bims-mimead 2025-07-20 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–07–20
twelve papers selected by
Rachel M. Handy, University of Guelph

B cell-derived nociceptin/orphanin FQ contributes to impaired glucose tolerance and insulin resistance in obesity.
Muscle very long-chain ceramides associate with insulin resistance independently of obesity.
Epigenetic Programming of Estrogen Receptor in Adipose Tissue by High Fat Diet Regulates Obesity-Induced Inflammation.
The extracellular vesicle transcriptome provides tissue-specific functional genomic annotation relevant to disease susceptibility in obesity.
Effects of FGF21, soluble TGFBR2, and environmental temperature on metabolic dysfunction in lipodystrophic mice.
Incretin-based approaches for type 2 diabetes therapy: effects on circulating cytokines and adipocyte's secretome.
p21-activated Kinases (PAKs) Regulate FGF1/PDE4D Antilipolytic Pathway and Insulin Resistance in Adipocytes.
Acute session of three endurance exercise intensities alters subcutaneous adipose tissue transcriptome in regular exercisers.
The GLP-1 Receptor Agonist Dulaglutide Attenuates Hepatic Steatosis in Obesity via a Weight-Independent Mechanism.
Subcutaneous Adipose Tissue-Secreted Proteins as Endocrine Regulators of Physical and Cognitive Function in Older Adults.
Cancer cells differentially modulate mitochondrial respiration to alter redox state and enable biomass synthesis in nutrient-limited environments.
From omics to AI-mapping the pathogenic pathways in type 2 diabetes.

iScience. 2025 Jul 18. 28(7): 112819

B cell-derived nociceptin/orphanin FQ contributes to impaired glucose tolerance and insulin resistance in obesity.

Stephanie C Puente-Ruiz, Leona Ide, Julia Schuller, Adel Ben-Kraiem, Anne Hoffmann, Adhideb Ghosh, Falko Noé, Christian Wolfrum, Kerstin Krause, Martin Gericke, Nora Klöting, Jens C Brüning, F Thomas Wunderlich, Matthias Blüher, Alexander Jais.

  Immune-derived opioid peptides have been implicated in immune regulation and inflammatory processes. Here, we investigate the effects of nociceptin/orphanin FQ (N/OFQ) on metabolic function and inflammation in obesity. Selectively targeting N/OFQ, encoded by the Pnoc gene, in B cells mitigates the adverse metabolic effects of diet-induced obesity and enhances insulin sensitivity and glucose tolerance. Notably, B cell-specific Pnoc knockout mice display a marked reduction in markers of immune cell migration and diminished macrophage recruitment in adipose tissue and liver. Mechanistically, we identify that N/OFQ promotes macrophage recruitment and metabolic inflammation, exacerbating glucose intolerance and insulin resistance during obesity. Overall, the immunomodulatory properties exhibited by the N/OFQ-NOP system render it a promising therapeutic target for mitigating metabolic inflammation.

Keywords:  Biological sciences; Endocrinology; Natural sciences; Physiology

DOI:  https://doi.org/10.1016/j.isci.2025.112819
Mol Metab. 2025 Jul 11. pii: S2212-8778(25)00119-X. [Epub ahead of print] 102212

Muscle very long-chain ceramides associate with insulin resistance independently of obesity.

Søren Madsen, Harry B Cutler, Kristen C Cooke, Meg Potter, Jasmine Khor, Christoph D Rau, Stewart Wc Masson, Anna Howell, Zora Modrusan, Anthony S Don, Jacqueline Stöckli, Alexis Diaz Vegas, David E James.

Lipids, in particular ceramides and diacylglycerols (DAGs), are implicated in insulin resistance (IR), however their precise roles remain unclear. Here, we leverage natural genetic variation to examine muscle lipids and systemic IR in 399 Diversity Outbred Australia mice fed either chow or a high-fat diet. Adipose tissue mass was significantly associated with 55% of muscle lipid features and whole-body insulin sensitivity, with DAGs as the only lipid class enriched in this association. To disentangle the contribution of adiposity and muscle lipids to whole-body insulin sensitivity, we employed two independent approaches: (1) a linear model correcting muscle lipid features for adipose tissue mass to assess their relationship with insulin sensitivity, and (2) stratifying mice into insulin sensitivity quartiles within adiposity bins. Both revealed that very long-chain ceramides, but not DAGs, were linked to IR. RNA sequencing and proteomics from the same muscles further associated these very long-chain ceramides with cellular stress, mitochondrial dysfunction, and protein synthesis. Meanwhile, DAGs correlated with leptin gene expression in skeletal muscle, suggesting they originate from contaminating adipocytes rather than myocytes per se. We propose that many muscle lipids, including DAGs, associate with muscle and systemic IR due to accumulation of adipose tissue rather than directly influencing muscle insulin sensitivity. By addressing the relationship between adiposity and metabolic state, we identified very long-chain muscle ceramides as being highly associated with IR independently of adiposity.

DOI: https://doi.org/10.1016/j.molmet.2025.102212
bioRxiv. 2025 Jun 26. pii: 2025.06.21.660886. [Epub ahead of print]

Epigenetic Programming of Estrogen Receptor in Adipose Tissue by High Fat Diet Regulates Obesity-Induced Inflammation.

Rui Wu, Fenfen Li, Shirong Wang, Jia Jing, Xin Cui, Yifei Huang, Xucheng Zhang, Jose A Carrillo, Zufeng Ding, Jiuzhou Song, Liqing Yu, Huidong Shi, Bingzhong Xue, Hang Shi.

Adipose inflammation plays a key role in obesity-induced metabolic abnormalities. Epigenetic regulation, including DNA methylation, is a molecular link between environmental factors and complex diseases. Here we found that high fat diet (HFD) feeding induced a dynamic change of DNA methylome in mouse white adipose tissue (WAT) analyzed by reduced representative bisulfite sequencing. Interestingly, DNA methylation at the promoter of estrogen receptor α ( Esr1 ) was significantly increased by HFD, concomitant with a down-regulation of Esr1 expression. HFD feeding in mice increased the expression of DNA methyltransferase 1 ( Dnmt1 ) and Dnmt3a, and binding of DNMT1 and DNMT3a to Esr1 promoter in WAT. Mice with adipocyte-specific Dnmt1 deficiency displayed increased Esr1 expression, decreased adipose inflammation and improved insulin sensitivity upon HFD challenge; while mice with adipocyte-specific Dnmt3a deficiency showed a mild metabolic phenotype. Using a modified CRISPR/RNA-guided system to specifically target DNA methylation at the Esr1 promoter in WAT, we found that reducing DNA methylation at Esr1 promoter increased Esr1 expression, decreased adipose inflammation and improved insulin sensitivity in HFD-challenged mice. Our study demonstrates that DNA methylation at Esr1 promoter plays an important role in regulating adipose inflammation, which may contribute to obesity-induced insulin resistance.

DOI: https://doi.org/10.1101/2025.06.21.660886
Cell Genom. 2025 Jul 09. pii: S2666-979X(25)00181-8. [Epub ahead of print] 100925

The extracellular vesicle transcriptome provides tissue-specific functional genomic annotation relevant to disease susceptibility in obesity.

Emeli Chatterjee, Michael J Betti, Quanhu Sheng, Phillip Lin, Margo P Emont, Guoping Li, Kaushik Amancherla, Marta Garcia-Contreras, Priyanka Gokulnath, Worawan B Limpitikul, Olivia Rosina Whittaker, Kathy Luong, Christopher Azzam, Denise Gee, Matthew Hutter, Karen Flanders, Parul Sahu, Charles R Flynn, Jonathan Brown, Danxia Yu, Evan D Rosen, Kendall Van-Keuren Jensen, Eric R Gamazon, Ravi Shah, Saumya Das.

  We characterized circulating extracellular vesicles (EVs) in obese and lean humans, identifying transcriptional cargo differentially expressed in obesity (277 unique genes; false discovery rate < 10%). Since circulating EVs may have broad origin, we compared this obesity EV transcriptome with expression from human visceral-adipose-tissue-derived EVs from freshly collected and cultured biopsies from the same obese individuals, observing high concordance. Using a comprehensive set of adipose-specific epigenomic and chromatin conformation assays, we found that the differentially expressed transcripts from the EVs were those regulated in adipose by body mass index-associated SNPs (p < 5 × 10-8) from a large-scale genome-wide association study (GWAS). Using a phenome-wide association study of the regulatory SNPs for the EV-derived transcripts, we identified a substantial enrichment for inflammatory phenotypes, including type 2 diabetes. Collectively, these findings represent the convergence of the GWAS (genetics), epigenomics (transcript regulation), and EV (liquid biopsy) fields, enabling powerful future genomic studies of complex diseases.

Keywords:  BMI; GWAS; PheWAS; RNA; extracellular vesicles; obesity; plasma; visceral adipose tissue

DOI:  https://doi.org/10.1016/j.xgen.2025.100925
JCI Insight. 2025 Jul 15. pii: e194882. [Epub ahead of print]

Effects of FGF21, soluble TGFBR2, and environmental temperature on metabolic dysfunction in lipodystrophic mice.

Jessica N Maung, Yang Chen, Keegan S Hoose, Rose E Adler, Hadla Hariri, Mia J Dickson, Taryn A Hetrick, Gabriel A Ferguson, Rebecca L Schill, Hiroyuki Mori, Romina M Uranga, Kenneth T Lewis, Isabel D K Hermsmeyer, Donatella Gilio, Christopher de Solis, Amber Toliver, Noah Davidsohn, Elif A Oral, Ormond A MacDougald.

  Metabolic health is influenced by adipose tissue, and obesity and lipodystrophy are characterized by inflammation and metabolic dysfunction. Whereas obesity and lipodystrophy treatments involve pharmacological approaches and lifestyle changes, these therapies require long-term, repeated dosing, and are not successful for all patients. Gene therapy with targets such as FGF21 and sTGFBR2 provides an alternative approach, specifically in lipodystrophy. Preclinical experiments in mice housed at 22°C are confounded by a mild cold stress not generally experienced by humans, which can negatively affect translation of metabolic therapeutics. In this study, we investigated effects of FGF21/sTGFBR2 combination gene therapy on obese and lipodystrophic mice, and how housing temperature influences therapeutic efficacy. In obese mice, FGF21/sTGFBR2 improved insulin resistance and hyperlipidemia more dramatically at warmer temperatures. In lipodystrophic mice on a high fat diet, combination therapy required adipose tissue to improve insulin resistance at 30°C, whereas FGF21 alone improved insulin resistance at 22°C. Transcriptomic analyses revealed that lipodystrophic mice had upregulated hepatic cell proliferation and fibrosis pathways, and that FGF21 promoted hepatic metabolism. Thus, metabolic dysfunction caused by lipodystrophy is improved by targeting FGF21 and TGFB signaling, but effectiveness in preclinical models may be dependent upon environmental temperature and presence of adipose tissue.

Keywords:  Adipose tissue; Bone biology; Bone marrow; Metabolism; Obesity

DOI:  https://doi.org/10.1172/jci.insight.194882
BMC Endocr Disord. 2025 Jul 17. 25(1): 182

Incretin-based approaches for type 2 diabetes therapy: effects on circulating cytokines and adipocyte's secretome.

Margarita Agareva, Svetlana Michurina, Alina Tomilova, Ekaterina Shestakova, Anastasia Voznesenskaya, Maria Sineokaya, Ekaterina Zubkova, Elizaveta Ratner, Iurii Stafeev, Yelena Parfyonova, Marina Shestakova.

   BACKGROUND: Adipose tissue secretome plays a crucial role in the mechanisms of metabolic diseases. Weight loss has a favourable effect on the adipose tissue secretome and prevents the development of type 2 diabetes mellitus (T2DM) and its complications. The most effective methods of glycaemic control are bariatric surgery (BS) and pharmacotherapy. The aim of our study is to evaluate changes in adipose tissue secretome after BS and semaglutide injections.
METHODS: 17 patients with T2DM were examined before and 6 months after BS or semaglutide therapy. The examination protocol included anthropometry, clinical biochemistry, insulin resistance evaluation and collection of subcutaneous adipose tissue biopsies. Adipose derived stem cells (ADSC) were isolated from biopsies according to a standard enzymatic protocol and differentiated into white and beige adipocytes. Adipogenesis and thermogenesis were assessed by confocal microscopy. Secretome of adipocytes and cytokines plasma levels were analyzed using a MILLIPLEX panel.
RESULTS: Following BS and semaglutide therapy, a decline in BMI, total fat content, HbA1c, and fasting blood glucose was observed. Insulin sensitivity increased only 6 months after BS. Semaglutide therapy resulted in the elevation of angiogenic and proinflammatory cytokines in adipocyte secretory profile. After BS we also detected the increase in proinflammatory cytokines both in adipocyte secretome and in plasma levels. However, the adipocyte secretome subsequent to bariatric surgery (BS) exhibited a reduced proinflammatory response in comparison to that observed following semaglutide therapy.
CONCLUSIONS: The effect of semaglutide injections directly on adipose tissue can change the function of ADSC, making them more angiogenic and adipogenic. A decrease in BMI, HbA1c and insulin resistance is achieved to a significant extent only after BS. BS-induced T2DM remission is related to lower pro-inflammatory secretion from adipocytes as compared to semaglutide. The regulation of inflammation in adipocytes may serve as a potential mechanism underlying BS-induced T2DM remission.

Keywords:  Adipocytes; Adipose-derived stem cells; Cytokines; Plasma; Secretome; Type 2 diabetes

DOI:  https://doi.org/10.1186/s12902-025-01999-w
Mol Metab. 2025 Jul 12. pii: S2212-8778(25)00117-6. [Epub ahead of print] 102210

p21-activated Kinases (PAKs) Regulate FGF1/PDE4D Antilipolytic Pathway and Insulin Resistance in Adipocytes.

Judith Seigner, Johannes Krier, David Spähn, Leontine Sandforth, Judith L Nono, Robert Lukowski, Andreas L Birkenfeld, Gencer Sancar.

Increasing evidence suggests that adipose tissue plays a key role in the development, progression, and treatment of the globally epidemic disease type 2 diabetes (T2D). For example, adipose tissue dysfunction, lipotoxicity, and insulin resistance (IR) are major contributors and targets for the treatment of T2D. We previously identified the Fibroblast growth factor 1 (FGF1) / Phosphodiesterase 4D (PDE4D) pathway, which lowers plasma glucose concentration by suppressing lipolysis in adipose tissue and ultimately regulating hepatic glucose production in obese insulin-resistant mice. While phosphorylation of PDE4D is critical for its activity, the upstream signaling mechanisms remain unclear. In this study, we identified p21-activated kinases (PAKs) as regulator of PDE4D phosphorylation and suppression of lipolysis by FGF1. Inhibition of PAK-induced cAMP accumulation prevented antilipolytic function of FGF1, and reversed suppression of lipolysis caused by PDE4D overexpression, linking PAKs to the regulation of cAMP by PDE4D in murine adipocytes in vitro. Chronic inhibition of PAKs decreased lipid accumulation in both mouse and human adipocyte cultures, lowered expression of adipogenic markers, and induced IR, suggesting a previously unidentified role of PAKs in adipocyte function and differentiation. We conclude that PAKs play a crucial role in regulating the FGF1/PDE4D antilipolytic pathway, adipogenesis and IR, thereby highlighting their potential as therapeutic targets for T2D.

DOI: https://doi.org/10.1016/j.molmet.2025.102210
bioRxiv. 2025 May 08. pii: 2025.05.02.651890. [Epub ahead of print]

Acute session of three endurance exercise intensities alters subcutaneous adipose tissue transcriptome in regular exercisers.

Cheehoon Ahn, Tao Zhang, Thomas Rode, Gayoung Yang, Olivia K Chugh, Sierra Ellis, Sophia Ghayur, Shriya Mehta, Ryan Salzman, Hui Jiang, Stephen C J Parker, Charles F Burant, Jeffrey F Horowitz.

The primary aim of this study was to compare the acute effects of three exercise intensities on abdominal subcutaneous adipose tissue (aSAT) transcriptome in regular exercisers. A total of 45 adults who exercise regularly were assigned to perform a single session of either low-intensity continuous (LOW; 60min at 30% VO 2 max; n=15), moderate-intensity continuous (MOD; 45min at 65% VO 2 max; n=15), or high-intensity interval exercise (HIGH; 10×1min at 90% VO 2 max interspersed with 1min active recovery; n=15). aSAT biopsy samples were collected before and 1.5hours after the exercise session for bulk RNA sequencing and targeted protein immunoassays. HIGH upregulated genes involved in cytokine secretion, insulin signaling, and proteolysis while MOD and LOW upregulated genes regulating ECM remodeling, ribosome biogenesis, and oxidative phosphorylation pathways. Exercise-induced changes in aSAT angiogenic, MAPK cascade, and clock genes, ERK protein phosphorylation, and circulating cytokines were similar after all three exercise treatments. Network analysis identified exercise-responsive gene clusters linked to cardiometabolic health traits. Cell-type analysis highlighted a heterogeneous response of aSAT cell types to exercise, with distinct patterns observed across exercise intensities. Collectively, our data characterizes early responses in aSAT after a single session of exercise. Because adaptations to exercise training stem from an accrual of responses after each session of exercise, these early responses to exercise are likely important contributors to the long-term structural and functional changes that occur in adipose tissue in response to exercise training.

DOI: https://doi.org/10.1101/2025.05.02.651890
Diabetes. 2025 Jul 15. pii: db240861. [Epub ahead of print]

The GLP-1 Receptor Agonist Dulaglutide Attenuates Hepatic Steatosis in Obesity via a Weight-Independent Mechanism.

Dharti Shantaram, Xilal Y Rima, David Bradley, Joey Z Liu, Valerie P Wright, Anastasiia Amari, Anahita Jalilvand, Joseph Rottinghaus, Jaden M Fernandes, Alan J Smith, Dana Middendorf, Martha Yearsley, Debasish Roy, Willa A Hsueh.

ARTICLE HIGHLIGHTS: Glucagon-like peptide-1 receptor agonists are promising therapies in treating various obesity-associated diseases; however, the mechanisms are convoluted with the benefits of weight loss. Dulaglutide has weight-independent therapeutic effects on the liver, reducing hepatic steatosis and improving liver function. Dulaglutide reduces de novo lipogenesis, lipid droplet stability, inflammation, and oxidative stress in the liver and lipolysis in adipose tissue. Weight loss may play an important role in glucagon-like peptide-1 receptor agonists' effect on decreasing coronary vascular disease risk.

DOI: https://doi.org/10.2337/db24-0861
Mol Metab. 2025 Jul 15. pii: S2212-8778(25)00120-6. [Epub ahead of print] 102213

Subcutaneous Adipose Tissue-Secreted Proteins as Endocrine Regulators of Physical and Cognitive Function in Older Adults.

Cheehoon Ahn, Ian Tamburini, James A Sanford, Mingqi Zhou, Farah Gamie, Reichelle X Yeo, Carlos H Viesi, Maria Pino, Katie L Whytock, Lauren E Oberlin, Theresa Mau, Joshua N Adkins, Jamie N Justice, Ashlee N Wood, Zana M Ross, Paul D Piehowski, Chelsea M Hutchinson Bunch, Kirk I Erickson, Frederico G S Toledo, Nancy E Lane, Peggy M Cawthon, Anne B Newman, Stephen B Kritchevsky, Steven R Cummings, Bret H Goodpaster, Erin E Kershaw, Marcus M Seldin, Lauren M Sparks.

Declines in skeletal muscle and cognitive function in older adults have been linked to abnormalities in abdominal subcutaneous adipose tissue (ASAT), yet the underlying molecular mediators remain poorly understood. Here, leveraging ASAT transcriptomics and explant-conditioned media proteomics from participants in the Study of Muscle, Mobility and Aging (SOMMA; age ≥70 years, n=229), we identified ASAT gene clusters and secreted proteins strongly associated with comprehensive assessments of physical and cognitive function in older adults. ASAT inflammation and secreted immunoglobulins were identified as key signatures of aging-associated physical and cognitive performance limitations. Systems genetics analysis confirmed secreted-SERPINF1 as a negative regulator of skeletal muscle contraction and highlighted its potential role in inducing inflammation in the heart in silico. Additionally, novel ASAT-secreted proteins such as NID2 and APOA4 were implicated in mediating ASAT crosstalk with skeletal muscle and brain in silico. Our framework provides insights into ASAT-driven tissue crosstalk underlying physical and cognitive performance in older adults and offers a valuable resource for understanding the role of ASAT in human aging.

DOI: https://doi.org/10.1016/j.molmet.2025.102213
bioRxiv. 2025 May 10. pii: 2025.05.09.653205. [Epub ahead of print]

Cancer cells differentially modulate mitochondrial respiration to alter redox state and enable biomass synthesis in nutrient-limited environments.

Sarah M Chang, Muhammad Bin Munim, Sonia E Trojan, Anna Shevzov-Zebrun, Keene L Abbott, Matthew G Vander Heiden.

The cell NAD+/NADH ratio can constrain biomass synthesis and influence proliferation in nutrient-limited environments. However, which cell processes regulate the NAD+/NADH ratio is not known. Here, we find that some cancer cells elevate the NAD+/NADH ratio in response to serine deprivation by increasing mitochondrial respiration. Cancer cells that elevate mitochondrial respiration have higher serine production and proliferation in serine limiting conditions than cells with no mitochondrial respiration response, independent of serine synthesis enzyme expression. Increases in mitochondrial respiration and the NAD+/NADH ratio promote serine synthesis regardless of whether serine is environmentally limiting. Lipid deprivation can also increase the NAD+/NADH ratio via mitochondrial respiration in some cells, including cells that do not increase respiration following serine deprivation. Thus, in cancer cells where lipid depletion raises the NAD+/NADH ratio, proliferation in serine depleted environments improves when lipids are also depleted. Taken together, these data suggest that changes in mitochondrial respiration in response to nutrient deprivation can influence the NAD+/NADH ratio in a cell-specific manner to impact oxidative biomass synthesis and proliferation. Given the complexity of tumor microenvironments, this work provides a metabolic framework for understanding how levels of more than one environmental nutrient affects cancer cell proliferation.

DOI: https://doi.org/10.1101/2025.05.09.653205
FEBS Lett. 2025 Jul 17.

From omics to AI-mapping the pathogenic pathways in type 2 diabetes.

Siobhán O'Sullivan, Lu Qi, Pierre Zalloua.

  Understanding the biochemical pathways and interorgan cross talk underlying type 2 diabetes (T2D) is essential for elucidating its pathophysiology. These pathways provide a mechanistic framework linking molecular dysfunction to clinical phenotypes, enabling patient stratification based on dominant metabolic disturbances. Advances in multi-omics, including genomics, transcriptomics, proteomics, microbiomics, and metabolomics, offer a systems-level view connecting genetic variants and regulatory elements to disease traits. Single-cell technologies further refine this perspective by identifying cell-type-specific drivers of β-cell failure, hepatic glucose dysregulation, and adipose inflammation. AI-driven analytics and machine learning integrate these high-dimensional datasets, uncovering molecular signatures and regulatory networks involved in insulin signaling, lipid metabolism, mitochondrial function, and immune-metabolic cross talk. This review synthesizes current evidence on T2D's molecular architecture, emphasizing key pathways such as PI3K-Akt, AMPK, mTOR, JNK, and sirtuins. It also explores the role of gut microbiota in modulating host metabolism and inflammation. Adopting a pathway-centric systems biology approach moves beyond statistical associations toward mechanistic insight. Integrating multi-omics with AI-based modeling represents a transformative strategy for stratifying patients and guiding precision therapies in diabetes care. Impact statement This review translates complex biochemical pathways into therapeutic direction for type 2 diabetes, addressing a critical gap between molecular research and clinical care. By integrating multi-omics, AI, and systems biology, it empowers the scientific community to develop targeted interventions that reduce the global burden of this escalating metabolic disease.

Keywords:  artificial intelligence; clinical translation; digital twins; multi‐omics integration; precision medicine; systems biology; type 2 diabetes

DOI:  https://doi.org/10.1002/1873-3468.70115