bims-mimead Biomed News
on Adipose tissue and metabolic disease
Issue of 2026–01–18
nine papers selected by
Rachel M. Handy, University of Guelph
  1. Single-cell-resolved transcriptional dynamics of human subcutaneous adipose tissue during lifestyle- and bariatric surgery-induced weight loss.
  2. Human MASLD is a diurnal disease driven by multisystem insulin resistance and reduced insulin availability at night.
  3. Circulating metabolites, genetics and lifestyle factors in relation to future risk of type 2 diabetes.
  4. The MetaboHealth Score Enhances Insulin Resistance Metabotyping for Targeted Fat Loss: The PERSON Study.
  5. Prior high fiber intake impinges on the cellular responses of mesenteric adipose and intestinal tissues to subsequent high fat feeding.
  6. Genetic regulation of fatty acid content in adipose tissue.
  7. Gpx4 Deletion-Mediated Macrophage Ferroptosis Alleviates Obesity-Associated Insulin Resistance.
  8. DGAT-driven futile lipid cycling has a pronounced, yet concealed, thermogenic function.
  9. Subcutaneous and visceral adipose tissue lipidome in children reveals novel lipid species involved in obesity.
  1. Nat Metab. 2026 Jan 12.
    Single-cell-resolved transcriptional dynamics of human subcutaneous adipose tissue during lifestyle- and bariatric surgery-induced weight loss.
    Anne Loft, Rasmus Rydbirk, Ellen Gammelmark Klinggaard, Elvira Laila Van Hauwaert, Charlotte Wilhelmina Wernberg, Andreas Fønss Møller, Trine Vestergaard Dam, Mohamed Nabil Hassan, Babukrishna Maniyadath, Ronni Nielsen, Aleksander Krag, Joanna Kalucka, Søren Fisker Schmidt, Mette Enok Munk Lauridsen, Jesper Grud Skat Madsen, Susanne Mandrup.
      Human white adipose tissue undergoes major remodelling during sustained weight gain that may compromise tissue function and drive cardiometabolic comorbidities. Although weight loss reverses many of these complications, the cellular and molecular adaptations of adipose tissue to different weight loss interventions are poorly understood. Here we show how abdominal subcutaneous adipose tissue (SAT) in men and women with severe obesity adapts to modest lifestyle-induced (8-10%) weight loss followed by substantial bariatric surgery-induced (20-45%) weight loss, using single-nucleus RNA sequencing (snRNA-seq) combined with bulk RNA-seq, and three-dimensional light-sheet fluorescence microscopy. To enable interactive exploration, all snRNA-seq data are available in a browsable format on the Single Cell Portal ( SCP2849 ). Lifestyle-induced weight loss activated proadipogenic gene programmes in progenitor cells, indicating early beneficial effects on SAT. Subsequent surgery-induced weight loss drove profound compositional and transcriptional remodelling of SAT, including increased vascularization and marked reduction of myeloid cell populations. Collectively, our study indicates that following major and sustained weight loss, SAT from individuals with severe obesity has the capacity to return to a state comparable to that observed in lean individuals.
    DOI:  https://doi.org/10.1038/s42255-025-01433-4
  2. Cell Metab. 2026 Jan 12. pii: S1550-4131(25)00535-2. [Epub ahead of print]
    Human MASLD is a diurnal disease driven by multisystem insulin resistance and reduced insulin availability at night.
    Thomas Marjot, Kieran Smith, Felix Westcott, Sarah White, Elspeth Johnson, Nikola Srnic, Amy Barrett, Ellis Hall, Kate Gralton, Kaitlyn Dennis, Hamish Miller, Riccardo Pofi, Jeremy F L Cobbold, Rebecca Richmond, Fredrik Karpe, Ronnie Blazev, Matthew J Watt, Benjamin L Parker, Leanne Hodson, David W Ray, Jeremy W Tomlinson.
      Hepatic lipid and glucose metabolism have been shown to be under tight circadian control in pre-clinical models. However, it remains unknown whether diurnal patterns exist in functional processes governing intrahepatic lipid accumulation in humans. We performed metabolic phenotyping, including state-of-the-art stable isotope techniques, during day and night in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and overweight controls (NCT05962099). The primary outcome was diurnal change in hepatic de novo lipogenesis (DNL), alongside a number of secondary outcomes, including changes in hepatic glucose production, glucose disposal, plasma non-esterified fatty acids (NEFAs), and whole-body glucose and lipid oxidation. We show that nighttime metabolic dysfunction is a hallmark of MASLD with multiple pathogenic pathways upregulated at night, including hepatic and peripheral insulin resistance, DNL, and systemic NEFA exposure. Insulin resistance is compounded by lower plasma insulin levels at night, secondary to reduced insulin secretion and elevated insulin clearance. Diurnal differences persist when performing identical investigations after weight loss with liver fat reductions, suggesting that nighttime metabolic dysfunction may be a primary driver of steatosis. These findings will help establish the optimal window for energy intake, exercise, and medication delivery in patients with MASLD. Integrated proteomics of plasma, adipose, and skeletal muscle tissue across day and night also identified a number of specific molecular targets that may offer therapeutic potential in the treatment of metabolic disease.
    Keywords:  GDF-15; adipose tissue; beta-oxidation; circadian; endogenous glucose production; glucose disposal; insulin clearance; insulin resistance; insulin secretion; lipid metabolism; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cmet.2025.12.004
  3. Nat Med. 2026 Jan 14.
    Circulating metabolites, genetics and lifestyle factors in relation to future risk of type 2 diabetes.
    Jun Li, Jie Hu, Huan Yun, Zhendong Mei, Xingyan Wang, Kai Luo, Marta Guasch-Ferré, Xikun Han, Buu Truong, Jordi Merino, Chengyong Jia, Miguel Ruiz-Canela, Casey M Rebholz, Eun Hye Moon, Taryn Alkis, Guning Liu, Jie Yao, Xiyuan Zhang, Bianca C Porneala, Jordi Salas-Salvadó, Thomas J Wang, Josée Dupuis, Elizabeth Selvin, Xiuqing Guo, Shilpa N Bhupathiraju, Jennifer A Brody, Yongmei Liu, Alexis C Wood, Kari E North, Su Yon Jung, Ching-Ti Liu, Nona Sotoodehnia, Simin Liu, Lesley F Tinker, A Heather Eliassen, JoAnn E Manson, Jose C Florez, Robert E Gerszten, Clary B Clish, Liming Liang, Rozenn N Lemaitre, Katherine L Tucker, Stephen S Rich, Jerome I Rotter, Miguel Angel Martínez-González, Kathryn M Rexrode, James B Meigs, Eric Boerwinkle, Robert C Kaplan, Frank B Hu, Bing Yu, Qibin Qi.
      The human metabolome reflects complex metabolic states affected by genetic and environmental factors. However, metabolites associated with type 2 diabetes (T2D) risk and their determinants remain insufficiently characterized. Here we integrated blood metabolomic, genomic and lifestyle data from up to 23,634 initially T2D-free participants from ten cohorts. Of 469 metabolites examined, 235 were associated with incident T2D during up to 26 years of follow-up, including 67 associations not previously reported across bile acid, lipid, carnitine, urea cycle and arginine/proline, glycine and histidine pathways. Further genetic analyses linked these metabolites to signaling pathways and clinical traits central to T2D pathophysiology, including insulin resistance, glucose/insulin response, ectopic fat deposition, energy/lipid regulation and liver function. Lifestyle factors-particularly physical activity, obesity and diet-explained greater variations in T2D-associated versus non-associated metabolites, with specific metabolites revealed as potential mediators. Finally, a 44-metabolite signature improved T2D risk prediction beyond conventional factors. These findings provide a foundation for understanding T2D mechanisms and may inform precision prevention targeting specific metabolic pathways.
    DOI:  https://doi.org/10.1038/s41591-025-04105-8
  4. Obesity (Silver Spring). 2026 Jan 14.
    The MetaboHealth Score Enhances Insulin Resistance Metabotyping for Targeted Fat Loss: The PERSON Study.
    Jordi Morwani-Mangnani, Fatih A Bogaards, Alexander Umanets, Gabby B Hul, Anouk Gijbels, Gijs H Goossens, Joris Deelen, Marian Beekman, Lydia Afman, Ellen E Blaak, P Eline Slagboom.
       OBJECTIVE: We previously identified distinct muscle and liver insulin resistance (IR) metabotypes in middle-aged and older adults. The PERSON study showed that a low-fat, high-protein, high-fiber diet benefits the muscle IR group, while a high-monounsaturated fatty acid diet benefits the liver IR group. We also developed the MetaboHealth score, reflecting risks of mortality, frailty, and cognitive decline. This study aimed to examine whether MetaboHealth interacts with IR metabotypes to influence (i) cardiometabolic health and (ii) body composition outcomes in the PERSON study, informing precision nutrition strategies.
    METHODS: In total, 242 adults aged 40-75 with IR were randomized to follow an isocaloric low-fat, high-protein, high-fiber or high-monounsaturated fatty acid diet for 12 weeks. Of these, 184 with complete data were grouped into MetaboHealth tertiles (higher = poorer health). Outcomes included a 7-point oral glucose tolerance test and DXA-based body composition. Linear mixed models assessed four-way interactions.
    RESULTS: No interaction was observed for cardiometabolic outcomes. Significant interactions were found for android, gynoid, total fat percentage, and fat mass index. In the healthiest tertile, matched diets led to greater fat loss. In the poorest tertile, both diets were similarly effective. MetaboHealth remained unchanged.
    CONCLUSIONS: Combining metabotype with MetaboHealth may enhance personalized dietary strategies for fat loss in insulin-resistant adults.
    Keywords:  DXA; aging; body composition; insulin resistance; metabolic disease; metabolomics
    DOI:  https://doi.org/10.1002/oby.70116
  5. Cell Rep. 2026 Jan 10. pii: S2211-1247(25)01573-6. [Epub ahead of print]45(1): 116801
    Prior high fiber intake impinges on the cellular responses of mesenteric adipose and intestinal tissues to subsequent high fat feeding.
    Zhi Peng, Houyu Zhang, Yifei Ding, Zhen Liu, Meng Xie.
      While high-fiber diets (HfiDs) promote weight loss, their long-term efficacy is limited by rapid weight regain upon returning to high-fat diets (HFDs). Using C57BL/6J mice in diet-switching paradigms, we characterized tissue-specific responses to HfiD-to-HFD transitions through single-nucleus and spatial transcriptomics. HfiD pre-feeding enhanced mesenteric white adipose tissue progenitor/adipocyte sensitivity to subsequent HFD exposure. In the intestine, HfiD prevented HFD-induced immune-enterocyte expansion in the duodenum and reversed the enterocyte-to-goblet cell shift in the colon while maintaining persistent epigenetic reprogramming. Although HfiD-induced microbiome changes were largely reversed by HFD, we identified sexually dimorphic remodeling of adipose cell populations during diet transitions. Our findings demonstrate that prior HfiD feeding fundamentally reprograms adipose and intestinal responses to subsequent HFD challenge, providing mechanistic insights into dietary intervention outcomes. This work establishes a spatiotemporal resource for understanding tissue plasticity during dietary changes, offering new perspectives for obesity management strategies.
    Keywords:  CP: metabolism; colon; diet switch; duodenum; high-fat diet; high-fiber diet; mesenteric adipose tissue; obesity; snRNA-seq; stereo-seq
    DOI:  https://doi.org/10.1016/j.celrep.2025.116801
  6. Am J Hum Genet. 2026 Jan 13. pii: S0002-9297(25)00479-3. [Epub ahead of print]
    Genetic regulation of fatty acid content in adipose tissue.
    Xinyu Yan, Amy L Roberts, Julia S El-Sayed Moustafa, Sergio Villicaña, Maryam Al-Hilal, Max Tomlinson, Cristina Menni, Thomas A B Sanders, Maxim B Freidin, Jordana T Bell, Kerrin S Small.
      Fatty acids are important as structural components, energy sources, and signaling mediators. While studies have extensively explored genetic regulation of fatty acids in serum and other bodily fluids, their regulation within adipose tissue, a crucial regulator of cardiovascular and metabolic health, remains unclear. Here, we investigated the genetic regulation of 18 fatty acids in subcutaneous adipose tissue from 569 female twins from TwinsUK. Using twin models, the heritability of fatty acids ranged from 5% to 59%, indicating a substantial genetic regulation of fatty acid levels within adipose tissue, which was also tissue specific in many cases. Genome-wide association studies identified 10 significant loci, in SCD, ADAMTSL1, ZBTB41, SNTB1, EXOC6B, ACSL3, LINC02055, MKRN2/TSEN2, FADS1, and HAPLN across 13 fatty acids or fatty acid product-to-precursor ratios. Using adipose gene expression and methylation, which were concurrently measured in these samples, we detected five fatty acid-associated signals that colocalized with expression quantitative trait locus (eQTL) and methylation quantitative trait locus (meQTL) signals, highlighting fatty acids that are regulated by molecular processes within adipose tissue. We explored links between polygenic scores of common metabolic traits and adipose fatty acid levels and identified associations between polygenic scores of BMI, body-fat distribution, and triglycerides and several fatty acids, indicating these risk scores impact local adipose tissue content. Overall, our results identified local genetic regulation of fatty acids within adipose tissue and highlighted their links with renal and cardio-metabolic health.
    Keywords:  adipose tissue; fatty acid; genome-wide association study; polygenic score
    DOI:  https://doi.org/10.1016/j.ajhg.2025.12.008
  7. FASEB J. 2026 Jan 31. 40(2): e71427
    Gpx4 Deletion-Mediated Macrophage Ferroptosis Alleviates Obesity-Associated Insulin Resistance.
    Suhua Wu, Juan Peng, Xiaodong Wang, Hong Gao, Huangrui Fang, Shiyi Hu, Qiufen Wei, Yuanye Dang, Haixia Tu, Mingyan Zhu, Jianye Peng, Yumiao Liu, Gaofeng Zeng, Xiaoyan Dai.
      Obesity has become a global epidemic and a major contributor to the development of Type 2 diabetes (T2D) through the promotion of insulin resistance. Emerging evidence has shown that GPX4 expression is reduced in macrophages under hyperglycemic conditions; however, the involvement of macrophage-specific GPX4 in obesity-associated insulin resistance remains unclear. We generated macrophage-specific Gpx4 knockout (Gpx4Mac-KO) mice and subjected both Gpx4Mac-KO and littermate Gpx4fl/fl mice to a high-fat diet (HFD) for 16 weeks. Metabolic parameters, adipose tissue morphology, hepatic lipid accumulation, and free fatty acid (FFA) metabolism were assessed. The results showed that macrophage-specific deletion of Gpx4 attenuated HFD-induced obesity and improved insulin sensitivity in mice in vivo. Gpx4-deficient mice exhibited lower levels of systemic inflammation, reduced adipocyte hypertrophy, and diminished hepatic steatosis. Deficiency of Gpx4 in macrophages affects FFA metabolism by regulating the expression of FFA breakdown-related genes, such as C/EBP-α, PPARγ, ATGL, Fabp4, and/or LPL, in white adipose tissue and the liver. These beneficial metabolic effects seemed to be associated with enhanced macrophage ferroptosis, suggesting a mechanistic link between Gpx4 deficiency, ferroptosis, and the alleviation of obesity-associated insulin resistance. Our findings identify macrophage GPX4 as a key mediator of obesity-induced insulin resistance and metabolic malfunction. Targeting macrophage GPX4 may represent a promising therapeutic strategy for the treatment of T2D.
    Keywords:  GPX4; ferroptosis; insulin resistance; macrophage; obesity
    DOI:  https://doi.org/10.1096/fj.202503596R
  8. Cell Metab. 2026 Jan 09. pii: S1550-4131(25)00540-6. [Epub ahead of print]
    DGAT-driven futile lipid cycling has a pronounced, yet concealed, thermogenic function.
    Anand Kumar Sharma, Radhika Khandelwal, Jelena Zurkovic, Fen Long, Tongtong Wang, Revati S Dewal, Chunyan Wu, Adhideb Ghosh, Klug Manuel, Alaa Othman, Chandramohan Chitraju, Robert V Farese, Tobias C Walther, Miroslav Balaz, Christoph Thiele, Christian Wolfrum.
      Thermoregulation is an essential yet incompletely understood homeostatic process in mammals. UCP1-mediated thermogenesis, while efficient, is dispensable, suggesting the existence of alternative mechanisms. Using a pharmacogenetic approach, we show that the adipose tissue futile lipid cycling (FLC) contributes to UCP1-independent thermogenesis, with DGATs being involved in the regulation of FLC. The loss of DGAT-driven FLC-mediated thermogenesis is compensated for by the hierarchical recruitment of alternative mechanisms such as shivering and enhanced lipid catabolism mediated by AMPK activation. Consistently, pharmacological inhibition of muscle shivering or AMPK in FLC-deficient mice leads to an acute reduction in energy expenditure and hypothermia. These findings demonstrate a substantial thermogenic potential of FLC and suggest previously unappreciated flexibility and adaptability in regulating the core body temperature through adaptive changes in adipocyte metabolism.
    Keywords:  AMPK; DGAT; adipose tissue; energy homeostasis; futile cycles; futile lipid cycling; lipid metabolism; shivering; thermal homeostasis; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2025.12.009
  9. J Physiol Biochem. 2026 Jan 15. 82(1): 2
    Subcutaneous and visceral adipose tissue lipidome in children reveals novel lipid species involved in obesity.
    Andrea Soria-Gondek, Carolina Gonzalez-Riano, Pablo Fernández-García, Belén Requena, Lorena González, Marjorie Reyes-Farias, Marta Murillo, Aina Valls, Nativitat Real, Francesc Villarroya, Patricia Corrales, Rubén Cereijo, Laura Herrero, Coral Barbas, David Sánchez-Infantes.
      Overweight impacts over 390 million children and adolescents worldwide, of whom around 160 million are living with obesity. Adipose tissue biology in pediatric obesity is still relatively unknown. Adaptations to obesity including fat mobilization and remodeling are being investigated. The objective was to examine the lipidomic profile of subcutaneous and visceral adipose tissue (sWAT and vWAT, respectively) in children with obesity compared to those with normal weight, in order to identify novel lipid species modulated by obesity. Thirty pediatric patients with and without obesity were prospectively recruited at a referral single center and clinical data were reported. sWAT and vWAT samples were obtained for lipidomic analysis. Novel lipid species, including ether-linked triglycerides, ether-linked phosphatidylethanolamine, and oxidized triglycerides, were identified as altered in the sWAT from children with obesity compared with normal-weight children. These species are involved in beige adipose tissue development, energy metabolism, mitochondrial function, and oxidative stress. Compared with normal-weight children, the vWAT lipidome from children with obesity showed significant changes in some glycerophosphocholines, ceramides, and diglycerides, with accumulation of lipid species involved in inflammation, insulin resistance, and cardiovascular risk. The observed lipid correlations between vWAT and sWAT highlighted systemic dysregulation of lipid storage in childhood obesity, identifying both shared and depot-specific mechanisms of lipid handling. Our study reveals several critical lipid species that are modulated across both WAT depots, with notable implications for oxidative stress, lipid storage, and adipose tissue dysfunction. Key Points • The adipose lipidome of children with obesity showed specific alterations. • Lipid correlations revealed shared and depot-specific lipid handling mechanisms. • The altered lipid species had an impact on oxidative stress and insulin resistance.
    Keywords:  Ceramides; Inflammation; Lipidomics; Oxidized lipids; Pediatric obesity
    DOI:  https://doi.org/10.1007/s13105-026-01147-5
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