bims-mimead Biomed News
on Adipose tissue and metabolic disease
Issue of 2025–03–16
ten papers selected by
Rachel M. Handy, University of Guelph
  1. SDCCAG3 inhibits adipocyte hypertrophy and improves obesity-related metabolic disorders via SDCCAG3/SMURF1/PPARγ axis.
  2. Impact of the metabolic disease status in obesity and surgical weight loss on human adipose tissue bioenergetics.
  3. Deficiency of neuronal LGR4 increases energy expenditure and inhibits food intake via hypothalamic leptin signaling.
  4. Fat absorption and metabolism after Roux-en-Y gastric bypass surgery.
  5. Effects of a protein kinase C epsilon inhibitor on insulin signalling in lipid-treated HepG2 hepatocytes and glucose tolerance in fat-fed mice.
  6. Novel cell-to-cell communications between macrophages and fibroblasts regulate obesity-induced adipose tissue fibrosis.
  7. Role of Perivascular Adipose Tissue in Vein Remodeling.
  8. Targeted Lipidomics and Transcriptomics Unveil Aberrant Lipid Metabolic Remodeling in Visceral and Subcutaneous Adipose Tissue under ER Stress.
  9. Timosaponin AⅢ inhibits ectopic lipid deposition and enhances the browning of white adipose tissue.
  10. The pro-inflammatory cytokine IL6 suppresses mitochondrial function via the gp130-JAK1/STAT1/3-HIF1α/ERRα axis.
  1. J Lipid Res. 2025 Mar 07. pii: S0022-2275(25)00032-X. [Epub ahead of print] 100772
    SDCCAG3 inhibits adipocyte hypertrophy and improves obesity-related metabolic disorders via SDCCAG3/SMURF1/PPARγ axis.
    Fenglei Huo, Chenghang Liu, Xi Wang, Jinzheng Li, Zhifeng Wang, Duanqin Liu, Weipeng Lan, Xingyan Zhu, Jing Lan.
      Obesity is a prevalent global disease associated with various metabolic disorders. The expansion of white adipose tissue plays a pivotal role in regulating obesity-related metabolic dysfunctions. This study identified serum-defined colon cancer antigen 3 (SDCCAG3) as a novel key modulator of adipocyte metabolism. In adipose-specific SDCCAG3 knockout mice fed a high-fat diet, pathological expansion of adipose tissue, impaired glucose tolerance, insulin resistance, increased inflammatory markers, and augmented hepatic lipid accumulation were observed. Conversely, obesity models by specific overexpression of SDCCAG3 in adipose tissue confirmed that SDCCAG3 alleviated pathological expansion of adipose tissue, improved obesity-related metabolic disorders, with no observed changes in adipose tissue development under normal dietary conditions. Mechanistically, SDCCAG3 enhanced the stability of peroxisome proliferator-activated receptor gamma (PPARγ) by preventing its degradation via the ubiquitin-proteasome system through the SMAD specific E3 ubiquitin protein ligase 1 (SMURF1). Additionally, SDCCAG3 was subjected to negative transcriptional regulation by PPARγ, forming a SDCCAG3-PPARγ-SDCCAG3 loop that enhanced adipocyte lipid metabolism. Collectively, these findings demonstrated that SDCCAG3 functioned as a beneficial positive regulator of adipose tissue expansion and metabolic homeostasis, indicating its potential as a therapeutic target for metabolic diseases associated with nutrient excess.
    Keywords:  PPARγ; SDCCAG3; SMURF1; adipose tissue; cell signaling; glucose; insulin resistance; metabolic disorders; obesity
    DOI:  https://doi.org/10.1016/j.jlr.2025.100772
  2. J Physiol. 2025 Mar 09.
    Impact of the metabolic disease status in obesity and surgical weight loss on human adipose tissue bioenergetics.
    Aryane Cruz Oliveira Pinho, André Lazaro, Pedro Barbosa, Craig Porter, José G Tralhão, Eugenia Carvalho.
      Obesity is associated with insulin resistance (IR) development, a risk factor for type 2 diabetes (T2D). How mitochondrial bioenergetics, in adipose tissue (AT), differs according to distinct metabolic profiles (i.e. insulin sensitive (IS), IR normoglycaemic (IR-NG), pre-diabetes (PD) and T2D) is still poorly understood. The purpose of this study was to evaluate and compare bioenergetics and energy substrate preference by omental AT (OAT) and subcutaneous AT (SAT) from subjects with obesity (OB, n = 40) at distinct metabolic stages. Furthermore, AT bioenergetics was also evaluated pre- and post-bariatric/metabolic surgery (BMS). High-resolution respirometry (HRR) was used to measure the real-time oxidative phosphorylation (OXPHOS) capacity and mitochondrial substrate preferences in both tissues. Substrate-uncoupler-inhibitor titration protocols were used: SUIT-P1 (complex I and II-linked mitochondrial respiration) and SUIT-P2 (fatty acid oxidation (FAO)-linked mitochondrial respiration). Flux control ratios (FCRs) were calculated. In SUIT-P1, lower OXPHOS capacity was observed in AT, particularly in SAT, during the establishment of IR (OB-IR-NG) and in the T2D group, due to alterations of mitochondrial coupling, evaluated by FCRs. In SUIT-P2, the OXPHOS coupling efficiency was highest in the OB-IR-NG group. AT from OB-IS, OB-IR-NG and OB-IR-PD preferred pyruvate, malate and glutamate oxidation and/or FAO during OXPHOS, whereas AT from T2D preferred succinate oxidation. BMS enhanced mitochondrial respiration in OAT, even under poor OXPHOS coupling efficiency. In conclusion, real-time OXPHOS analysis by HRR may be a sensitive biomarker of mitochondrial fitness, particularly in AT. Interventions based on modulating energetic substrate availability may become a good tool for obesity treatment stratification. KEY POINTS: Omental adipose tissue shows higher oxidative phosphorylation (OXPHOS) capacity compared to subcutaneous adipose tissue in paired explants from subjects with obesity. The OXPHOS capacity of adipose tissue differs through the progression of metabolic disease. Subjects with obesity and diabetes have the lowest OXPHOS capacity in paired explants of subcutaneous and omental adipose tissues. Bariatric surgery enhanced the OXPHOS capacity in omental adipose tissue, even under poor OXPHOS coupling efficiency. Assessment of the oxidative capacity in fresh adipose tissue explants could be a sensitive tool for early diagnosis of metabolic disease.
    Keywords:  OXPHOS capacity; adipose tissue; bariatric surgery; insulin resistance; mitochondria; obesity; type 2 diabetes
    DOI:  https://doi.org/10.1113/JP286103
  3. EMBO Rep. 2025 Mar 11.
    Deficiency of neuronal LGR4 increases energy expenditure and inhibits food intake via hypothalamic leptin signaling.
    Liping Zhang, Yuan Li, Wenbin Gao, Ziru Li, Tong Wu, Chunhui Lang, Liangyou Rui, Weizhen Zhang.
      The metabolic effects of leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) remain largely unknown. Here, we showed that knockdown of Lgr4 in nestin progenitor or Sp1 mature neurons reduced high fat diet (HFD)-induced obesity by increasing energy expenditure and inhibiting food intake. Deficiency of LGR4 in AgRP neurons increased energy expenditure, and inhibited food intake, leading to alterations in glucose and lipid metabolism. Knock-down of Lgr4 in Sf1 neurons enhanced energy expenditure, reduced adiposity, and improved glucose and lipid metabolism. The metabolic benefits of neuronal LGR4 occurred via improvement of leptin signaling in AgRP and Sf1 neurons. Knockdown of Lgr4 in nestin, Sp1, AgRP or Sf1 neurons decreased hypothalamic levels of SOCS-3, and increased phosphorylation of STAT3. These alterations were associated with a significant reduction in the hypothalamic levels of β-catenin. Inhibition of β-catenin signaling by Dkk1 significantly attenuated the decrement of phospho-STAT3 and concurrent increase of SOCS-3 induced by Rspondin 3, an endogenous ligand for LGR4. Our results thus demonstrate that hypothalamic LGR4 may promote energy conversation by increasing food intake and decreasing energy expenditure. Deficiency of neuronal LGR4 improves hypothalamic leptin sensitivity via suppression of β-catenin signaling.
    Keywords:  Hypothalamus; Leptin Signaling; Leucine-rich Repeat-containing G Protein-coupled Receptor 4 (LGR4); Obesity; β-catenin
    DOI:  https://doi.org/10.1038/s44319-025-00398-5
  4. Metabolism. 2025 Mar 10. pii: S0026-0495(25)00058-7. [Epub ahead of print] 156189
    Fat absorption and metabolism after Roux-en-Y gastric bypass surgery.
    Morten Hindsø, Annemarie Lundsgaard, Bojan Marinkovic, Mikkel Helmuth Jensen, Nora Hedbäck, Maria Saur Svane, Carsten Dirksen, Nils Bruun Jørgensen, Amalie London, Palle Bekker Jeppesen, Mark Krogh Hvistendahl, Christina Christoffersen, Hartwig Roman Siebner, Bente Kiens, Jens Juul Holst, Sten Madsbad, Gerrit van Hall, Kirstine Nyvold Bojsen-Møller.
       BACKGROUND: Triacylglycerol (TAG) plasma excursions after a high-fat meal are blunted after Roux-en-Y gastric bypass (RYGB), but underlying mechanisms are poorly understood. We studied TAG absorption and metabolism in 12 RYGB-operated individuals and 12 unoperated controls (CON) matched on sex, age, and BMI.
    METHODS: Participants followed a 7-day controlled diet and on day 4 underwent 1H-MR Spectroscopy of liver TAG and a high-fat liquid meal with oral and intravenous labeled stable isotope metabolites, subcutaneous abdominal fat biopsies, and indirect calorimetry. Subsequently, participants collected stool for 96 h.
    RESULTS: Overall fat absorption from the controlled diet was moderately lower in RYGB than CON (88 % versus 93 %, P < 0.01), without indication of greater specific malabsorption of fat from the high-fat test meal (recovery of TAG and labeled TAG in 96-hour stool samples). After an overnight fast, plasma TAG concentrations and incorporation of plasma fatty acids (IV tracer) into TAG did not differ between groups. The postprandial 6-hour iAUC of plasma TAG plasma concentrations was markedly lower in RYGB than CON (15 versus 70 mmol/L × min, P = 0.03). The postprandial chylomicron (CM) particle response (plasma ApoB48) was initially higher in RYGB, but with lower CM-TAG plasma concentrations and appearance of labeled palmitate from the oral tripalmitin tracer over the 6 h.
    CONCLUSION: Fat absorption is only moderately lower after RYGB compared with unoperated matched controls. Nevertheless, postprandial TAG and CM plasma kinetics after a high-fat meal are markedly altered after RYGB with substantially lower TAG and CM-TAG concentrations despite a faster CM particle release.
    Keywords:  Absorption; Bariatric surgery; Chylomicron; Fat; Lipids; Lipoprotein; Obesity; Triacylglycerol; Very-low-density lipoprotein
    DOI:  https://doi.org/10.1016/j.metabol.2025.156189
  5. Eur J Pharmacol. 2025 Mar 05. pii: S0014-2999(25)00219-5. [Epub ahead of print]997 177465
    Effects of a protein kinase C epsilon inhibitor on insulin signalling in lipid-treated HepG2 hepatocytes and glucose tolerance in fat-fed mice.
    Miguel L Agoncillo, Zhongmin Gao, Harmannus C De Kraker, Stanton F McHardy, Robert O Messing, Lewin Small, Carsten Schmitz-Peiffer.
       AIMS: Protein kinase C epsilon (PKCε) plays a causative role in the development of glucose intolerance, and is a potential target for the treatment of type 2 diabetes. Here, we examined the effects of the PKCε inhibitor CIDD-0150612 (CP612) on insulin action in palmitate-treated HepG2 hepatocytes in vitro and on glucose homeostasis in fat-fed mice in vivo.
    METHODS: HepG2 cells were treated with palmitate and CP612 and stimulated with insulin. Insulin signalling was examined by immunoblotting and glucose incorporation into glycogen was measured using glucose tracer. Mice were fed a high-fat diet and treated with CP612 prior to glucose tolerance tests and tissue harvest. Proteomic analysis of liver was carried out by mass spectrometry.
    RESULTS: CP612 promoted Akt phosphorylation in a highly insulin-dependent manner and reversed the inhibition of insulin-stimulated Akt phosphorylation and glucose incorporation into glycogen by palmitate. Fat-fed mice treated with CP612 had reduced fat mass, but not lean mass, compared with vehicle-treated littermates. Mice treated acutely with CP612 exhibited elevated fasting blood glucose. However, mice studied 24h after the last dose had lower fasting glucose and improved glucose tolerance with a lower insulin excursion. Proteomic analysis of liver from CP612-treated fat-fed mice indicated a reduction in gluconeogenic gene expression and decreased phosphorylation of the transcription factor Foxk1.
    CONCLUSIONS: The PKCε inhibitor CP612 had beneficial effects on insulin action in hepatocytes and on fat mass and glucose homeostasis in mice. Because certain effects were not previously observed in genetically PKCε-deficient mice, off-target effects may be partly responsible.
    Keywords:  Coiled-coil containing protein kinase; Glucose tolerance; Insulin resistance; Insulin signalling; Obesity; Protein kinase C; Rho-associated; Type 2 diabetes
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177465
  6. Diabetes. 2025 Mar 10. pii: db240762. [Epub ahead of print]
    Novel cell-to-cell communications between macrophages and fibroblasts regulate obesity-induced adipose tissue fibrosis.
    Hiro Kohda, Miyako Tanaka, Shigeyuki Shichino, Satoko Arakawa, Tadasuke Komori, Ayaka Ito, Eri Wada, Kozue Ochi, Xunmei Yuan, Takehiko Takeda, Atsuhito Saiki, Ichiro Tatsuno, Kenji Ikeda, Yuki Miyai, Atsushi Enomoto, Yoshihiro Morikawa, Shigeomi Shimizu, Satoshi Ueha, Kouji Matsushima, Yoshihiro Ogawa, Takayoshi Suganami.
      Recent evidence has shown that adipose tissue eventually develops fibrosis through complex cellular crosstalk. Although advances in single-cell transcriptomics have provided new insights into cell diversity during this process, little is known about the interactions among the distinct cell types. In this study, we employed single-cell analytical approaches to investigate cell-tocell communications between macrophages and fibroblasts in the adipose tissue of diet-induced obese mice. Spatial transcriptomics was used to understand local cellular interaction within crown-like structures (CLSs), a characteristic histological feature of adipose tissue in obesity driving inflammation and fibrosis. Macrophages and fibroblasts were divided into several subclusters that appeared to interact more intensely and complexly with the degree of obesity. Besides previously reported Lipid-associated macrophages (LAMs), we found a small subcluster expressing Macrophage-inducible C-type lectin (Mincle), specifically localizing to CLSs. Mincle signaling increased the expression of Oncostatin M (Osm), suppressing collagen gene expression in adipose tissue fibroblasts. Consistent with these findings, Osm-deficiency in immune cells enhanced obesity-induced adipose tissue fibrosis in vivo. Moreover, Osm expression was positively correlated with Mincle expression in human adipose tissue during obesity. Our results suggest that Osm secreted by Mincle-expressing macrophages is involved in dynamic adipose tissue remodeling in the proximity of CLSs.
    DOI:  https://doi.org/10.2337/db24-0762
  7. Arterioscler Thromb Vasc Biol. 2025 Mar 13.
    Role of Perivascular Adipose Tissue in Vein Remodeling.
    Nicky Kruit, Thijs J Sluiter, Margreet R de Vries.
      Perivascular adipose tissue (PVAT) plays a crucial, yet underexplored, role in vein remodeling, which occurs after bypass surgery using a venous graft or creation of arteriovenous fistulae for hemodialysis access. PVAT exhibits significant heterogeneity in phenotype and tissue composition depending on the vascular bed, as well as its anatomic location within the vasculature. Through the excretion of adipokines, cytokines, and chemokines, PVAT can shape the vascular response to local and systemic perturbations. Moreover, the active exchange of cells reinforces the bidirectional cross talk between the vessel wall and PVAT. In this review, we describe the role of PVAT in relation to postinterventional vein remodeling, specifically focusing on the effect of surgery on the PVAT phenotype. Moreover, we discuss the pathophysiological mechanisms that ultimately affect clinical outcomes and highlight the therapeutic potential of PVAT to improve vein remodeling.
    Keywords:  adipokines; arteriovenous fistula; chemokines; cytokines; inflammation
    DOI:  https://doi.org/10.1161/ATVBAHA.124.321692
  8. J Proteome Res. 2025 Mar 11.
    Targeted Lipidomics and Transcriptomics Unveil Aberrant Lipid Metabolic Remodeling in Visceral and Subcutaneous Adipose Tissue under ER Stress.
    Ping He, Li Zhang, Peng Ma, Tianshu Xu, Zijing Wang, Li Li, Guanhua Du, Guifen Qiang, Cuiqing Liu.
      Endoplasmic reticulum (ER) stress is known to impair the function of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), disrupting lipid metabolism. Despite the crucial role lipid plays in regulating adipose tissue function, the specific lipidomic alterations in VAT and SAT under ER stress remain unclear. In this study, ER stress was induced in VAT and SAT, and targeted lipidomic and transcriptomic approaches were used to analyze lipid metabolism and gene expression profiles. The results revealed that VAT exhibited a stronger ER stress response, characterized by a significant increase in binding immunoglobulin protein (BiP) expression and notable lipidomic disruptions, especially in glycerides and sterols. These disruptions were marked by a decrease in protective polyunsaturated fatty acyl species and the accumulation of lipotoxic molecules. In contrast, SAT displayed less severe lipidomic alterations. Transcriptomic analysis indicated that VAT was more susceptible to immune activation, inflammation, and metabolic dysfunction, while SAT primarily showed alterations in protein folding processes. These findings underscore the tissue-specific mechanisms of ER stress adaptation in VAT and SAT. In conclusion, VAT appears to be a critical target for addressing metabolic dysfunction in obesity and related disorders, with potential therapeutic implications for managing ER stress-induced metabolic diseases.
    Keywords:  ER stress; lipidomics; subcutaneous adipose tissue; transcriptomics; visceral adipose tissue
    DOI:  https://doi.org/10.1021/acs.jproteome.4c00952
  9. Eur J Pharmacol. 2025 Mar 10. pii: S0014-2999(25)00260-2. [Epub ahead of print] 177506
    Timosaponin AⅢ inhibits ectopic lipid deposition and enhances the browning of white adipose tissue.
    Wenjun Zhao, Xiaoying Wang, Yun Liu, Lu Lu, Yue Ding, Tong Zhang.
      Timosaponin AⅢ(TAⅢ), derived from the Chinese medicinal herb Anemarrhena asphodeloides Bunge, has been reported to have a range of pharmacological effects including improvement of learning and memory deficits, anti-tumor, hypoglycemic effect and anti-hypertension. This study explored the therapeutic effects and preliminary mechanisms of TAⅢ in improving insulin resistance in ob/ob mice. We found that treatment with 10 mg·kg-1·d-1 of TAⅢ reduced the expression of SREBPs and alleviated ectopic lipid deposition by decreasing DAG accumulation in liver. The decrease of DAG further inhibited the membrane translocation of PKC-ε, releasing its inhibition of phosphorylation at Ser307 of IRS1, and ultimately enhancing the AKT signaling response to insulin stimulation. In addition, TAⅢ promoted the browning of iWAT by activating the PGC1α-UCP1 axis on ob/ob mice, thereby enhancing fatty acid oxidation and increasing energy consumption, thus reducing its interference with insulin signaling. TAⅢ worked by enhancing the function of adipose tissue and inhibited lipid synthesis. These actions collectively ameliorated metabolic disturbances associated with insulin resistance. Therefore, we preliminarily concluded that TAⅢ improved metabolic disturbances related to insulin resistance. However, further research is needed,additional studies are necessary to validate these potential mechanisms.
    Keywords:  Adipose tissue browning; Ectopic lipid deposition; Insulin resistance; Thermogenesis; Timosaponin AⅢ
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177506
  10. Cell Rep. 2025 Mar 06. pii: S2211-1247(25)00174-3. [Epub ahead of print]44(3): 115403
    The pro-inflammatory cytokine IL6 suppresses mitochondrial function via the gp130-JAK1/STAT1/3-HIF1α/ERRα axis.
    Jianing Xu, Matthew Wakai, Kun Xiong, Yanfeng Yang, Adithya Prabakaran, Sophia Wu, Diana Ahrens, Maria Del Pilar Molina-Portela, Min Ni, Yu Bai, Tea Shavlakadze, David J Glass.
      Chronic inflammation and a decline in mitochondrial function are hallmarks of aging. Here, we show that the two mechanisms may be linked. We found that interleukin-6 (IL6) suppresses mitochondrial function in settings where PGC1 (both PGC1α and PGC1β) expression is low. This suppression is mediated by the JAK1/STAT1/3 axis, which activates HIF1α through non-canonical mechanisms involving upregulation of HIF1A and ERRα transcription, and subsequent stabilization of the HIF1A protein by ERRα. HIF1α, in turn, inhibits ERRα, which is a master regulator of mitochondrial biogenesis, thus contributing to the inhibition of mitochondrial function. When expressed at higher levels, PGC1 rescues ERRα to boost baseline mitochondrial respiration, including under IL6-treated conditions. Our study suggests that inhibition of the IL6 signaling axis could be a potential treatment for those inflammatory settings where mitochondrial function is compromised.
    Keywords:  ATP; CP: Immunology; ERRα; ESRRA; HIF1A; HIF1α; IL6; PGC1α; PGC1β; PPARGC1A; PPARGC1B; aging; gp130; inflammation; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2025.115403
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