bims-mimead Biomed News
on Adipose tissue and metabolic disease
Issue of 2025–05–11
seven papers selected by
Rachel M. Handy, University of Guelph
  1. Adipocyte exosome miR-4472 inhibits glucose uptake in skeletal muscle through downregulation of MEF2D.
  2. Global deletion of COX-2 Attenuates Hepatic Inflammation but Impairs Metabolic Homeostasis in Diet-Induced Obesity.
  3. Mitochondrial GCN5L1 coordinates with YME1L and MICOS to remodel mitochondrial cristae in white adipocytes and modulate obesity.
  4. Transcriptomic analysis of adipose tissue reveals adipogenesis is modulated by the degree of weight loss in patients with obesity.
  5. Metabolic effects of late-onset estradiol replacement in high-fat-fed ovariectomized mice.
  6. Adipose Tissue-Derived Extracellular Vesicles Loaded with miR-141-3p Regulate Obesity-Induced Insulin Resistance by Targeting Glycogen Synthesis and Gluconeogenesis.
  7. Distinct gut microbiota and metabolome features of tissue-specific insulin resistance in overweight and obesity.
  1. J Diabetes Investig. 2025 May 08.
    Adipocyte exosome miR-4472 inhibits glucose uptake in skeletal muscle through downregulation of MEF2D.
    Chaoyue Sun, Xin Wen, Xiaolong Chu, Fangyuan Yuan, Yao Chen, Chaoling Peng, Meiyu Qian, Jin Mei, Juan Wang, Yidan Jiang, Shibo Xu, Cuizhe Wang, Wei Li, Jun Zhang.
       AIMS/INTRODUCTION: Previous studies have found that miR-4472 is overexpressed in the serum of individuals with obesity and type 2 diabetes mellitus (T2DM), which may participate in the process of obesity-induced T2DM. However, a role for miR-4472 in the process has not been demonstrated. Here, we aim to investigate whether the increased content of miR-4472 in adipose tissue derived from exosomes inhibits glucose uptake in skeletal muscle by downregulating the expression of its target gene.
    MATERIALS AND METHODS: In vitro C2C12 and 3T3-L1 cells, and in vivo diet-induced obesity mouse models and AT-Dicer KO mice were used to assess the impact of miR-4472 on glucose uptake and insulin sensitivity. We also evaluated the effects of serum exosomes from normal and obese individuals on insulin sensitivity in mice and the expression of miR-4472 and target genes in skeletal muscle.
    RESULTS: miR-4472 exhibits a strong positive correlation with BMI, waist circumference, hip circumference, and FPG. The content of miR-4472 derived from adipose tissue exosomes increases in the circulation in a state of obesity, which can induce insulin resistance by targeting the expression of MEF2D/GLUT4, inhibiting the glucose consumption and uptake ability of skeletal muscle cells. Both exosome inhibitors and miR-4472 inhibitors can reverse the inhibitory effect of miR-4472 on MEF2D/GLUT4 expression and glucose intake and uptake ability. Additionally, they can improve insulin resistance caused by increased miR-4472 levels in mice with obesity.
    CONCLUSIONS: Adipocyte exosome miR-4472 inhibits glucose uptake in skeletal muscle through downregulating the expression of MEF2D/GLUT4.
    Keywords:  MEF2D; Skeletal muscle; miR‐4472
    DOI:  https://doi.org/10.1111/jdi.70054
  2. J Lipid Res. 2025 May 07. pii: S0022-2275(25)00083-5. [Epub ahead of print] 100823
    Global deletion of COX-2 Attenuates Hepatic Inflammation but Impairs Metabolic Homeostasis in Diet-Induced Obesity.
    Jeyakumar Balakrishnan, Cyrus Desouza, Rishikesh Thakare, Yazen Alnouti, Viswanathan Saraswathi.
      The role of cyclooxygenase-2 (COX-2), a well-known pharmacological target for attenuating inflammation, in regulating obesity and its co-morbidities remains unclear. We sought to determine the role of COX-2 in modulating metabolic inflammation and systemic metabolic homeostasis in obesity. Male wild type (WT) and COX-2 knock-out (KO) mice were fed a chow diet (CD) or a high fat diet (HF, 45% fat) for 13 wk. While the body weight gain did not alter, the visceral adipose tissue (VAT) mass was significantly higher in KO-HF mice compared to WT-HF mice. Plasma triglycerides and total cholesterol levels were higher in KO-HF mice compared to WT-HF mice. Total body fat mass was higher with a concomitant reduction in lean mass in KO-HF mice compared to WT-HF mice. Paradoxically, hepatic steatosis was reduced in KO-HF mice. While liver triglycerides were reduced, the liver cholesterol was increased in KO-HF mice. Bile acids and markers of cholesterol biosynthesis were unaltered between WT-HF and KO-HF groups. The mRNA and/or protein levels of autophagy markers were significantly decreased in KO-HF mice compared to WT-HF mice, indicating that a reduction in autophagy may increase cholesterol levels in these mice. The liver inflammatory markers were significantly increased only in WT mice fed a HF diet but not in KO-HF fed mice compared to their respective controls. VAT showed a reduction in inflammatory markers in spite of an increase in adiposity. These data suggest that despite being effective in attenuating the inflammatory processes, inhibition of COX-2 exerts undesirable consequences on metabolic homeostasis.
    Keywords:  COX-2; MASLD; cholesterol; inflammation; obesity; triglycerides
    DOI:  https://doi.org/10.1016/j.jlr.2025.100823
  3. Cell Rep. 2025 May 07. pii: S2211-1247(25)00453-X. [Epub ahead of print]44(5): 115682
    Mitochondrial GCN5L1 coordinates with YME1L and MICOS to remodel mitochondrial cristae in white adipocytes and modulate obesity.
    Juan Xu, Qiqi Zhang, Xinyu Yang, Qiqi Tang, Yitong Han, Jiahui Meng, Jiaqi Zhang, Xin Lu, Danni Wang, Jing Liu, Bo Shan, Xue Bai, Kai Zhang, Longhao Sun, Lingdi Wang, Lu Zhu.
      The relationship between mitochondrial architecture and energy homeostasis in adipose tissues is not well understood. In this study, we utilized GCN5L1-knockout mice in white (AKO) and brown (BKO) adipose tissues to examine mitochondrial homeostasis in adipose tissues. GCN5L1, a regulator of mitochondrial metabolism and dynamics, influences resistance to high-fat-diet-induced obesity in AKO but not BKO mice. This resistance is mediated by an increase in mitochondrial cristae that stabilizes oxidative phosphorylation (OXPHOS) complexes and enhances energy expenditure. Our protein-interactome analysis reveals that GCN5L1 is associated with the mitochondrial crista complex MICOS (MIC13) and the protease YME1L, facilitating the degradation of MICOS and disassembly of cristae during obesity. This interaction results in decreased OXPHOS levels and subsequent adipocyte expansion. Accumulation of GCN5L1 in the mitochondrial intermembrane space is triggered by a high-fat diet. Our findings highlight a regulatory pathway involving YME1L/GCN5L1/MIC13 that remodels mitochondrial cristae in WAT in response to overnutrition-induced obesity.
    Keywords:  CP: Cell biology; CP: Metabolism; MICOS; OXPHOS; YME1L; beige; mitochondria; mitochondrial crista remodeling; white adipose tissue
    DOI:  https://doi.org/10.1016/j.celrep.2025.115682
  4. Nutr Metab Cardiovasc Dis. 2025 Apr 22. pii: S0939-4753(25)00247-9. [Epub ahead of print] 104093
    Transcriptomic analysis of adipose tissue reveals adipogenesis is modulated by the degree of weight loss in patients with obesity.
    Kaitlin J Day, Vivian Ballestro, Linghan Mei, Chiara Murgia.
       BACKGROUND AND AIMS: Obesity is a complex condition with a diverse presentation and highly variable response to treatment. It is increasingly evident that obesity requires a plethora of interventions informed by biomarkers to optimise the chance of success. Adipose tissue is a metabolically active endocrine tissue and its metabolic response to intervention has the potential to provide key information to design targeted treatments to tackle obesity. To this aim, this study sought to identify, through transcriptomics analysis, common elements between adipose tissue of those undergoing bariatric surgery to those who were successful in losing weight through a lifestyle intervention.
    METHODS AND RESULTS: Transcriptomic data from Gene Expression Omnibus were extracted from three bariatric surgery interventions and three lifestyle interventions. Paired linear mixed modelling using the limma package in R was used to determine differentially expressed genes before and after the interventions. Unpaired linear mixed modelling was used to determine differentially expressed genes between high and low responders to the intervention. Differentially modulated pathways were analysed with PathVisio and downloaded for graphic representation from the WikiPathways database.
    CONCLUSION: We demonstrated that successful lifestyle interventions and bariatric surgery share the modulation of the Adipogenesis pathway (WP236). Leptin expression was positively correlated with weight loss, only up to a 10 % weight loss, suggesting a possible involvement of its dysregulation in explaining individual propensity to weight regain and potentially indicating who requires a targeted intervention. We also identify an interesting relationship between RBL2 expression and weight loss that requires further investigation.
    Keywords:  Adipose tissue; Pathways analysis; Transcriptomics; Weight loss
    DOI:  https://doi.org/10.1016/j.numecd.2025.104093
  5. Curr Res Physiol. 2025 ;8 100144
    Metabolic effects of late-onset estradiol replacement in high-fat-fed ovariectomized mice.
    Alessandra Gonçalves da Cruz, Jessica Denielle Matos Dos Santos, Ester Dos Santos Alves, Anne Raissa Melo Dos Santos, Bruna Fantini Trinca, Felipe Nunes de Camargo, Guilherme Fancio Bovolin, João Paulo Camporez.
       Background: Decreased estrogen levels in postmenopausal women negatively impact metabolic health. It is known that estradiol (E2) replacement can reverse this condition. However, there is no consensus on whether the effects mediated by E2 depend on the starting time of E2 replacement after menopause. We aimed to investigate the effects of different onset E2 treatments on glucose tolerance and metabolic parameters in high-fat-fed ovariectomized mice.
    Material and methods: Eight-week-old female C57BL/6J mice were divided into three groups: SHAM, OVX, and E2, to evaluate three different time points of E2 replacement after ovariectomy: early (after 4 weeks), intermediate (after 12 weeks), and late replacement (after 20 weeks). E2 groups received treatment through subcutaneous pellets.
    Results: E2 replacement improved the parameters analyzed independently of the time since ovariectomy, reducing body weight gain and fat mass, as well as increasing the percentage of lean mass. Glucose intolerance, fasting insulin, HOMA-IR, and cholesterol levels were also reduced after treatment with E2. In the liver, there was a decrease in triacylglycerol (TAG) deposition, with no difference in the expression of SREBP1 and ERα proteins. In the muscle, there was a decrease in TAG deposition. In periuterine adipose tissue, there was an increase in the expression of SREBP1, FASN, and SCD, with no difference in the expression of ERα.
    Conclusions: Our findings reinforce the critical role of E2 in regulating both glucose and lipid metabolism and indicate that E2 action on metabolic health was not dependent on time since ovariectomy for the parameters analyzed.
    Keywords:  Estradiol replacement; Insulin resistance; Lipid metabolism; Menopause; Ovariectomy
    DOI:  https://doi.org/10.1016/j.crphys.2025.100144
  6. Int J Nanomedicine. 2025 ;20 5709-5726
    Adipose Tissue-Derived Extracellular Vesicles Loaded with miR-141-3p Regulate Obesity-Induced Insulin Resistance by Targeting Glycogen Synthesis and Gluconeogenesis.
    Zixian Wang, Tianyu Ma, Ge Bai, Qianchen Fang, Biqian Ou, Meng Chen, Pei Xu, Meng Tian, Anding Xu, Yi Ma.
       Purpose: Insulin resistance, a hallmark feature of type 2 diabetes and cardiovascular diseases, is critically influenced by liver-adipose tissue crosstalk, offering a novel therapeutic strategy for its management. Emerging evidence indicates that extracellular vesicles (EVs) secreted from adipose tissue serve as essential carriers of miRNA-mediated interorgan communication. This study aimed to investigate the regulatory effects of adipose tissue-derived EVs on obesity-induced hepatic insulin resistance and to elucidate the underlying molecular mechanisms by which EV-mediated signaling contributes to metabolic dysfunction.
    Methods: EVs with miR-141-3p knockout or overexpression were constructed and administered to both in vitro cell models and in vivo mouse models to investigate the regulatory role and underlying mechanisms of miR-141-3p-mediated adipose tissue-derived EVs in obesity-induced hepatic insulin resistance.
    Results: miR-141-3p is significantly upregulated in adipose tissue-derived EVs from high-fat diet (HFD)-fed mice, as well as in other obesity-related conditions. Furthermore, the knockdown of miR-141-3p in EVs from chow diet (CD-EVs) counteracted the effect in improving obesity-induced hepatic insulin resistance, whereas the overexpression of miR-141-3p in HFD-EVs improved hepatic insulin resistance. Mechanistically, EVs-derived miR-141-3p directly targets PTEN to promote PI3K/AKT signaling, thereby mediating hepatic glucose homeostasis through the regulation of hepatic gluconeogenesis and glycogen synthesis.
    Conclusion: In summary, our results highlight the emerging role of miR-141-3p in mediating adipose tissue-derived EVs to alleviate obesity-induced hepatic insulin resistance, providing potential therapeutic targets for type 2 diabetes.
    Keywords:  PTEN; extracellular vesicles; gluconeogenesis; glycogen synthesis; insulin resistance; miRNA
    DOI:  https://doi.org/10.2147/IJN.S511842
  7. Gut Microbes. 2025 Dec;17(1): 2501185
    Distinct gut microbiota and metabolome features of tissue-specific insulin resistance in overweight and obesity.
    Kelly M Jardon, Alexander Umanets, Anouk Gijbels, Inez Trouwborst, Gabby B Hul, Els Siebelink, Lars M M Vliex, Jacco J A J Bastings, Rosa Argamasilla, Elodie Chenal, Koen Venema, Lydia A Afman, Gijs H Goossens, Ellen E Blaak.
      Insulin resistance (IR) is an early marker of cardiometabolic deterioration which may develop heterogeneously in key metabolic organs, including the liver (LIR) and skeletal muscle (MIR). This tissue-specific IR is characterized by distinct metabolic signatures, but the role of the gut microbiota in its etiology remains unclear. Here, we profiled the gut microbiota, its metabolites and the plasma metabolome in individuals with either a LIR or MIR phenotype (n = 233). We observed distinct microbial community structures LIR and MIR, and higher short-chain fatty acid (SCFA) producing bacteria, fecal SCFAs and branched-chain fatty acids and a higher postprandial plasma glucagon-like-peptide-1 response in LIR. In addition, we found variations in metabolome profiles and phenotype-specific associations between microbial taxa and functional metabolite groups. Overall, our study highlights association between gut microbiota and its metabolites composition with IR heterogeneity that can be targeted in precision-based strategies to improve cardiometabolic health. Clinicaltrials.gov registration: NCT03708419.
    Keywords:  GLP-1; Tissue-specific insulin resistance: obesity; gut metabolites; gut microbiota; metabolic subtyping; precision health
    DOI:  https://doi.org/10.1080/19490976.2025.2501185
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