bims-mimead 2025-06-15 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–06–15
nine papers selected by
Rachel M. Handy, University of Guelph

Insulin- and exercise-induced phosphoproteomics of human skeletal muscle identify REPS1 as a regulator of muscle glucose uptake.
Thermogenesis and reduced lipid synthesis: one-anastomosis gastric bypass bariatric surgery 6-month follow ups in adipose tissue context for type 2 diabetes.
Targeting the leptin receptor promotes MDA-MB-231 cells' metabolic reprogramming and malignancy: the role of extracellular vesicles derived from obese adipose tissue.
Sarcospan, a candidate gene of fat distribution, may affect lipid storage in adipocytes.
A Biological-Systems-Based Analyses Using Proteomic and Metabolic Network Inference Reveals Mechanistic Insights into Hepatic Lipid Accumulation: An IMI-DIRECT Study.
Ketogenesis is dispensable for the metabolic adaptations to caloric restriction.
microRNA-1 Regulates Metabolic Flexibility by Programming Adult Skeletal Muscle Pyruvate Metabolism.
Elevation of hepatic de novo lipogenesis in mice with overnutrition is dependent on multiple substrates.
Genetic and physiological insights into satiation variability predict responses to obesity treatment.

Cell Rep Med. 2025 May 29. pii: S2666-3791(25)00236-8. [Epub ahead of print] 102163

Insulin- and exercise-induced phosphoproteomics of human skeletal muscle identify REPS1 as a regulator of muscle glucose uptake.

Jeppe Kjærgaard, Cecilie B Lindqvist, Júlia Prats Quesada, Søren Jessen, Farina Schlabs, Amy M Ehrlich, Caio Y Yonamine, Mario García-Ureña, Johann H Schmalbruch, Lewin Small, Martin Thomassen, Anders Krogh Lemminger, Kasper Eibye, Alba Gonzalez-Franquesa, Jacob V Stidsen, Kurt Højlund, Juleen R Zierath, Tuomas O Kilpeläinen, Jens Bangsbo, Jonas T Treebak, Morten Hostrup, Atul S Deshmukh.

  Skeletal muscle glucose uptake, essential for metabolic health, is regulated by both insulin and exercise. Using phosphoproteomics, we analyze skeletal muscle from healthy individuals following acute exercise or insulin stimulation, generating a valuable dataset. We identify 71 phosphosites on 55 proteins regulated by both stimuli in the same direction, suggesting a convergence of exercise and insulin signaling pathways. Among these, the vesicle-associated protein, REPS1, is highly phosphorylated at Ser709 in response to both stimuli. We identify p90 ribosomal S6 kinase (RSK) to be a key upstream kinase of REPS1 S709 phosphorylation and that the RSK-REPS1 signaling axis is involved in insulin-stimulated glucose uptake. Insulin-induced REPS1 Ser709 phosphorylation is closely linked to muscle and whole-body insulin sensitivity and is impaired in insulin-resistant mice and humans. These findings highlight REPS1 as a convergence point for insulin and exercise signaling, presenting a potential therapeutic target for treating individuals with insulin resistance.

Keywords:  REPS1; RSK; exercise; glucose metabolism; insulin; phosphoproteomics; skeletal muscle signaling

DOI:  https://doi.org/10.1016/j.xcrm.2025.102163
Am J Physiol Endocrinol Metab. 2025 Jun 11.

Thermogenesis and reduced lipid synthesis: one-anastomosis gastric bypass bariatric surgery 6-month follow ups in adipose tissue context for type 2 diabetes.

I Stafeev, M Agareva, S Michurina, A Tomilova, E Shestakova, A Voznesenskaya, M Sineokaya, N Alekseeva, M Boldyreva, E Ratner, Ye Parfyonova, Marina V Shestakova.

  Background: One-anastomosis gastric bypass (OAGB) represents a novel less invasive bariatric surgery technique which can significantly improve systemic metabolism and adipose tissue health in type 2 diabetes mellitus (T2DM) patients. Previously, we demonstrated that T2DM impairs proliferation and differentiation of adipose tissue progenitors. Methods: Obese patients with T2DM (N=10) underwent clinical examination and subcutaneous fat biopsy during bariatric surgery and in 6-months. Adipose-derived stem cells (ADSC) were isolated by enzymatic method. Cell proliferation was analyzed using MTT assay and immunocytochemistry. Adipogenesis and thermogenesis were assessed by confocal microscopy. Adipocytes metabolism was estimated by radioisotope tracing. Western blotting was employed to quantify protein expression. Results: Median weight loss after OAGB was 40 kg. OAGB resolved hyperinsulinemia and stimulated insulin sensitivity with changes in HOMA-IR and M-index up to 2-fold. Bariatric surgery significantly influenced properties of ADSC adipocytes: there were an increase in ADSC proliferation, decrease in white adipogenesis, activation of white and beige adipocytes lipid droplet fragmentation, activation of thermogenesis and inhibition of lipogenesis. Conclusions: OAGB promotes weight loss and insulin sensitivity and changes regenerative potential of ADSC. Enhanced ability of ADSC to proliferate and differentiate into thermogenic adipocytes with reduced activity of lipogenesis may prevent weight gain after bariatric surgery.

Keywords:  adipocytes; adipose-derived stem cells; bariatric surgery; obesity; one anastomosis gastric bypass; type 2 diabetes

DOI:  https://doi.org/10.1152/ajpendo.00033.2025
Front Oncol. 2025 ;15 1568524

Targeting the leptin receptor promotes MDA-MB-231 cells' metabolic reprogramming and malignancy: the role of extracellular vesicles derived from obese adipose tissue.

Carol Costa Encarnação, Carolinne Souza Amorim, Victor Aguiar Franco, Luiz Gabriel Xavier Botelho, Ronan Christian Machado Dos Santos, Isadora Ramos-Andrade, Luiz Guilherme Kraemer-Aguiar, Christina Barja-Fidalgo, João Alfredo Moraes, Mariana Renovato-Martins.

   Introduction: Leptin, a key adipokine secreted by adipose tissue (AT), has emerged as a critical mediator linking obesity and breast cancer, both of which are major global health concerns. Elevated leptin levels are detected in the circulation and in extracellular vesicles (EVs) released by adipose tissue, particularly in cases of obesity. These leptin-enriched EVs have been implicated in various stages of tumor progression. In this study, we investigated the effects of leptin within extracellular vesicles (EVs) secreted by obese adipose tissue on the functional properties and metabolism of MDA-MB-231 breast cancer cells, a model for triple-negative breast cancer (TNBC).
Method: MDA-MB-231 cells were treated with EVs derived from the subcutaneous adipose tissue of eutrophic (EUT EVs) and obese (OB EVs) individuals.
Results: Our findings revealed that OB EVs induced significant phosphorylation of STAT3, a key signaling molecule in cancer progression, and promoted increased cell migration, dependent on fatty acid oxidation (FAO). This effect was reversed in the presence of a leptin receptor antagonist, highlighting leptin's pivotal role in these processes. Additionally, OB EVs caused metabolic changes, including reduced lactate levels and decreased pyruvate kinase (PK) activity, while increasing glucose-6-phosphate dehydrogenase (G6PDH) activity, suggesting metabolic reprogramming that supports tumor cell survival and proliferation. In addition to metabolic alterations, OB EVs also impacted mitochondrial dynamics. We observed an upregulation of fusion and fission markers and a redistribution of mitochondria toward the cell periphery, which supports migration. Moreover, OB EVs increased the invasive capacity of MDA-MB-231 cells, an effect mediated by matrix metalloproteinase-9 (MMP-9).
Discussion: Overall, our results highlight how obese adipose tissue modulates breast cancer cell behavior, with leptin-enriched EVs playing a central role in driving migration, metabolic reprogramming, and invasiveness, thereby promoting tumor malignancy. This study underscores the importance of EVs in the obesity-cancer link and offers new insights for therapeutic strategies targeting leptin signaling and EV-mediated communication in breast cancer.

Keywords:  adipose tissue; breast cancer; extracellular vesicles; leptin; obesity

DOI:  https://doi.org/10.3389/fonc.2025.1568524
Mol Cell Endocrinol. 2025 Jun 07. pii: S0303-7207(25)00153-4. [Epub ahead of print] 112602

Sarcospan, a candidate gene of fat distribution, may affect lipid storage in adipocytes.

Katharina Anastasia Dinter, Samantha Aurich, Luise Müller, Adhideb Ghosh, Falko Noé, Christian Wolfrum, Matthias Blüher, Anne Hoffmann, Peter Kovacs, Maria Keller.

   BACKGROUND AND AIMS: Genetic and epigenetic variations in the Sarcospan (SSPN) gene are associated with parameters of fat distribution (body mass index, waist-to-hip ratio), glucose homeostasis and adipocyte size in human potentially by affecting adipogenesis. This study aims at clarifying the impact of SSPN on adipogenesis, particularly focusing on its promoter methylation.
MATERIALS AND METHODS: Immortalized murine epididymal preadipocytes were transfected with fluorescence-marked plasmids coding for DNMT3a, CRISPR/dCas9-Suntag and vectors carrying guide RNAs complementary to the transcription start site region and differentiated to mature adipocytes. We performed siRNA-mediated Sspn knockdown in epididymal preadipocytes, measured target DNA methylation using pyrosequencing and quantified transcriptional changes of Sspn and adipogenic genes by qPCR. Additionally, we correlated SSPN mRNA values and clinical characteristics from a large human adipose tissue biobank (Leipzig Obesity Biobank).
RESULTS: Epigenetic editing of the Sspn regulatory region in preadipocytes resulted in a significant increase (up to 35 %) in DNA promoter methylation throughout adipocyte differentiation but showed only minor effects on Sspn expression and fat storage. Though siRNA knockdown could also not contribute to understand the role of Sspn in a 2D adipogenesis model, large-scale correlation analyses still indicate the gene to be a key player in fat distribution and glucose homeostasis.
CONCLUSIONS: Although the epigenetic downregulation of Sspn showed only marginal effects on adipogenesis, associations of SSPN expression in human adipose tissue with parameters of fat distribution and glucose homeostasis make it a promising candidate for further studies addressing metabolic processes in adipose tissue.

Keywords:  Adipocytes; Adipogenesis; Adipose Tissue; CRISPR; DNA Methylation; Obesity; Small Interfering RNA

DOI:  https://doi.org/10.1016/j.mce.2025.112602
medRxiv. 2025 Jun 02. pii: 2025.06.02.25328773. [Epub ahead of print]

A Biological-Systems-Based Analyses Using Proteomic and Metabolic Network Inference Reveals Mechanistic Insights into Hepatic Lipid Accumulation: An IMI-DIRECT Study.

Natalie N Atabaki, Daniel E Coral, Hugo Pomares-Millan, Kieran Smith, Harry H Behjat, Robert W Koivula, Andrea Tura, Hamish Miller, Katherine Pinnick, Leandro Agudelo, Kristine H Allin, Andrew A Brown, Elizaveta Chabanova, Piotr J Chmura, Ulrik P Jacobsen, Adem Y Dawed, Petra J M Elders, Juan J Fernandez-Tajes, Ian M Forgie, Mark Haid, Tue H Hansen, Elizaveta L Hansen, Angus G Jones, Tarja Kokkola, Sebastian Kalamajski, Anubha Mahajan, Timothy J McDonald, Donna McEvoy, Mirthe Muilwijk, Konstantinos D Tsirigos, Jagadish Vangipurapu, Sabine van Oort, Henrik Vestergaard, Jerzy Adamski, Joline W Beulens, Søren Brunak, Emmanouil T Dermitzakis, Giuseppe N Giordano, Ramneek Gupta, Torben Hansen, Leen T Hart, Andrew T Hattersley, Leanne Hodson, Markku Laakso, Ruth J F Loos, Jordi Merino, Mattias Ohlsson, Oluf Pedersen, Martin Ridderstråle, Hartmut Ruetten, Femke Rutters, Jochen M Schwenk, Jeremy Tomlinson, Mark Walker, Hanieh Yaghootkar, Fredrik Karpe, Mark I McCarthy, Elizabeth Louise Thomas, Jimmy D Bell, Andrea Mari, Imre Pavo, Ewan R Pearson, Ana Viñuela, Paul W Franks.

Objective: To delineate organ-specific and systemic drivers of metabolic dysfunction-associated steatotic liver disease (MASLD), we applied integrative causal inference across clinical, imaging, and proteomic domains in individuals with and without type 2 diabetes (T2D).
Research Design and Methods: We used Bayesian network analyses to quantify causal pathways linking adipose distribution, glycemia, and insulin dynamics with fatty liver using data from the IMI-DIRECT prospective cohort study. Measurements were made of glucose and insulin dynamics (using frequently-sampled metabolic challenge tests), MRI-derived abdominal and liver fat content, serological biomarkers, and Olink plasma proteomics from 331 adults with new-onset T2D and 964 adults free from diabetes at enrolment. The common protocols used in these two cohorts provided the opportunity for replication analyses to be performed. When the direction of the effect could not be determined with high probability through Bayesian networks, complementary two-sample Mendelian randomization (MR) was employed.
Results: High basal insulin secretion rate (BasalISR) was identified as the primary causal driver of liver fat accumulation in both diabetes and non-diabetes. Excess visceral adipose tissue (VAT) was bidirectionally associated with liver fat, indicating a self-reinforcing metabolic loop. Basal insulin clearance (Clinsb) worsened as a consequence of liver fat accumulation to a greater degree before the onset of T2D. Out of 446 analysed proteins, 34 mapped to these metabolic networks and 27 were identified in the non-diabetes network, 18 in the diabetes network, and 11 were common between the two networks. Key proteins directly associated with liver fat included GUSB, ALDH1A1, LPL, IGFBP1/2, CTSD, HMOX1, FGF21, AGRP, and ACE2. Sex-stratified analyses revealed distinct proteomic drivers: GUSB and LEP were most predictive of liver fat in females and males, respectively.
Conclusions: Basal insulin hypersecretion is a modifiable, causal driver of MASLD, particularly prior to glycaemic decompensation. Our findings highlight a multifactorial, sex-and disease-stage-specific proteo-metabolic architecture of hepatic steatosis. Proteins such as GUSB, ALDH1A1, LPL, and IGFBPs warrant further investigation as potential biomarkers or therapeutic targets for MASLD prevention and treatment.

DOI: https://doi.org/10.1101/2025.06.02.25328773
bioRxiv. 2025 Jun 01. pii: 2025.05.29.656153. [Epub ahead of print]

Ketogenesis is dispensable for the metabolic adaptations to caloric restriction.

Chung-Yang Yeh, Lexie Borgelt, Brynn J Vogt, Alyssa A Clark, Ted T Wong, Isaac Grunow, Michelle M Sonsalla, Reji Babygirija, Yang Liu, Michaela E Trautman, Mariah F Calubag, Bailey A Knopf, Fan Xiao, Dudley W Lamming.

Caloric restriction (CR) robustly extends the health and lifespan of diverse species. When fed once daily, CR-treated mice rapidly consume their food and endure a prolonged fast between meals. As fasting is associated with a rise in circulating ketones, we decided to investigate the role of ketogenesis in CR using mice with whole-body ablation of Hmgcs2 , the rate-limiting enzyme producing the main ketone body β-hydroxybutyrate (βHB). Here, we report that Hmgcs2 is largely dispensable for many metabolic benefits of CR, including CR-driven changes in adiposity, glycemic control, liver autophagy, and energy balance. Although we observed sex-specific effects of Hmgcs2 on insulin sensitivity, fuel selection, and adipocyte gene expression, the overall physiological response to CR remains robust in mice lacking Hmgcs2 . To gain insight into why deletion of Hmgcs2 does not disrupt CR, we measured fasting βHB levels as mice began a CR diet. Surprisingly, as CR-fed mice adapt to CR, they no longer engage high levels of ketogenesis during the daily fast. Our work suggests that the benefits of long-term CR in mice are not mediated by ketogenesis.

DOI: https://doi.org/10.1101/2025.05.29.656153
Mol Metab. 2025 Jun 07. pii: S2212-8778(25)00089-4. [Epub ahead of print] 102182

microRNA-1 Regulates Metabolic Flexibility by Programming Adult Skeletal Muscle Pyruvate Metabolism.

Ahmed Ismaeel, Bailey D Peck, McLane M Montgomery, Benjamin I Burke, Jensen Goh, Abigail B Franco, Qin Xia, Katarzyna Goljanek-Whysall, Brian McDonagh, Jared M McLendon, Pieter J Koopmans, Daniel Jacko, Kirill Schaaf, Wilhelm Bloch, Sebastian Gehlert, Kevin A Murach, Kelsey H Fisher-Wellman, Ryan L Boudreau, Yuan Wen, John J McCarthy.

  Metabolic flexibility refers to the ability of a tissue to adjust cellular fuel choice in response to conditional changes in metabolic demand and activity. A loss of metabolic flexibility is now recognized as a defining feature of various diseases and cellular dysfunction. In this study, using an inducible, skeletal muscle-specific knockout (KO) mouse, we found microRNA-1 (miR-1), the most abundant microRNA (miRNA) in skeletal muscle, was necessary to maintain whole-body metabolic flexibility. This was demonstrated by a loss of diurnal oscillations in whole-body respiratory exchange ratio and higher fasting blood glucose in miR-1 KO mice. Argonaute 2 enhanced crosslinking and immunoprecipitation sequencing (AGO2 eCLIP-seq) and RNA-seq analyses identified, for the first time, bona fide miR-1 target genes in adult skeletal muscle that regulated pyruvate metabolism. Comprehensive bioenergetic phenotyping combined with skeletal muscle proteomics and metabolomics showed that miR-1 was necessary to maintain metabolic flexibility by regulating pyruvate metabolism through mechanisms including the alternative splicing of pyruvate kinase (Pkm). The loss of metabolic flexibility in the miR-1 KO mouse was rescued by pharmacological inhibition of the miR-1 target, monocarboxylate transporter 4 (MCT4), which redirects glycolytic carbon flux toward oxidation. The maintenance of metabolic flexibility by miR-1 was necessary for sustained endurance activity in mice and in C. elegans. The physiological down-regulation of miR-1 in response to a hypertrophic stimulus in both humans and mice caused a similar metabolic reprogramming necessary for muscle cell growth. Taken together, these data identify a novel post-transcriptional mechanism of whole-body metabolism regulation mediated by a tissue-specific miRNA.

Keywords:  MCT4; PKM; VB124; aerobic glycolysis; eCLIP-seq; resistance training

DOI:  https://doi.org/10.1016/j.molmet.2025.102182
J Lipid Res. 2025 Jun 09. pii: S0022-2275(25)00098-7. [Epub ahead of print] 100838

Elevation of hepatic de novo lipogenesis in mice with overnutrition is dependent on multiple substrates.

Jordan W Strober, Stephan Siebel, Susan F Murray, Manuel González Rodríguez, Carlos Rodriguez-Navas Gonzalez, Daniel F Vatner.

  Increased de novo lipogenesis (DNL) contributes to hyperlipidemia, MASLD, and ASCVD in insulin resistant subjects. However, multiple pathways support lipogenesis and few have sought to quantify the contributions of the discrete metabolic pathways that contribute to lipogenesis. In this study, antisense oligonucleotides (ASOs) targeting glucokinase (Gck), lactate dehydrogenase A (Ldha), and glutamic-pyruvic transaminase 2 (Gpt2) were utilized to restrict substrate flux from lipogenic precursors in C57BL6/J mice, comparing controls (CO) and chronic overnutrition (ON). In CO mice, ASO treatments did not significantly alter lipogenesis; however, there was a trend toward decreased hepatic triglyceride content and DNL, especially with the GPT2 ASO (TG=-46.8%; DNL=-53.7%). Expectedly, increased hepatic TG content and DNL (ON vs CO: TG=+187.9%; DNL=+41.8%) was observed in mice with chronic overnutrition. Gas chromatography-mass spectrometry analyses demonstrated increased hepatic TCA cycle metabolites (ON vs CO: fumarate +74.2%; malate +54.0%; and citrate +43.2) and decreased hepatic concentrations of multiple amino acids (ON vs CO: Leu -41.7%; Ile -45.0%; Val -56.3%; Ser -22.6%). With ON, TG content and DNL were reduced by restricting lipogenic carbon entry from alanine (GPT2: TG=-45.5%; DNL=-48.1%), lactate (LDHA: TG=-25.8%; DNL=-33.1%), or glucose (GCK: TG=-59.2%; DNL=-69.2%). Amino acids appear to be a consistent carbon source for DNL in mice; however, carbon entry from all sources is required to maintain the significantly elevated rates of hepatic DNL in chronically overfed mice. These findings may inform the development of novel therapies and underscore the importance of peripheral substrate storage and oxidation in the prevention of dyslipidemia in the metabolic syndrome.

Keywords:  Antisense oligonucleotide; De Novo Lipogenesis; Insulin Resistance; Lipolysis and fatty acid metabolism; Liver; Mitochondria; TCA cycle; Triglyceride

DOI:  https://doi.org/10.1016/j.jlr.2025.100838
Cell Metab. 2025 Jun 03. pii: S1550-4131(25)00264-5. [Epub ahead of print]

Genetic and physiological insights into satiation variability predict responses to obesity treatment.

Lizeth Cifuentes, Diego Anazco, Timothy O'Connor, Maria Daniela Hurtado, Wissam Ghusn, Alejandro Campos, Sima Fansa, Alison McRae, Sunil Madhusudhan, Elle Kolkin, Michael Ryks, William S Harmsen, Serban Ciotlos, Barham K Abu Dayyeh, Donald D Hensrud, Michael Camilleri, Andres Acosta.

  Satiation, the process that regulates meal size and termination, varies widely among adults with obesity. To better understand and leverage this variability, we assessed calories to satiation (CTS) through an ad libitum meal, combined with physiological and behavioral evaluations, including calorimetry, imaging, blood sampling, and gastric emptying tests. Although factors like baseline characteristics, body composition, and hormone levels partially explain CTS variability, they leave substantial variability unaccounted for. To address this gap, we developed a machine-learning-assisted genetic risk score (CTSGRS) to predict high CTS. In a randomized clinical trial, participants with high CTS or CTSGRS achieved greater weight loss with phentermine-topiramate over 52 weeks, whereas those with low CTS or CTSGRS responded better to liraglutide at 16 weeks in a separate trial. These findings highlight the potential of combining satiation measurements with genetic modeling to predict treatment outcomes and inform personalized strategies for obesity management.

Keywords:  calories to satiation; genetic risk score; liraglutide; machine learning; obesity treatment; personalized obesity management; phentermine-topiramate; precision medicine; satiation; satiety; weight loss outcomes

DOI:  https://doi.org/10.1016/j.cmet.2025.05.008