bims-mimead 2025-04-20 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–04–20
eleven papers selected by
Rachel M. Handy, University of Guelph

Spatial regulation of glucose and lipid metabolism by hepatic insulin signaling.
Difference Analysis of MiRNA Expression Profiles in Aged Female Rat Adipose Tissue Regulated by HIIT and MICT.
GDF15 links adipose tissue lipolysis with anxiety.
MicroRNAs in adipose tissue fibrosis: Mechanisms and therapeutic potential.
Targeting IRE1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in male obese mice.
Active control of mitochondrial network morphology by metabolism-driven redox state.
Interleukin-6 from the Adipose Secretome Potentiate Differentiation of Adipose Progenitors Through Activation of Redox Signaling.
Sex differences in lipid profiles of visceral adipose tissue with obesity and gonadectomy.
Sex-specific systemic metabolic predictors of resistance to calorie restriction-induced weight loss in obese Diversity Outbred mice.
Association of Lifestyle-Induced Weight Loss With Gene Expression in Subcutaneous Adipose Tissue in Metabolic Syndrome.
MitoSNO inhibits mitochondrial hydrogen peroxide (mtH2O2) generation by α-ketoglutarate dehydrogenase (KGDH).

Cell Metab. 2025 Apr 09. pii: S1550-4131(25)00207-4. [Epub ahead of print]

Spatial regulation of glucose and lipid metabolism by hepatic insulin signaling.

Baiyu He, Kyle D Copps, Oliver Stöhr, Beikl Liu, Songhua Hu, Shakchhi Joshi, Marcia C Haigis, Morris F White, Hao Zhu, Rongya Tao.

  Hepatic insulin sensitivity is critical for systemic glucose and lipid homeostasis. The liver is spatially organized into zones in which hepatocytes express distinct metabolic enzymes; however, the functional significance of this zonation to metabolic dysregulation caused by insulin resistance is undetermined. Here, we used CreER mice to selectively disrupt insulin signaling in periportal (PP) and pericentral (PC) hepatocytes. PP-insulin resistance has been suggested to drive combined hyperglycemia and excess lipogenesis in individuals with type 2 diabetes. However, PP-insulin resistance in mice impaired lipogenesis and suppressed high-fat diet (HFD)-induced hepatosteatosis, despite elevated gluconeogenesis and insulin. In contrast, PC-insulin resistance reduced HFD-induced PC steatosis while preserving normal glucose homeostasis, in part by shifting glycolytic metabolism from the liver to the muscle. These results demonstrate distinct roles of insulin in PP versus PC hepatocytes and suggest that PC-insulin resistance might be therapeutically useful to combat hepatosteatosis without compromising glucose homeostasis.

Keywords:  de novo lipogenesis; gluconeogenesis; hepatic glucose production; insulin resistance; insulin signaling; lipid metabolism; liver zonation; pericentral hepatocytes; periportal hepatocytes

DOI:  https://doi.org/10.1016/j.cmet.2025.03.015
Cell Biochem Biophys. 2025 Apr 18.

Difference Analysis of MiRNA Expression Profiles in Aged Female Rat Adipose Tissue Regulated by HIIT and MICT.

Pinshi Ni, Yingmin Su, Zhuangzhi Wang, Jianmei Cui, Peng Lu, Fanghui Li.

  Aging is frequently associated with dysregulated lipid metabolism, while exercise may improve metabolic health, a process in which microRNAs (miRNAs) play a pivotal regulatory role. However, the specific modulation of miRNA expression profiles by different exercise modalities remains poorly characterized. This study aimed to investigate adipose tissue miRNA profiles in aged rats following high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT). Eighteen-month-old female rats were divided into three groups (n = 12/group): sedentary (SED), MICT, and HIIT. After 8 weeks of exercise interventions, metabolic outcomes were assessed using Oil Red O staining to quantify intracellular lipid deposition, alongside Western blotting, immunofluorescence, and RT-qPCR to evaluate mRNA and protein expression of adipose tissue markers. Additionally, miRNA sequencing was performed on visceral adipose tissue to identify differentially expressed miRNAs (DEMs), followed by bioinformatic prediction of miRNA-mRNA interactions. Key findings revealed that the HIIT group exhibited more pronounced metabolic benefits compared to MICT, including reduced lipid accumulation (fewer Oil Red O-positive adipocytes) and upregulated expression of lipolytic and autophagy-related proteins (ATGL, HSL, PPAR-γ, ATG3, ATG5, ATG7, ATG12, and ATG16L). miRNA sequencing demonstrated greater divergence in expression profiles between HIIT and SED groups than between MICT and SED groups. KEGG pathway analysis highlighted significant enrichment in the MAPK, PI3K-Akt, and Rap1 signaling pathways. Furthermore, 11 DEMs (e.g., miR-34a, miR-146a) were identified as potential regulators of adipose aging, with hub genes including Shc1, Grb2, Itgb1, Ptpn11, Mapk14, Fyn, Plcg1, Sos1, and Actg1. In conclusion, HIIT significantly ameliorates age-related adipocyte inflammation and metabolic dysfunction. Exercise-induced miRNA reprogramming may alleviate the functional decline of aged adipose tissue, and HIIT-induced miRNA reprogramming is more abundant. The miRNA sequencing data pinpoint critical regulatory genes and pathways, providing novel insights into the molecular mechanisms by which exercise counteracts metabolic abnormalities in aged adipose tissue.

Keywords:  Aging; Exercise physiology; High-intensity interval training; Lipid metabolism; MicroRNA; Moderate-intensity continuous training

DOI:  https://doi.org/10.1007/s12013-025-01757-8
Nat Metab. 2025 Apr 15.

GDF15 links adipose tissue lipolysis with anxiety.

Logan K Townsend, Dongdong Wang, Carly M Knuth, Russta Fayyazi, Ahmad Mohammad, Léa J Becker, Evangelia E Tsakiridis, Eric M Desjardins, Zeel Patel, Celina M Valvano, Junfeng Lu, Alice E Payne, Ofure Itua, Kyle D Medak, Daniel M Marko, Jonathan D Schertzer, David C Wright, Shawn M Beaudette, Katherine M Morrison, André C Carpentier, Denis P Blondin, Rebecca E K MacPherson, Jordan G McCall, Marc G Jeschke, Gregory R Steinberg.

Psychological stress changes both behaviour and metabolism to protect organisms. Adrenaline is an important driver of this response. Anxiety correlates with circulating free fatty acid levels and can be alleviated by a peripherally restricted β-blocker, suggesting a peripheral signal linking metabolism with behaviour. Here we show that adrenaline, the β3 agonist CL316,243 and acute restraint stress induce growth differentiation factor 15 (GDF15) secretion in white adipose tissue of mice. Genetic inhibition of adipose triglyceride lipase or genetic deletion of β-adrenergic receptors blocks β-adrenergic-induced increases in GDF15. Increases in circulating GDF15 require lipolysis-induced free fatty acid stimulation of M2-like macrophages within white adipose tissue. Anxiety-like behaviour elicited by adrenaline or restraint stress is eliminated in mice lacking the GDF15 receptor GFRAL. These data provide molecular insights into the mechanisms linking metabolism and behaviour and suggest that inhibition of GDF15-GFRAL signalling might reduce acute anxiety.

DOI: https://doi.org/10.1038/s42255-025-01264-3
Genes Dis. 2025 Jul;12(4): 101287

MicroRNAs in adipose tissue fibrosis: Mechanisms and therapeutic potential.

Mei Tian, Yang Zhou, Yitong Guo, Qing Xia, Zehua Wang, Xinying Zheng, Jinze Shen, Junping Guo, Shiwei Duan, Lijun Wang.

  Adipose tissue fibrosis, characterized by abnormal extracellular matrix deposition within adipose tissue, signifies a crucial indicator of adipose tissue malfunction, potentially leading to organ tissue dysfunction. Various factors, including a high-fat diet, non-alcoholic fatty liver disease, and insulin resistance, coincide with adipose tissue fibrosis. MicroRNAs (miRNAs) represent a class of small non-coding RNAs with significant influence on tissue fibrosis through diverse signaling pathways. For instance, in response to a high-fat diet, miRNAs can modulate signaling pathways such as TGF-β/Smad, PI3K/AKT, and PPAR-γ to impact adipose tissue fibrosis. Furthermore, miRNAs play roles in inhibiting fibrosis in different contexts: suppressing corneal fibrosis via the TGF-β/Smad pathway, mitigating cardiac fibrosis through the VEGF signaling pathway, reducing wound fibrosis via regulation of the MAPK signaling pathway, and diminishing fibrosis post-fat transplantation via involvement in the PDGFR-β signaling pathway. Notably, the secretome released by miRNA-transfected adipose-derived stem cells facilitates targeted delivery of miRNAs to evade host immune rejection, enhancing their anti-fibrotic efficacy. Hence, this study endeavors to elucidate the role and mechanism of miRNAs in adipose tissue fibrosis and explore the mechanisms and advantages of the secretome released by miRNA-transfected adipose-derived stem cells in combating fibrotic diseases.

Keywords:  Adipose tissue fibrosis; Adipose-derived stem cell; Extracellular matrix; Signaling pathways; miRNAs

DOI:  https://doi.org/10.1016/j.gendis.2024.101287
Elife. 2025 Apr 17. pii: RP100581. [Epub ahead of print]13

Targeting IRE1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in male obese mice.

Dan Wu, Venkateswararao Eeda, Zahra Maria, Komal Rawal, Audrey Wang, Oana Herlea-Pana, Ram Babu Undi, Hui-Ying Lim, Weidong Wang.

  Overnutrition engenders the expansion of adipose tissue and the accumulation of immune cells, in particular, macrophages, in the adipose tissue, leading to chronic low-grade inflammation and insulin resistance. In obesity, several proinflammatory subpopulations of adipose tissue macrophages (ATMs) identified hitherto include the conventional 'M1-like' CD11C-expressing ATM and the newly discovered metabolically activated CD9-expressing ATM; however, the relationship among ATM subpopulations is unclear. The ER stress sensor inositol-requiring enzyme 1α (IRE1α) is activated in the adipocytes and immune cells under obesity. It is unknown whether targeting IRE1α is capable of reversing insulin resistance and obesity and modulating the metabolically activated ATMs. We report that pharmacological inhibition of IRE1α RNase significantly ameliorates insulin resistance and glucose intolerance in male mice with diet-induced obesity. IRE1α inhibition also increases thermogenesis and energy expenditure, and hence protects against high fat diet-induced obesity. Our study shows that the 'M1-like' CD11c+ ATMs are largely overlapping with but yet non-identical to CD9+ ATMs in obese white adipose tissue. Notably, IRE1α inhibition diminishes the accumulation of obesity-induced metabolically activated ATMs and 'M1-like' ATMs, resulting in the curtailment of adipose inflammation and ensuing reactivation of thermogenesis, without augmentation of the alternatively activated M2 macrophage population. Our findings suggest the potential of targeting IRE1α for the therapeutic treatment of insulin resistance and obesity.

Keywords:  ER stress; IRE1 alpha; adipose remodeling; adipose tissue macrophage; cell biology; insulin resistance; mouse; obesity

DOI:  https://doi.org/10.7554/eLife.100581
Proc Natl Acad Sci U S A. 2025 Apr 22. 122(16): e2421953122

Active control of mitochondrial network morphology by metabolism-driven redox state.

Gaurav Singh, Vineeth Vengayil, Aayushee Khanna, Swagata Adhikary, Sunil Laxman.

  Mitochondria are dynamic organelles that constantly change morphology. What controls mitochondrial morphology however remains unresolved. Using actively respiring yeast cells growing in distinct carbon sources, we find that mitochondrial morphology and activity are unrelated. Cells can exhibit fragmented or networked mitochondrial morphology in different nutrient environments independent of mitochondrial activity. Instead, mitochondrial morphology is controlled by the intracellular redox state, which itself depends on the nature of electron entry into the electron transport chain (ETC)-through complex I/II or directly to coenzyme Q/cytochrome c. In metabolic conditions where direct electron entry is high, reactive oxygen species (ROS) increase, resulting in an oxidized cytosolic environment and rapid mitochondrial fragmentation. Decreasing direct electron entry into the ETC by genetic or chemical means, or reducing the cytosolic environment rapidly restores networked morphologies. Using controlled disruptions of electron flow to alter ROS and redox state, we demonstrate minute-scale, reversible control between networked and fragmented forms in an activity-independent manner. Mechanistically, the fission machinery through Dnm1 responds in minute-scale to redox state changes, preceding the change in mitochondrial form. Thus, the metabolic state of the cell and its consequent cellular redox state actively control mitochondrial form.

Keywords:  electron transport chain; mitochondrial network; reactive oxygen species; redox state

DOI:  https://doi.org/10.1073/pnas.2421953122
Am J Physiol Cell Physiol. 2025 Apr 18.

Interleukin-6 from the Adipose Secretome Potentiate Differentiation of Adipose Progenitors Through Activation of Redox Signaling.

Jessica L Wager, Larissa G Baker, Taylor B Scheidl, Sophie Z Yonan, Pina Colarusso, Daniel Young, Antoine Dufour, Jennifer A Thompson.

  Under obesogenic conditions, it is thought that a signal arising from the adipose microenvironment triggers differentiation of adipose progenitor cell (APC); yet the identity and source of this signal remains unknown. Redox signaling was shown to influence adipogenesis in primary murine APCs treated with pharmacologic agents to manipulate the levels of reactive oxygen species (ROS). Increased generation of superoxide (O2-) and hydrogen peroxide (H2O2) via redox cyclers amplified APC differentiation, while differentiation was blunted with ROS scavengers and antioxidants. Protein was concentrated from conditioned media of adipose tissue explants cultured ex vivo to capture secreted factors. Differentiation was enhanced in APCs cultured in the presence of the adipose protein secretome, an effect that was diminished with scavenging of ROS and amplified when the secretome was collected from mice fed a high fat diet. Proteomic analysis revealed that the adipose secretome from animals on a high fat diet was enriched in pathways involved in immune cell responses and contained higher levels of cytokines including interleukin 6 (IL-6). A multiplex assay confirmed higher IL-6, which was predicted as a central regulator of differential levels of secretome proteins. Exposure of APCs to IL-6 increased adipogenesis, while treatment of APCs with an IL-6 blocking antibody diminished the adipogenic effect of the adipose secretome. Together, these findings substantiate a role for redox signaling in the regulation of adipogenesis and identify IL-6 as a potential secreted factor that may mediate activation of adipogenesis via ROS generation under obesogenic conditions.

Keywords:  Adipogenesis; Cross talk; Cytokine; Obesity; Redox Signaling

DOI:  https://doi.org/10.1152/ajpcell.00024.2025
J Lipid Res. 2025 Apr 15. pii: S0022-2275(25)00063-X. [Epub ahead of print] 100803

Sex differences in lipid profiles of visceral adipose tissue with obesity and gonadectomy.

Mita Varghese, Rajendiran Thekkelnaycke, Tanu Soni, Jiayu Zhang, Krishnarao Maddipati, Kanakadurga Singer.

  In obesity, adipose tissue (AT) expansion is accompanied by chronic inflammation. Altered lipid composition in the visceral or gonadal white AT (GWAT) directly drive AT macrophage (ATM) accumulation and activation to a proinflammatory phenotype. Sex steroid hormones modulate visceral vs subcutaneous lipid accumulation that correlates with metabolic syndrome, especially in men and post-menopausal women who are more prone to abdominal obesity. Prior studies demonstrated sex differences in GWAT lipid species in HFD-fed mice, but the role of sex hormones is still unclear. We hypothesized that sex hormone alterations with gonadectomy (GX) would further impact lipid composition in the obese GWAT. Untargeted lipidomics of obese GWAT identified sex differences in phospholipids, sphingolipids, sterols, fatty acyls, saccharo-lipids and prenol-lipids. Males had significantly more precursor fatty acids (palmitic, oleic, linoleic and arachidonic acid) than females and GX mice. Targeted lipidomics for fatty acids and oxylipins in the HFD-fed male and female GWAT stromal vascular fraction (SVF) identified higher omega-6 to omega-3 free fatty acid profile in males and differences in polyunsaturated fatty acids (PUFAs)-derived prostaglandins, thromboxanes and leukotrienes. Both obese male and female GWAT SVF showed increased levels of arachidonic acid (AA) derived oxylipins compared to their lean counterparts. Bulk RNA sequencing of sorted GWAT ATMs highlighted sex and diet differences in PUFA and oxylipin metabolism genes. These findings of sexual dimorphism in both stored lipid species and PUFA derived mediators with diet and GX emphasize sex-differences in lipid metabolism pathways that drive inflammation responses and metabolic disease risk in obesity.

Keywords:  Obesity; adipose tissue; fatty acids; inflammation; lipidomics; metabolism; phospholipids; prostaglandins; sex hormones; sex-differences

DOI:  https://doi.org/10.1016/j.jlr.2025.100803
Am J Physiol Regul Integr Comp Physiol. 2025 Apr 18.

Sex-specific systemic metabolic predictors of resistance to calorie restriction-induced weight loss in obese Diversity Outbred mice.

Evan M Paules, Melissa VerHague, Anju A Lulla, Katie A Meyer, Michael F Coleman, Jody Albright, Brian J Bennett, Kari E North, Annie-Green Howard, Penny Gordon-Larsen, Isis Trujillo-Gonzalez, John E French, Stephen D Hursting.

  Calorie restriction (CR) is a well-established weight loss strategy, albeit with variation in response. Using genetically heterogeneous mice, we sought to identify metabolic predictors of resistance to CR-induced weight loss. Diversity Outbred mice (150 males, 150 females) were fed a high-fat diet for 12 weeks to generate diet-induced obesity (DIO), then underwent CR for 8 weeks. Body weight and composition, blood glucose, and plasma levels of 9 metabolic hormones were assessed at baseline, following DIO, and following CR. In response to each dietary intervention, the mice displayed substantial heterogeneity across all outcomes, often with sexual dimorphism. Among the metabolic markers, leptin changed the most in response to each dietary intervention. Logistic regression found that resistance to CR-induced weight loss in obese mice was associated with lower glucose levels in males, and with lower levels of insulin, resistin, homeostatic model assessment for insulin resistance (HOMA-IR), and plasminogen activator inhibitor-1, and higher levels of ghrelin in females. Moreover, lower leptin levels predicted resistance to CR-induced weight loss in obese mice, regardless of sex. These preclinical findings provide proof-of-principle that the genetic and phenotypic heterogeneity of DO mice can be leveraged to identify mechanistic predictors that may enhance the personalization of weight loss interventions.

Keywords:  Calorie restriction; Diversity-Outbred mice; diet-induced obesity; leptin; sexual dimorphism

DOI:  https://doi.org/10.1152/ajpregu.00220.2024
J Diabetes. 2025 Apr;17(4): e70083

Association of Lifestyle-Induced Weight Loss With Gene Expression in Subcutaneous Adipose Tissue in Metabolic Syndrome.

Silke Zimmermann, Kirsten Roomp, Hans-Jonas Meyer, Akash Mathew, Manuel Florian Struck, Matthias Blüher, Hugo N G Martin, Maria Keller, Kathrin Landgraf, Antje Körner, Anne Hoffmann, Yvonne Böttcher, Kathleen Biemann, Adhideb Ghosh, Christian Wolfrum, Falko Noé, Berend Isermann, Jochen G Schneider, Ronald Biemann.

   AIMS: Lifestyle-induced weight loss (LIWL) is considered an effective therapy for the treatment of metabolic syndrome (MetS). The role of differentially expressed genes (DEGs) in adipose tissue function and in the success of LIWL in MetS is still unclear. We investigated the effect of 6 months of LIWL on transcriptional regulation in subcutaneous adipose tissue (SAT). Aiming to identify a LIWL-associated "gene signature" in SAT, DEGs were fitted into a linear regression model.
MATERIALS AND METHODS: The study is embedded in a prospective, two-arm, controlled, monocentric, randomized, 6-month interventional trial in individuals with MetS following LIWL. The trial included 43 nonsmoking, nondiabetic men aged 45-55 years with MetS.
RESULTS: In total, we identified 642 DEGs in SAT after 6 months of LIWL. The identified DEGs were validated in two cross-sectional cohorts analyzing SAT from individuals with and without obesity. Gene enrichment analysis of the DEGs revealed the strongest association with cholesterol metabolic processes. Accordingly, DEGs were correlated with the lipid parameters HDL cholesterol, LDL cholesterol, and triglycerides in corresponding serum samples. We identified 3 genes with an AUC of 0.963 (95% CI: 0.906-1.0) associated with a loss of more than 10% of initial body weight that was maintained for at least 12 months after LIWL, namely SUMO3 (Small ubiquitin-related modifier 3), PRKG2 (Protein Kinase CGMP-Dependent 2), and ADAP2 (ArfGAP with Dual PH Domains 2).
CONCLUSION: In summary, we have identified DEGs in SAT after LIWL, which may play an important role in metabolic functions. In particular, altered gene expression in SAT may predict sustained weight loss.

Keywords:  differentially expressed genes (DEGs); lifestyle‐induced weight loss (LIWL); metabolic syndrome (MetS); subcutaneous adipose tissue (SAT)

DOI:  https://doi.org/10.1111/1753-0407.70083
J Biol Chem. 2025 Apr 16. pii: S0021-9258(25)00359-X. [Epub ahead of print] 108510

MitoSNO inhibits mitochondrial hydrogen peroxide (mtH2O2) generation by α-ketoglutarate dehydrogenase (KGDH).

Olivia Chalifoux, Samantha Sterman, Ben Faerman, Meijing Li, Stephanie Trezza, Marek Michalak, Luis B Agellon, Ryan J Mailloux.

Here, we demonstrate mitochondrial hydrogen peroxide (mtH2O2) production by α-ketoglutarate dehydrogenase (KGDH) can be inhibited by MitoSNO, alleviating lipotoxicity. MitoSNO in the nanomolar range inhibits mtH2O2 by ∼50% in isolated liver mitochondria without disrupting respiration, whereas the mitochondria-selective derivative used to synthesize MitoSNO, mitochondria-selective N-acetyl-penicillamine (MitoNAP), had no effect on either mtH2O2 generation or oxidative phosphorylation (OxPhos). Additionally, mtH2O2 generation in isolated liver mitochondria was almost abolished when MitoSNO was administered in the low micromolar range. The potent inhibitory effect of MitoSNO was comparable to 2-keto-3-methyl-valeric acid (KMV) and valproic acid (VA), selective inhibitors for KGDH-mediate mH2O2 production. S1QEL 1.1 (S1) and S3QEL (S3), which are known to selectively suppress mtH2O2 genesis through inhibition of complex I and complex III respectively, without disrupting respiration, had little to no effect on mtH2O2 production by liver mitochondria. We also identified it was a major mtH2O2 source as well but MitoSNO and MitoNAP did not affect mtH2O2 production by this ETC-linked enzyme. The MitoSNO also suppressed mtH2O2 production and partially rescued mitochondrial respiration in Huh-7 cells subjected to palmitate (PA) and fructose (Fruc) induced lipotoxicity. MitoSNO also prevented cell death and abrogated intrahepatic lipid accumulation in these Huh-7 cells. MitoSNO nullified mtH2O2 overgeneration and partially rescued OxPhos in liver mitochondria from mice fed a high fat diet (HFD). Our findings demonstrate that MitoSNO interferes with mtH2O2 production through KGDH S-nitrosation and may be useful in alleviating non-alcoholic fatty liver disease (NAFLD).

DOI: https://doi.org/10.1016/j.jbc.2025.108510