bims-obesme 2024-04-28 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2024‒04‒28
fourteen papers selected by
Xiong Weng, University of Edinburgh

AZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation.
TM7SF3 controls TEAD1 splicing to prevent MASH-induced liver fibrosis.
Gamma-aminobutyric acid supplementation improves olanzapine-induced insulin resistance by inhibiting macrophage infiltration in mice subcutaneous adipose tissue.
BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.
Alcohol-Associated Liver Disease Outcomes: Critical Mechanisms of Liver Injury Progression.
Editorial: The role of GPCRs in obesity.
Cold induces brain region-selective neuronal activity-dependent lipid metabolism.
Gkongensin A, an HSP90β inhibitor, improves hyperlipidemia, hepatic steatosis, and insulin resistance.
Hepatic Sirt6 activation abrogates acute liver failure.
Adipocyte PI3K links adipostasis with baseline insulin secretion at fasting through an adipoincretin effect.
miR-141/200c contributes to ethanol-mediated hepatic glycogen metabolism.
Trauma-associated extracellular histones mediate inflammation via a MYD88-IRAK1-ERK signaling axis and induce lytic cell death in human adipocytes.
The molecular mechanism of macrophage-adipocyte crosstalk in maintaining energy homeostasis.
M2 macrophage-derived TGF-β induces age-associated loss of adipogenesis through progenitor cell senescence.

Nat Commun. 2024 Apr 20. 15(1): 3377

AZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation.

Sheng Qiu, Qinan Wu, Hao Wang, Dongfang Liu, Chen Chen, Zhiming Zhu, Hongting Zheng, Gangyi Yang, Ling Li, Mengliu Yang.

Zinc-alpha2-glycoprotein (AZGP1) has been implicated in peripheral metabolism; however, its role in regulating energy metabolism in the brain, particularly in POMC neurons, remains unknown. Here, we show that AZGP1 in POMC neurons plays a crucial role in controlling whole-body metabolism. POMC neuron-specific overexpression of Azgp1 under high-fat diet conditions reduces energy intake, raises energy expenditure, elevates peripheral tissue leptin and insulin sensitivity, alleviates liver steatosis, and promotes adipose tissue browning. Conversely, mice with inducible deletion of Azgp1 in POMC neurons exhibit the opposite metabolic phenotypes, showing increased susceptibility to diet-induced obesity. Notably, an increase in AZGP1 signaling in the hypothalamus elevates STAT3 phosphorylation and increases POMC neuron excitability. Mechanistically, AZGP1 enhances leptin-JAK2-STAT3 signaling by interacting with acylglycerol kinase (AGK) to block its ubiquitination degradation. Collectively, these results suggest that AZGP1 plays a crucial role in regulating energy homeostasis and glucose/lipid metabolism by acting on hypothalamic POMC neurons.

DOI: https://doi.org/10.1038/s41467-024-47684-9
Cell Metab. 2024 Apr 22. pii: S1550-4131(24)00123-2. [Epub ahead of print]

TM7SF3 controls TEAD1 splicing to prevent MASH-induced liver fibrosis.

Roi Isaac, Gautam Bandyopadhyay, Theresa V Rohm, Sion Kang, Jinyue Wang, Narayan Pokhrel, Sadatsugu Sakane, Rizaldy Zapata, Avraham M Libster, Yaron Vinik, Asres Berhan, Tatiana Kisseleva, Zea Borok, Yehiel Zick, Francesca Telese, Nicholas J G Webster, Jerrold M Olefsky.

  The mechanisms of hepatic stellate cell (HSC) activation and the development of liver fibrosis are not fully understood. Here, we show that deletion of a nuclear seven transmembrane protein, TM7SF3, accelerates HSC activation in liver organoids, primary human HSCs, and in vivo in metabolic-dysfunction-associated steatohepatitis (MASH) mice, leading to activation of the fibrogenic program and HSC proliferation. Thus, TM7SF3 knockdown promotes alternative splicing of the Hippo pathway transcription factor, TEAD1, by inhibiting the splicing factor heterogeneous nuclear ribonucleoprotein U (hnRNPU). This results in the exclusion of the inhibitory exon 5, generating a more active form of TEAD1 and triggering HSC activation. Furthermore, inhibiting TEAD1 alternative splicing with a specific antisense oligomer (ASO) deactivates HSCs in vitro and reduces MASH diet-induced liver fibrosis. In conclusion, by inhibiting TEAD1 alternative splicing, TM7SF3 plays a pivotal role in mitigating HSC activation and the progression of MASH-related fibrosis.

Keywords:  ASO; Hippo pathway; MASH; NASH; TEAD1; TM7SF3; alternative splicing; fibrosis; hepatic stellate cells

DOI:  https://doi.org/10.1016/j.cmet.2024.04.003
Diabetes Obes Metab. 2024 Apr 25.

Gamma-aminobutyric acid supplementation improves olanzapine-induced insulin resistance by inhibiting macrophage infiltration in mice subcutaneous adipose tissue.

Lulu Ren, Lingling Xuan, Anning Li, Yaqi Yang, Wen Zhang, Jie Zhang, Yi Zhang, Zhuoling An.

  AIMS: To investigate whether gamma-aminobutyric acid (GABA) supplementation improves insulin resistance during olanzapine treatment in mice and to explore the underlying mechanisms.MATERIALS AND METHODS: Insulin resistance and body weight gain were induced in mice by 10 weeks of olanzapine treatment. Simultaneously, the mice were administered GABA after 4 weeks of olanzapine administration.
RESULTS: We found that mice treated with olanzapine had lower GABA levels in serum and subcutaneous white adipose tissue (sWAT). GABA supplementation restored GABA levels and improved olanzapine-induced lipid metabolism disorders and insulin resistance. Chronic inflammation in adipose tissue is one of the main contributors to insulin resistance. We found that GABA supplementation inhibited olanzapine-induced adipose tissue macrophage infiltration and M1-like polarization, especially in sWAT. In vitro studies showed that stromal vascular cells, rather than adipocytes, were sensitive to GABA. Furthermore, the results suggested that GABA improves olanzapine-induced insulin resistance at least in part through a GABAB receptor-dependent pathway.
CONCLUSIONS: These findings suggest that targeting GABA may be a potential therapeutic approach for olanzapine-induced metabolic disorders.

Keywords:  ATM; GABA; adipose; insulin resistance; olanzapine

DOI:  https://doi.org/10.1111/dom.15585
Cell. 2024 Apr 17. pii: S0092-8674(24)00346-5. [Epub ahead of print]

BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.

Anthony R P Verkerke, Dandan Wang, Naofumi Yoshida, Zachary H Taxin, Xu Shi, Shuning Zheng, Yuka Li, Christopher Auger, Satoshi Oikawa, Jin-Seon Yook, Melia Granath-Panelo, Wentao He, Guo-Fang Zhang, Mami Matsushita, Masayuki Saito, Robert E Gerszten, Evanna L Mills, Alexander S Banks, Yasushi Ishihama, Phillip J White, Robert W McGarrah, Takeshi Yoneshiro, Shingo Kajimura.

  Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is protective against type 2 diabetes, independent of body weight. The mechanism underlying this dissociation remains unclear. Here, we report that impaired mitochondrial catabolism of branched-chain amino acids (BCAAs) in BAT, by deleting mitochondrial BCAA carriers (MBCs), caused systemic insulin resistance without affecting energy expenditure and body weight. Brown adipocytes catabolized BCAA in the mitochondria as nitrogen donors for the biosynthesis of non-essential amino acids and glutathione. Impaired mitochondrial BCAA-nitrogen flux in BAT resulted in increased oxidative stress, decreased hepatic insulin signaling, and decreased circulating BCAA-derived metabolites. A high-fat diet attenuated BCAA-nitrogen flux and metabolite synthesis in BAT, whereas cold-activated BAT enhanced the synthesis. This work uncovers a metabolite-mediated pathway through which BAT controls metabolic health beyond thermogenesis.

Keywords:  amino acid metabolism; bioenergetics; brown adipose tissue; diabetes; glucose homeostasis; insulin resistance; inter-organ communication; mitochondria; thermogenesis

DOI:  https://doi.org/10.1016/j.cell.2024.03.030
Biomolecules. 2024 Mar 27. pii: 404. [Epub ahead of print]14(4):

Alcohol-Associated Liver Disease Outcomes: Critical Mechanisms of Liver Injury Progression.

Natalia A Osna, Irina Tikhanovich, Martí Ortega-Ribera, Sebastian Mueller, Chaowen Zheng, Johannes Mueller, Siyuan Li, Sadatsugu Sakane, Raquel Carvalho Gontijo Weber, Hyun Young Kim, Wonseok Lee, Souradipta Ganguly, Yusuke Kimura, Xiao Liu, Debanjan Dhar, Karin Diggle, David A Brenner, Tatiana Kisseleva, Neha Attal, Iain H McKillop, Shilpa Chokshi, Ram Mahato, Karuna Rasineni, Gyongyi Szabo, Kusum K Kharbanda.

  Alcohol-associated liver disease (ALD) is a substantial cause of morbidity and mortality worldwide and represents a spectrum of liver injury beginning with hepatic steatosis (fatty liver) progressing to inflammation and culminating in cirrhosis. Multiple factors contribute to ALD progression and disease severity. Here, we overview several crucial mechanisms related to ALD end-stage outcome development, such as epigenetic changes, cell death, hemolysis, hepatic stellate cells activation, and hepatic fatty acid binding protein 4. Additionally, in this review, we also present two clinically relevant models using human precision-cut liver slices and hepatic organoids to examine ALD pathogenesis and progression.

Keywords:  MetAld; alcohol-associated liver disease; cell death; epigenetics; fatty acid binding protein 4; fibrosis; hemolysis; hepatic stellate cells; hepatocellular carcinoma; models

DOI:  https://doi.org/10.3390/biom14040404
Front Endocrinol (Lausanne). 2024 ;15 1404969

Editorial: The role of GPCRs in obesity.

Chunye Zhang, Yi Wang, Takefumi Kimura, Ahmad H Al-Mrabeh.



Keywords:  GPCR; genetic variation; inflammation; metabolic abnormality; obesity

DOI:  https://doi.org/10.3389/fendo.2024.1404969
bioRxiv. 2024 Apr 17. pii: 2024.04.15.589506. [Epub ahead of print]

Cold induces brain region-selective neuronal activity-dependent lipid metabolism.

Hyeonyoung Min, Yale Y Yang, Yunlei Yang.

Previous studies have been focused on lipid metabolism in peripheral tissues such as adipose tissues, while little or nothing is known about that in the brain. It is well recognized that cold acclimations enhance adipocyte functions, including white adipose tissue (WAT) lipid lipolysis and beiging, and brown adipose tissue (BAT) thermogenesis in mammals. However, it remains unclear whether and how the genes responsible for lipid metabolism in the brain are also under the control of cold acclimations. Here, we show that cold exposure predominantly increases the expressions of the genes encoding lipid lipolysis in the paraventricular nucleus of the hypothalamus (PVH). Mechanistically, we find that inactivation of neurons in the PVH blunts the cold-induced lipid peroxidation and lipolysis. Together, these findings indicate that lipid metabolism in the PVH is cold sensitive, potentially participating in cold regulations of energy metabolism.

DOI: https://doi.org/10.1101/2024.04.15.589506
Heliyon. 2024 Apr 30. 10(8): e29367

Gkongensin A, an HSP90β inhibitor, improves hyperlipidemia, hepatic steatosis, and insulin resistance.

Kun Miao, Yawei Zhao, Ning Xue.

  The prevalence of obesity and its primary associated comorbidities, such as type 2 diabetes and fatty liver disease, has reached epidemic proportions, with no successful treatment available at present. Heat shock protein 90 (HSP90), a crucial chaperone, plays a key role in de novo lipogenesis (DNL) by stabilizing and maintaining sterol regulatory element binding protein (SREBP) activity. Kongensin A (KA), derived from Croton kongensis, inhibits RIP3-mediated necrosis, showing promise as an anti-necrotic and anti-inflammatory agent. It is not yet clear if KA, acting as an HSP90 inhibitor, can enhance hyperlipidemia, hepatic steatosis, and insulin resistance in obese individuals by controlling lipid metabolism. In this study, we first found that KA can potentially decrease lipid content at the cellular level. C57BL/6J mice were given a high-fat diet (HFD) and received KA and lovastatin through oral administration for 7 weeks. KA improved hyperlipidemia, fatty liver, and insulin resistance, as well as reduced body weight in diet-induced obese (DIO) mice, with no significant alteration in food intake. In vitro, KA suppressed DNL and reduced the amounts of mSREBPs. KA promoted mSREBP degradation via the FBW7-mediated ubiquitin-proteasome pathway. KA decreased the level of p-Akt Ser308, and p-GSK3β Ser9 by inhibiting the interaction between HSP90β and Akt. Overall, KA enhanced hyperlipidemia, hepatic steatosis, and insulin resistance by blocking SREBP activity, thereby impacting the FBW7-controlled ubiquitin-proteasome pathway.

Keywords:  DNL; Hsp90β; Hyperlipidemia; Insulin resistance; Kongensin a; SREBPs

DOI:  https://doi.org/10.1016/j.heliyon.2024.e29367
Cell Death Dis. 2024 Apr 22. 15(4): 283

Hepatic Sirt6 activation abrogates acute liver failure.

Jinque Luo, Huan Liu, Yanni Xu, Nanhui Yu, Rebbeca A Steiner, Xiaoqian Wu, Shuyi Si, Zheng Gen Jin.

Acute liver failure (ALF) is a deadly illness due to insufficient detoxification in liver induced by drugs, toxins, and other etiologies, and the effective treatment for ALF is very limited. Among the drug-induced ALF, acetaminophen (APAP) overdose is the most common cause. However, the molecular mechanisms underlying APAP hepatoxicity remain incompletely understood. Sirtuin 6 (Sirt6) is a stress responsive protein deacetylase and plays an important role in regulation of DNA repair, genomic stability, oxidative stress, and inflammation. Here, we report that genetic and pharmacological activation of Sirt6 protects against ALF in mice. We first observed that Sirt6 expression was significantly reduced in the liver tissues of human patients with ALF and mice treated with an overdose of APAP. Then we developed an inducible Sirt6 transgenic mice for Cre-mediated overexpression of the human Sirt6 gene in systemic (Sirt6-Tg) and hepatic-specific (Sirt6-HepTg) manners. Both Sirt6-Tg mice and Sirt6-HepTg mice exhibited the significant protection against APAP hepatoxicity. In contrast, hepatic-specific Sirt6 knockout mice exaggerated APAP-induced liver damages. Mechanistically, Sirt6 attenuated APAP-induced hepatocyte necrosis and apoptosis through downregulation of oxidative stress, inflammation, the stress-activated kinase JNK activation, and apoptotic caspase activation. Moreover, Sirt6 negatively modulated the level and activity of poly (ADP-ribose) polymerase 1 (PARP1) in APAP-treated mouse liver tissues. Importantly, the specific Sirt6 activator MDL-800 exhibited better therapeutic potential for APAP hepatoxicity than the current drug acetylcysteine. Furthermore, in the model of bile duct ligation induced ALF, hepatic Sirt6-KO exacerbated, but Sirt6-HepTg mitigated liver damage. Collectively, our results demonstrate that Sirt6 protects against ALF and suggest that targeting Sirt6 activation could be a new therapeutic strategy to alleviate ALF.

DOI: https://doi.org/10.1038/s41419-024-06537-5
Cell Rep. 2024 Apr 23. pii: S2211-1247(24)00460-1. [Epub ahead of print]43(5): 114132

Adipocyte PI3K links adipostasis with baseline insulin secretion at fasting through an adipoincretin effect.

Barbara Becattini, Angela Molinaro, Marcus Henricsson, Jan Borén, Giovanni Solinas.

  Insulin-PI3K signaling controls insulin secretion. Understanding this feedback mechanism is crucial for comprehending how insulin functions. However, the role of adipocyte insulin-PI3K signaling in controlling insulin secretion in vivo remains unclear. Using adipocyte-specific PI3Kα knockout mice (PI3KαAdQ) and a panel of isoform-selective PI3K inhibitors, we show that PI3Kα and PI3Kβ activities are functionally redundant in adipocyte insulin signaling. PI3Kβ-selective inhibitors have no effect on adipocyte AKT phosphorylation in control mice but blunt it in adipocytes of PI3KαAdQ mice, demonstrating adipocyte-selective pharmacological PI3K inhibition in the latter. Acute adipocyte-selective PI3K inhibition increases serum free fatty acid (FFA) and potently induces insulin secretion. We name this phenomenon the adipoincretin effect. The adipoincretin effect operates in fasted mice with increasing FFA and decreasing glycemia, indicating that it is not primarily a control system for blood glucose. This feedback control system defines the rates of adipose tissue lipolysis and chiefly controls basal insulin secretion during fasting.

Keywords:  AKT; CP: Metabolism; PI3K; diabetes; growth factors; incretin; insulin; insulin resistance; insulin secretion; mTOR; obesity

DOI:  https://doi.org/10.1016/j.celrep.2024.114132
Mol Metab. 2024 Apr 18. pii: S2212-8778(24)00073-5. [Epub ahead of print] 101942

miR-141/200c contributes to ethanol-mediated hepatic glycogen metabolism.

Melanie Tran, Shaynian Gilling, Jianguo Wu, Li Wang, Dong-Ju Shin.

  OBJECTIVE: Hepatic glucose metabolism is profoundly perturbed by excessive alcohol intake. miR-141/200c expression is significantly induced by chronic ethanol feeding. This study aimed at identifying the role of miR-141/200c in glucose homeostasis during chronic ethanol exposure.METHODS: WT and miR-141/200c KO mice were fed a control or an ethanol diet for 30 days, followed by a single binge of maltose dextrin or ethanol, respectively. Untargeted metabolomics analysis of hepatic primary metabolites was performed along with analyses for liver histology, gene expression, intracellular signaling pathways, and physiological relevance. Primary hepatocytes were used for mechanistic studies.
RESULTS: Mir-141/200c deficiency rewires hepatic glucose metabolism during chronic ethanol feeding, increasing the abundance of glucose intermediates including G6P, an allosteric activator for GS. miR-141/200c deficiency replenished glycogen depletion during chronic ethanol feeding accompanied by reduced GS phosphorylation in parallel with increased expression of PP1 glycogen targeting subunits. Moreover, miR-141/200c deficiency prevented ethanol-mediated increases in AMPK and CaMKK2 activity. Ethanol treatment reduced glycogen content in WT-hepatocytes, which was reversed by dorsomorphin, a selective AMPK inhibitor, while KO-hepatocytes displayed higher glycogen content than WT-hepatocytes in response to ethanol treatment. Furthermore, treatment of hepatocytes with A23187, a calcium ionophore activating CaMKK2, lowered glycogen content in WT-hepatocytes. Notably, the suppressive effect of A23187 on glycogen deposition was reversed by dorsomorphin, demonstrating that the glycogen depletion by A23187 is mediated by AMPK. KO-hepatocytes exhibited higher glycogen content than WT-hepatocytes in response to A23187. Finally, miR-141/200c deficiency led to improved glucose tolerance and insulin sensitivity during chronic ethanol feeding.
CONCLUSIONS: MIR-141/200c deficiency replenishes ethanol-mediated hepatic glycogen depletion through the regulation of GS activity and calcium signaling coupled with the AMPK pathway, improving glucose homeostasis and insulin sensitivity. These results underscore miR-141/200c as a potential therapeutic target for the management of alcohol intoxication.

Keywords:  Alcohol; Glucose; Glycogen; Liver; microRNA

DOI:  https://doi.org/10.1016/j.molmet.2024.101942
Cell Death Dis. 2024 Apr 23. 15(4): 285

Trauma-associated extracellular histones mediate inflammation via a MYD88-IRAK1-ERK signaling axis and induce lytic cell death in human adipocytes.

Julian Roos, Julia Zinngrebe, Markus Huber-Lang, Ludmila Lupu, Miriam A Schmidt, Hannah Strobel, Mike-Andrew Westhoff, Ulrich Stifel, Florian Gebhard, Martin Wabitsch, Tom Eirik Mollnes, Klaus-Michael Debatin, Rebecca Halbgebauer, Pamela Fischer-Posovszky.

Despite advances in the treatment and care of severe physical injuries, trauma remains one of the main reasons for disability-adjusted life years worldwide. Trauma patients often suffer from disturbances in energy utilization and metabolic dysfunction, including hyperglycemia and increased insulin resistance. White adipose tissue plays an essential role in the regulation of energy homeostasis and is frequently implicated in traumatic injury due to its ubiquitous body distribution but remains poorly studied. Initial triggers of the trauma response are mainly damage-associated molecular patterns (DAMPs) such as histones. We hypothesized that DAMP-induced adipose tissue inflammation contributes to metabolic dysfunction in trauma patients. Therefore, we investigated whether histone release during traumatic injury affects adipose tissue. Making use of a murine polytrauma model with hemorrhagic shock, we found increased serum levels of histones accompanied by an inflammatory response in white adipose tissue. In vitro, extracellular histones induced an inflammatory response in human adipocytes. On the molecular level, this inflammatory response was mediated via a MYD88-IRAK1-ERK signaling axis as demonstrated by pharmacological and genetic inhibition. Histones also induced lytic cell death executed independently of caspases and RIPK1 activity. Importantly, we detected increased histone levels in the bloodstream of patients after polytrauma. Such patients might benefit from a therapy consisting of activated protein C and the FDA-approved ERK inhibitor trametinib, as this combination effectively prevented histone-mediated effects on both, inflammatory gene activation and cell death in adipocytes. Preventing adipose tissue inflammation and adipocyte death in patients with polytrauma could help minimize posttraumatic metabolic dysfunction.

DOI: https://doi.org/10.1038/s41419-024-06676-9
Front Immunol. 2024 ;15 1378202

The molecular mechanism of macrophage-adipocyte crosstalk in maintaining energy homeostasis.

Yudie Zhang, Bin Zhang, Xiaobo Sun.

  Interactions between macrophages and adipocytes in adipose tissue are critical for the regulation of energy metabolism and obesity. Macrophage polarization induced by cold or other stimulations can drive metabolic reprogramming of adipocytes, browning, and thermogenesis. Accordingly, investigating the roles of macrophages and adipocytes in the maintenance of energy homeostasis is critical for the development of novel therapeutic approaches specifically targeting macrophages in metabolic disorders such as obesity. Current review outlines macrophage polarization not only regulates the release of central nervous system and inflammatory factors, but controls mitochondrial function, and other factor that induce metabolic reprogramming of adipocytes and maintain energy homeostasis. We also emphasized on how the adipocytes conversely motivate the polarization of macrophage. Exploring the interactions between adipocytes and macrophages may provide new therapeutic strategies for the management of obesity-related metabolic diseases.

Keywords:  brown adipose tissue; energy metabolism; fat; inflammation; macrophage polarization; mitochondrial function; obesity

DOI:  https://doi.org/10.3389/fimmu.2024.1378202
Mol Metab. 2024 Apr 22. pii: S2212-8778(24)00074-7. [Epub ahead of print] 101943

M2 macrophage-derived TGF-β induces age-associated loss of adipogenesis through progenitor cell senescence.

Xinyi Zeng, Teh-Wei Wang, Kiyoshi Yamaguchi, Seira Hatakeyama, Satoshi Yamazaki, Eigo Shimizu, Seiya Imoto, Yoichi Furukawa, Yoshikazu Johmura, Makoto Nakanishi.

OBJECTIVES: Adipose tissue is an endocrine and energy storage organ composed of several different cell types, including mature adipocytes, stromal cells, endothelial cells, and a variety of immune cells. Adipose tissue aging contributes to the pathogenesis of metabolic dysfunction and is likely induced by crosstalk between adipose progenitor cells (APCs) and immune cells, but the underlying molecular mechanisms remain largely unknown. In this study, we revealed the biological role of p16high senescent APCs, and investigated the crosstalk between each cell type in the aged white adipose tissue.METHODS: We performed the single-cell RNA sequencing (scRNA-seq) analysis on the p16high adipose cells sorted from aged p16-CreERT2/Rosa26-LSL-tdTomato mice. We also performed the time serial analysis on the age-dependent bulk RNA-seq datasets of human and mouse white adipose tissues to infer the transcriptome alteration of adipogenic potential within aging.
RESULTS: We show that M2 macrophage-derived TGF-β induces APCs senescence which impairs adipogenesis in vivo. p16high senescent APCs increase with age and show loss of adipogenic potential. The ligand-receptor interaction analysis reveals that M2 macrophages are the donors for TGF-β and the senescent APCs are the recipients. Indeed, treatment of APCs with TGF-β1 induces senescent phenotypes through mitochondrial ROS-mediated DNA damage in vitro. TGF-β1 injection into gonadal white adipose tissue (gWAT) suppresses adipogenic potential and induces fibrotic genes as well as p16 in APCs. A gWAT atrophy is observed in cancer cachexia by APCs senescence, whose induction appeared to be independent of TGF-β induction.
CONCLUSIONS: Our results suggest that M2 macrophage-derived TGF-β induces age-related lipodystrophy by APCs senescence. The TGF-β treatment induced DNA damage, mitochondrial ROS, and finally cellular senescence in APCs.

DOI: https://doi.org/10.1016/j.molmet.2024.101943