bims-mimead Biomed News
on Adipose tissue and metabolic disease
Issue of 2025–04–06
eight papers selected by
Rachel M. Handy, University of Guelph
  1. Loss of PGC-1α causes depot-specific alterations in mitochondrial capacity, ROS handling and adaptive responses to metabolic stress in white adipose tissue.
  2. The serine protease KLK7 promotes immune cell infiltration in visceral adipose tissue in obesity.
  3. Optimized RNA sequencing deconvolution illustrates the impact of obesity and weight loss on cell composition of human adipose tissue.
  4. Changes in lipid metabolism in visceral rather than the subcutaneous adipose tissue depot attenuate metabolic disturbances in obesity-resistant mice fed a high-fat diet.
  5. Brd9 antagonism induces beige adipocytes in white adipose tissues and protects against diet-induced obesity.
  6. Detection of liver mitochondrial oxaloacetate by NMR spectroscopy and membrane potential-dependent accumulation.
  7. Deletion of GFRAL blunts weight lowering effects of FGF21 in female mice.
  8. Physiology and clinical applications of GIP.
  1. Mitochondrion. 2025 Mar 27. pii: S1567-7249(25)00031-5. [Epub ahead of print]83 102034
    Loss of PGC-1α causes depot-specific alterations in mitochondrial capacity, ROS handling and adaptive responses to metabolic stress in white adipose tissue.
    Anders Gudiksen, Eva Zhou, Louise Pedersen, Catherine A Zaia, Cecilie E Wille, Elisabeth V Eliesen, Henriette Pilegaard.
      White adipose tissue (WAT) delivers lipid-fueled metabolic support to systemic energy expenditure through control of lipolytic and re-esterifying regulatory pathways, facilitated by mitochondrial bioenergetic support. Mitochondria are important sources of reactive oxygen species (ROS) and oxidative damage may potentially derail adipocyte function when mitochondrial homeostasis is challenged by overproduction of ROS. Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α is a transcriptional co-activator that in skeletal muscle plays a central role in mitochondrial biogenesis and function but whether PGC-1α is equally important for mitochondrial function and adaptations in white adipose tissue remains to be fully resolved. The aim of the present study was to characterize the necessity of adipocyte PGC-1α for adaptive regulation of mitochondrial function in distinct white adipose depots. PGC-1α adipose tissue-specific knockout (ATKO) and floxed littermate control mice (CTRL) were subjected to either 24 h of fasting or 48 h of cold exposure. Bioenergetics, ROS handling, basal and adaptive protein responses, markers of protein damage as well as lipid cycling capacity and regulation were characterized in distinct WAT depots. ATKO mice demonstrated impairments in respiration as well as reduced OXPHOS protein content in fed and fasted conditions. Increased ROS emission in tandem with diminished mitochondrial antioxidant defense capacity resulted in increased protein oxidation in ATKO WAT. Adipose tissue PGC-1α knockout also led to changes in regulation of lipolysis and potentially triglyceride reesterification in WAT. In conclusion, PGC-1α regulates adipose tissue mitochondrial respiration and ROS balance as well as lipid cycling during metabolic challenges in a depot specific manner.
    Keywords:  Bioenergetics; Cold exposure; Fasting; Mitochondria; PGC-1α; ROS; White adipose tissue
    DOI:  https://doi.org/10.1016/j.mito.2025.102034
  2. Metabolism. 2025 Mar 26. pii: S0026-0495(25)00108-8. [Epub ahead of print]168 156239
    The serine protease KLK7 promotes immune cell infiltration in visceral adipose tissue in obesity.
    Aleix Ribas-Latre, Anne Hoffmann, Claudia Gebhardt, Juliane Weiner, Lilli Arndt, Nora Raulien, Martin Gericke, Adhideb Ghosh, Kerstin Krause, Nora Klöting, Paul T Pfluger, Bilal N Sheikh, Thomas Ebert, Anke Tönjes, Michael Stumvoll, Christian Wolfrum, Matthias Blüher, Ulf Wagner, Joan Vendrell, Sonia Fernández-Veledo, John T Heiker.
      Obesity is a major health problem associated with global metabolic dysfunction and increased inflammation. It is thus critical to identify the mechanisms underlying the crosstalk between immune cells and adipose tissue that drive cardiovascular and metabolic dysfunction in obesity. Expression of the kallikrein-related serine protease 7 (KLK7) in adipose tissue is linked to inflammation and insulin resistance in high fat diet (HFD)-fed mice. Here, we engineered mice with a macrophage-specific KLK7 knockout (KLK7MKO) to investigate how KLK7 loss impacts immune cell function and obesity-related pathology. Compared to control mice, we observed lower levels of systemic inflammation, with less infiltration and activation of inflammatory macrophages in HFD-fed KLK7MKO mice, particularly in the epididymal adipose tissue. Mechanistically, we uncover that Klk7 deficiency reduces pro-inflammatory gene expression in macrophages and restricts their migration through higher cell adhesion, hallmark features of macrophages in obese conditions. Importantly, through analyses of 1143 human visceral adipose tissue samples, we uncover that KLK7 expression is associated with pathways controlling cellular migration and inflammatory gene expression. In addition, serum KLK7 levels were strongly correlated with circulating inflammatory markers in a second cohort of 60 patients with obesity and diabetes. Our work uncovers the pro-inflammatory role of KLK7 in controlling inflammatory macrophage polarization and infiltration in visceral obesity, thereby contributing to metabolic disease. Thus, targeting KLK7 to control immune cell activation may dissociate adipose dysfunction from obesity, thereby representing an alternative obesity therapy.
    Keywords:  Adipose tissue; Inflammation; Metabolic disease; Obesity; Protease; Serpin
    DOI:  https://doi.org/10.1016/j.metabol.2025.156239
  3. Obesity (Silver Spring). 2025 Apr 02.
    Optimized RNA sequencing deconvolution illustrates the impact of obesity and weight loss on cell composition of human adipose tissue.
    Cheehoon Ahn, Adeline Divoux, Mingqi Zhou, Marcus M Seldin, Lauren M Sparks, Katie L Whytock.
       OBJECTIVE: Cellular heterogeneity of human adipose tissue is linked to the pathophysiology of obesity and may impact the response to energy restriction and changes in fat mass. Herein, we provide an optimized pipeline to estimate cellular composition in human abdominal subcutaneous adipose tissue (ASAT) bulk RNA sequencing (RNA-seq) datasets using a single-nuclei RNA-seq signature matrix.
    METHODS: A deconvolution pipeline for ASAT was optimized by benchmarking publicly available algorithms using a signature matrix derived from ASAT single-nuclei RNA-seq data from 20 adults and then applied to estimate ASAT cell-type proportions in publicly available obesity and weight loss studies.
    RESULTS: Individuals with obesity had greater proportions of macrophages and lower proportions of adipocyte subpopulations and vascular cells compared with lean individuals. Two months of diet-induced weight loss increased the estimated proportions of macrophages; however, 2 years of diet-induced weight loss reduced the estimated proportions of macrophages, thereby suggesting a biphasic nature of cellular remodeling of ASAT during weight loss.
    CONCLUSIONS: Our optimized high-throughput pipeline facilitates the assessment of composition changes of highly characterized cell types in large numbers of ASAT samples using low-cost bulk RNA-seq. Our data reveal novel changes in cellular heterogeneity and its association with cardiometabolic health in humans with obesity and following weight loss.
    DOI:  https://doi.org/10.1002/oby.24264
  4. J Nutr Biochem. 2025 Mar 31. pii: S0955-2863(25)00075-0. [Epub ahead of print] 109912
    Changes in lipid metabolism in visceral rather than the subcutaneous adipose tissue depot attenuate metabolic disturbances in obesity-resistant mice fed a high-fat diet.
    Miloš Vratarić, Ana Teofilović, Danijela Vojnović Milutinović, Nataša Veličković, Ljubica Vučićević, Goran Đmura, Ana Djordjevic.
      Obesity is characterized by an enlargement of white adipose tissue caused by caloric excess. The depot-specific adaptation of white adipose tissue in individuals resistant to obesity despite a high-calorie diet is crucial for understanding the pathogenesis of obesity and related metabolic disorders. Our aim was to characterize the metabolic and morphological state of obesity resistance and to investigate depot-specific changes in signaling pathways in epididymal visceral (eVAT) and inguinal subcutaneous (iSAT) white adipose tissue of C57BL/6J male mice on a high-fat diet (60 kcal% fats). After 14 weeks, the mice were categorized as obese (at least 30% higher body mass compared to the control group) or obesity-resistant (weight gain below 30%). Biochemical and morphological parameters, as well as histology, and signaling pathways involved in lipid metabolism, inflammation, and insulin sensitivity were investigated in eVAT and iSAT. The results showed unaltered body, total VAT and iSAT mass in obesity-resistant mice despite increased caloric intake. Leptin levels and glucose homeostasis were improved in these animals compared to the obese mice. In both eVAT and iSAT of the obesity-resistant mice, adipocyte size and lipolytic capacity were retained at control levels, while compared to the obese mice, preserved capacity for adipogenesis, improved local insulin sensitivity and the absence of inflammation were observed only in the eVAT. In conclusion, metabolic adaptation of eVAT rather than iSAT may have a substantial impact on the maintenance of the obesity-resistant phenotype with fewer metabolic complications, which could contribute to the improvement of existing obesity therapies.
    Keywords:  inflammation; insulin sensitivity; lipid metabolism; obesity-resistance; white adipose tissue
    DOI:  https://doi.org/10.1016/j.jnutbio.2025.109912
  5. Obesity (Silver Spring). 2025 Apr 02.
    Brd9 antagonism induces beige adipocytes in white adipose tissues and protects against diet-induced obesity.
    Yang Liu, Amelia Yin, Kendall Seese, Wenyan Fu, Hang Yin.
       OBJECTIVE: Thermogenic beige adipocytes emerge in white adipose tissue (WAT) under certain physiological and pathological conditions, leading to increased energy expenditure, insulin sensitivity, and glucose tolerance. The induction of beige adipocyte formation represents a promising therapeutic approach for obesity and associated chronic diseases; however, the mechanisms controlling WAT beiging remain incompletely understood.
    METHODS: We conducted a genome-wide knockout screening in the white adipose progenitors of mice to identify lineage repressors of beige adipocyte formation. We further investigated the metabolic effects and gene expression alterations upon Brd9 antagonism in obesity mouse models.
    RESULTS: An unbiased genetic screen identified the following four lineage repressors of beige adipocytes: Brd9; Ankib1; Cacng1; and Cfap20. Knockout of each gene individually promoted beige adipocyte differentiation in vitro and WAT beiging in vivo. In diet-induced obesity mouse models, oral administration of Brd9 inhibitors induced beige adipocytes within subcutaneous and visceral WAT, enhanced thermogenic gene expression in brown adipose tissue, and suppressed gluconeogenic gene expression in the liver. These beneficial effects were concomitant with augmented whole-body energy expenditure, reduced body weight/adiposity, and improved endurance and glucose metabolism.
    CONCLUSIONS: Antagonism of Brd9 and other beige lineage repressors may have significant implications for therapeutic induction of WAT beiging and thermogenesis to treat obesity and its associated chronic diseases.
    DOI:  https://doi.org/10.1002/oby.24280
  6. FASEB J. 2025 Apr 15. 39(7): e70490
    Detection of liver mitochondrial oxaloacetate by NMR spectroscopy and membrane potential-dependent accumulation.
    Liping Yu, Brian D Fink, William I Sivitz.
      Oxaloacetate (OAA) is a central liver metabolite fundamental to critical metabolic pathways. However, understanding OAA metabolism in the liver has been limited because the compound is very difficult to measure by mass spectroscopy and not abundant enough for detection by other methods. Here we describe a novel approach to quantifying OAA in liver mitochondria. Moreover, we provide evidence for membrane potential-dependent OAA accumulation in mitochondria during complex II-energized respiration consistent with OAA inhibition of succinate dehydrogenase.
    Keywords:  inner membrane potential; liver; metabolites; mitochondria; oxaloacetate; respiration
    DOI:  https://doi.org/10.1096/fj.202500039R
  7. J Endocrinol. 2025 Apr 01. pii: JOE-25-0017. [Epub ahead of print]
    Deletion of GFRAL blunts weight lowering effects of FGF21 in female mice.
    Alberte Silke Buch-Rasmussen, Helle Andersen, Christina Stage, Ann Maria Kruse Hansen, Sarah Juel Paulsen, Matthew Paul Gillum, Birgitte Andersen, Anna Secher, Markus Latta, Christoffer Clemmensen, Sebastian Jorgensen.
      The role of the GDF15 receptor, GDNF family receptor alpha like (GFRAL), in the metabolic effects of FGF21 was investigated by treating female GFRAL knockout mice with recombinant human FGF21. In contrast to FGF21-treated wildtype mice, which lost 12% body weight relative to vehicle, the absence of GFRAL coincided with a greater compensatory increase in food intake, and accordingly, the weight-lowering effect of FGF21 treatment was blunted. Interestingly, the glycaemic benefits of FGF21 persisted in the absence of GFRAL. Potential crosstalk between FGF21 and GDF15 was further investigated acutely in obese male rats in which a single dose of FGF21 did not increase endogenous circulating GDF15 levels and vice versa. Lastly, overexpression of GDF15 or FGF21 with hydrodynamic gene delivery in obese male mice did not alter the expression of the other's receptor complex in regions of the hypothalamus and hindbrain. Collectively, we demonstrate an impaired weight lowering effect of exogenous FGF21 in female GFRAL knockout mice. Yet, the further examination of the interconnectedness between GDF15 and FGF21 endocrine axes in male rodents imply that they largely operate in parallel and are not extensively intertwined. In future studies, it will be important to investigate the influence of sex, particularly on the role of GDF15-GFRAL signalling in regulating compensatory food intake induced by FGF21 pharmacology.
    DOI:  https://doi.org/10.1530/JOE-25-0017
  8. Endocr J. 2025 Apr 03.
    Physiology and clinical applications of GIP.
    Shunsuke Yamane, Norio Harada, Nobuya Inagaki.
      Glucose-dependent insulinotropic polypeptide (GIP) is secreted by enteroendocrine K cells, primarily located in the upper small intestine, in response to food intake and plays a significant role in the postprandial regulation of nutrient metabolism. Although the importance of GIP in metabolic regulation has long been recognized, progress in developing GIP as a therapeutic target has been limited. However, the GIP/GIP receptor (GIPR) axis has garnered increasing attention in recent years. Emerging evidence suggests that dual GIP/GLP-1 receptor agonists and triple GIP/GLP-1/glucagon receptor agonists provide beneficial metabolic effects in individuals with type 2 diabetes and obesity. In this review, we outline the physiological roles of GIP, detailing the mechanisms of GIP secretion from K cells in response to macronutrients, its actions on key target organs involved in metabolic regulation, and ongoing developments in its therapeutic applications.
    Keywords:  Diabetes; Glucose-dependent insulinotropic polypeptide (GIP); Incretin; Obesity
    DOI:  https://doi.org/10.1507/endocrj.EJ25-0087
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