pathway is highly upregulated in HSC-enriched cell populations after Trmt6 deletion. m1A-tRNA-seq and Western blot analysis suggest that TRMT6 promotes methylation modification of specific tRNA and expression of TSC1, fine-tuning mTORC1 signaling levels. Furthermore, Pharmacological inhibition of the mTORC1 pathway rescued functional defect in TRMT6-deficient HSCs. To our knowledge, this study is the first to elucidate a mechanism by which TRMT6-TRMT61A complex-mediated tRNA-m1A58 modification regulates HSC homeostasis.

DOI: https://doi.org/10.1038/s41467-024-50110-9
Trends Endocrinol Metab. 2024 Jul 06. pii: S1043-2760(24)00167-X. [Epub ahead of print]

Ceramides in the central control of metabolism.

Miguel López, Carlos Diéguez, Manuel Tena-Sempere, Ismael González-García.

  Central ceramides regulate energy metabolism by impacting hypothalamic neurons. This allows ceramides to integrate endocrine signals - such as leptin, ghrelin, thyroid hormones, or estradiol - and to modulate the central control of puberty. In this forum article we discuss recent evidence suggesting that specific ceramide species and neuronal populations are involved in these effects.

Keywords:  ceramides; food intake; glucose metabolism; hypothalamus; thermogenesis

DOI:  https://doi.org/10.1016/j.tem.2024.06.007
EMBO J. 2024 Jul 08.

The caspase-activated DNase promotes cellular senescence.

Aladin Haimovici, Valentin Rupp, Tarek Amer, Abdul Moeed, Arnim Weber, Georg Häcker.

  Cellular senescence is a response to many stressful insults. DNA damage is a consistent feature of senescent cells, but in many cases its source remains unknown. Here, we identify the cellular endonuclease caspase-activated DNase (CAD) as a critical factor in the initiation of senescence. During apoptosis, CAD is activated by caspases and cleaves the genomic DNA of the dying cell. The CAD DNase is also activated by sub-lethal signals in the apoptotic pathway, causing DNA damage in the absence of cell death. We show that sub-lethal signals in the mitochondrial apoptotic pathway induce CAD-dependent senescence. Inducers of cellular senescence, such as oncogenic RAS, type-I interferon, and doxorubicin treatment, also depend on CAD presence for senescence induction. By directly activating CAD experimentally, we demonstrate that its activity is sufficient to induce senescence in human cells. We further investigate the contribution of CAD to senescence in vivo and find substantially reduced signs of senescence in organs of ageing CAD-deficient mice. Our results show that CAD-induced DNA damage in response to various stimuli is an essential contributor to cellular senescence.

Keywords:  Ageing; Apoptosis; Caspase-activated DNase; Senescence

DOI:  https://doi.org/10.1038/s44318-024-00163-9
Adipocyte. 2024 Dec;13(1): 2376571

Quantification of cell cycle re-entry during dedifferentiation of primary adipocytes in vitro.

Ewa Bielczyk-Maczynska.

  Dedifferentiated adipose tissue (DFAT) has been proposed as a promising source of patient-specific multipotent progenitor cells (MPPs). During induced dedifferentiation, adipocytes exhibit profound gene expression and cell morphology changes. However, dedifferentiation of post-mitotic cells is expected to enable proliferation, which is critical if enough MPPs are to be obtained. Here, lineage tracing was employed to quantify cell proliferation in mouse adipocytes subjected to a dedifferentiation-inducing protocol commonly used to obtain DFAT cells. No evidence of cell proliferation in adipocyte-derived cells was observed, in contrast to the robust proliferation of non-adipocyte cells present in adipose tissue. We conclude that proliferative MPPs derived using the ceiling culture method most likely arise from non-adipocyte cells in adipose tissue.

Keywords:  Adipocyte; DFAT cells; cell cycle; dedifferentiation; lineage tracing

DOI:  https://doi.org/10.1080/21623945.2024.2376571
Nat Commun. 2024 Jul 12. 15(1): 5859

KAP1 negatively regulates RNA polymerase II elongation kinetics to activate signal-induced transcription.

Usman Hyder, Ashwini Challa, Micah Thornton, Tulip Nandu, W Lee Kraus, Iván D'Orso.

Signal-induced transcriptional programs regulate critical biological processes through the precise spatiotemporal activation of Immediate Early Genes (IEGs); however, the mechanisms of transcription induction remain poorly understood. By combining an acute depletion system with several genomics approaches to interrogate synchronized, temporal transcription, we reveal that KAP1/TRIM28 is a first responder that fulfills the temporal and heightened transcriptional demand of IEGs. Acute KAP1 loss triggers an increase in RNA polymerase II elongation kinetics during early stimulation time points. This elongation defect derails the normal progression through the transcriptional cycle during late stimulation time points, ultimately leading to decreased recruitment of the transcription apparatus for re-initiation thereby dampening IEGs transcriptional output. Collectively, KAP1 plays a counterintuitive role by negatively regulating transcription elongation to support full activation across multiple transcription cycles of genes critical for cell physiology and organismal functions.

DOI: https://doi.org/10.1038/s41467-024-49905-7
Sci Rep. 2024 Jul 12. 14(1): 16093

Dynamics of single-nuclei transcriptomic profiling of adipose tissue from diverse anatomical locations during mouse aging process.

Yujie Wu, Ying Sun, Long Chen, Xingyan Tong, Can Liu, Lu Lu, Rui Zhang, Siyuan Wang, Ziyu Chen, Jiaman Zhang, Ziyin Han, Bo Zeng, Mingzhou Li, Long Jin.

Adipose tissue plays critical roles in an individual's aging process. In this research, we use single-nucleus RNA sequencing to create highly detailed transcriptional maps of subcutaneous adipose tissue and visceral adipose tissue in young and aged mice. We comprehensively identify the various cell types within the white adipose tissue of mice, our study has elucidated seven distinct cell types within this tissue. Further analyses focus on adipocytes, fibro-adipogenic progenitors, and immune cells, revealing age-related declines in the synthetic metabolic activity of adipocytes, diminished immune regulation, and reduced maturation or proliferation of fibroblasts in undifferentiated adipocytes. We confirm the presence of distinct subpopulations of adipocytes, highlighting decreases in adipogenesis subgroups due to aging. Additionally, we uncover a reduction in immune cell subpopulations, driven by age-associated immune system dysregulation. Furthermore, pseudo-time analyses indicate that Adipocyte1 represents the 'nascent' phase of adipocyte development, while Adipocyte2 represents the 'mature' phase. We use cell-cell interaction to explore the age-dependent complexities of the interactions between FAPs and adipocytes, and observed increased expression of the inflammation-related Retn-Tlr4 interaction in older mice, while the anti-inflammatory Angpt1-Tek interaction was only detected in young mice. These transcriptional profiles serve as a valuable resource for understanding the functional genomics underlying metabolic disorders associated with aging in human adipose tissue.

DOI: https://doi.org/10.1038/s41598-024-66918-w
Nat Commun. 2024 Jul 09. 15(1): 5761

PKM2 aggregation drives metabolism reprograming during aging process.

Juntao Bie, Ridong Li, Yutong Li, Chen Song, Zhaoming Chen, Tianzhuo Zhang, Zhiheng Tang, Li Su, Liangyi Zhu, Jiaxin Wang, You Wan, Jun Chen, Xiaoyun Liu, Tingting Li, Jianyuan Luo.

While protein aggregation's association with aging and age-related diseases is well-established, the specific proteins involved and whether dissolving them could alleviate aging remain unclear. Our research addresses this gap by uncovering the role of PKM2 aggregates in aging. We find that PKM2 forms aggregates in senescent cells and organs from aged mice, impairing its enzymatic activity and glycolytic flux, thereby driving cells into senescence. Through a rigorous two-step small molecule library screening, we identify two compounds, K35 and its analog K27, capable of dissolving PKM2 aggregates and alleviating senescence. Further experiments show that treatment with K35 and K27 not only alleviate aging-associated signatures but also extend the lifespan of naturally and prematurely aged mice. These findings provide compelling evidence for the involvement of PKM2 aggregates in inducing cellular senescence and aging phenotypes, and suggest that targeting these aggregates could be a promising strategy for anti-aging drug discovery.

DOI: https://doi.org/10.1038/s41467-024-50242-y