bims-mimead 2026-03-08 papers

Issue of 2026–03–08
seven papers selected by
Rachel M. Handy, University of Guelph

Sci Data. 2026 Mar 05.

Proteomic profiling of human omental and subcutaneous adipose tissue in individuals with a broad range of BMI.

Alex Zelter, Yue Winnie Wen, Michael Riffle, Lindsay C Czuba, Aprajita S Yadav, Jerry Zhu, Jessica M Snyder, Aaron Maurais, Jeffrey LaFrance, Saurabh Khandelwal, Judy Y Chen, Estell Williams, Zoe Parr, Daniel Kim, Katya B Rubinow, Michael J MacCoss, Nina Isoherranen.

Obesity is a major public health challenge affecting an ever-increasing proportion of the global population. It is associated with numerous comorbidities. Progressive expansion and remodeling of adipose tissue may lead to depot specific changes in adipose tissue biology and energy partitioning. Such changes likely precede the development of obesity-related complications. To facilitate a deeper understanding of adipose tissue biology, a comprehensive quantitative proteomic dataset is presented at the peptide and protein level. Data-independent acquisition LC-MS/MS data were acquired from matched subcutaneous and omental adipose tissues from metabolically healthy individuals with no comorbidities and covering a wide range of body mass indexes. Adipose tissue samples were collected during elective surgeries and immediately processed for histology or frozen until proteomic analysis. Internal and external quality control systems ensured high quality data. All data presented are available via ProteomeXchange. This dataset will allow new insights into biological changes that evolve with increasing adiposity captured before the onset of comorbidities. Matched sampling across fat depots provides an opportunity to uncover depot-specific physiological signatures.

DOI: https://doi.org/10.1038/s41597-026-06948-3

Nat Commun. 2026 Feb 28.

Dynamic subcellular proteomics identifies regulators of adipocyte insulin action.

Olivia J Conway, Josie A Christopher, Lisa M Breckels, Hanqi Li, Dilip Menon, Meghna Birla, Bethan L Hawkins, Lu Liang, Satish Patel, Francoise Koumanov, David C Gershlick, David B Savage, Michael P Weekes, Kathryn S Lilley, Daniel J Fazakerley.

Insulin acts on adipocytes to suppress lipolysis and increase glucose uptake to control whole-body glucose and lipid metabolism. Regulation of these processes by insulin signalling depends on changes in protein localisation. However, the extent of insulin-stimulated changes to the adipocyte spatial proteome, and the importance of these in the cellular insulin response, is unknown. Here, we use subcellular proteomics approaches to map acute insulin-stimulated protein relocalisation in adipocytes on a cell-wide scale. These data reveal extensive insulin-regulated protein redistribution, with hundreds of insulin-responsive proteins. These include the uncharacterised protein C3ORF18, which redistributes to the plasma membrane in response to insulin. Studies in C3ORF18-depleted adipocytes suggest this protein is required to maintain adipocyte insulin sensitivity. Overall, our data highlight the scale of protein relocalisation in the adipocyte insulin response, and provide an accessible resource to inform further studies into how changes in protein localisation contribute to cellular insulin responses.

DOI: https://doi.org/10.1038/s41467-026-70116-9

Curr Opin Lipidol. 2026 Apr 01. 37(2): 45-51

Beyond cellular distress: reframing GDF15 as a lipid-sensitive metabolic signal.

Dongdong Wang, Logan K Townsend, Gregory R Steinberg.

PURPOSE OF REVIEW: Growth differentiation factor-15 (GDF15) is widely described as a hormone that conveys somatic distress to the brain, yet this framework does not explain why GDF15 is elevated in many common metabolic states. Recent work shows that GDF15 rises most consistently when fatty acid availability exceeds mitochondrial and endoplasmic reticulum capacity. This review synthesizes emerging evidence that positions GDF15 as an endocrine sensor of lipid load rather than a general stress signal.
RECENT FINDINGS: Across acute dietary lipid exposure, endogenous lipolysis during fasting, chronic overnutrition, ketogenic feeding, and mitochondrial dysfunction, free fatty acids activate lipid-sensitive transcriptional pathways that induce GDF15 expression in kidney, liver, intestine, and adipose tissue macrophages. Once elevated, GDF15 engages hindbrain glial-cell-derived neurotrophic factor family receptor α-like (GFRAL) signaling to increase sympathetic outflow, promote whole-body fatty acid oxidation, redistribute lipid burden, and improve metabolic flexibility. These effects occur independently of reduced food intake and reflect coordinated actions across liver, adipose tissue, and skeletal muscle.
SUMMARY: Viewing GDF15 as a lipid-responsive hormonal signal reshapes our understanding of its physiological role and provides new insight into metabolic adaptations to lipid overload. This pattern suggests that GDF15 is part of a feedback system that attempts to match fatty acid oxidation with supply, analogous to how carbohydrate ingestion stimulates insulin to promote glucose oxidation and suppress hepatic glucose production to restore euglycemia. Within this framework, individual tissues respond in complementary ways to reduce lipid burden and maintain metabolic balance. Understanding this coordinated lipid-responsive network highlights opportunities to target the GDF15 pathway in disorders characterized by impaired fatty acid handling including obesity, type 2 diabetes, cardiovascular disease, cancer cachexia and metabolic dysfunction-associated steatotic liver disease (MASLD).

Keywords: GFRAL; MASH; MASLD; adipose tissue; diabetes; fatty acids; growth differentiation factor-15; lipotoxicity; mitochondrial stress; triglycerides

DOI: https://doi.org/10.1097/MOL.0000000000001025

J Immunol. 2026 Feb 09. pii: vkag010. [Epub ahead of print]215(2):

Context-dependent roles of sex hormone signaling in controlling visceral adipose tissue Treg heterogeneity and clonal expansion.

Cody Elkins, Jianliang Zhang, Chengyu Ye, Samara Moll, M Neale Weitzmann, Chaoran Li.

Sex hormones are important for maintaining metabolic health. Females with low estrogen or high androgen levels exhibit an elevated risk for developing obesity-associated metabolic syndromes. Chronic low-grade inflammation in the visceral adipose tissue (VAT) is a major contributor to metabolic dysfunction during obesity. However, how sex hormones impact the VAT inflammatory environment to curtail obesity-associated pathology remain incompletely understood. Regulatory T cells (Tregs) expressing a clonally expanded T cell receptor (TCR) repertoire and high levels of the IL-33 receptor ST2 are highly enriched in male epididymal VAT (eVAT), in which they suppress tissue inflammation and protect against metabolic diseases. While TCR specificity and activation are critical for the accumulation of ST2+ eVAT Tregs in males, the factors governing Treg clonality in female ovarian VAT (oVAT) and their relevance to obesity-associated metabolic diseases remain largely unexplored. In this study, we used estrogen receptor α (ERα)-deficient mice, which exhibit impaired estrogen signaling and elevated androgen levels, to investigate the impact of sex hormone disruption on oVAT Tregs in lean and obese female mice. At steady state, ERα deficiency promoted age-dependent clonal expansion of specific ST2+ oVAT Treg subsets indirectly through modulating antigen presentation. However, combinations of obesity and ERα deficiency induced IFNγ production to deplete ST2+ oVAT Tregs, exacerbating oVAT inflammation and insulin resistance. Together, these findings reveal distinct, diet-dependent roles for sex hormones in regulating oVAT Tregs and suggest that loss of ST2+ oVAT Treg subsets during obesity may contribute to increased metabolic risk in females with disrupted sex hormone signaling.

Keywords: metabolism; regulatory T cells; sex hormones

DOI: https://doi.org/10.1093/jimmun/vkag010

Cell Rep. 2026 Mar 05. pii: S2211-1247(26)00139-7. [Epub ahead of print]45(3): 117061

Large adipocytes increase vesicle-mediated lipid release and promote breast cancer malignancy.

Garrett F Beeghly, Irina Kopyeva, Jenny Deng, Marlee I Pincus, Rohan R Varshney, Dilip D Giri, Domenick J Falcone, Michael C Rudolph, Marc A Antonyak, Neil M Iyengar, Claudia Fischbach.

Primary adipocytes exhibit striking variability in size, yet the functional consequences of adipocyte hypertrophy remain unclear due to insufficient experimental approaches to control for cell size. Here, we establish methods to culture large and small primary adipocytes isolated from the same adipose depot, enabling size-resolved analyses independent of systemic obesity. Using transcriptomic, lipidomic, and functional profiling across two mouse models of obesity, as well as human clinical samples, we show that adipocyte size-rather than body weight-drives distinct phenotypic cell states. Notably, large adipocytes increase extracellular vesicle-mediated lipid release. In coculture assays, this shift enhances lipid uptake, migration, and proliferation of breast cancer cells through fatty acid oxidation. Consistent with these findings, individuals with larger mammary adipocytes exhibit elevated fasting triglycerides independent of body mass index. Together, our results identify adipocyte size as a key determinant of adipose tissue function with implications for both metabolic disease and cancer progression.

Keywords: CP: cancer; CP: metabolism; adipocyte; adipose tissue; breast cancer; extracellular vesicles; hypertrophy; lipid metabolism; obesity; tumor microenvironment

DOI: https://doi.org/10.1016/j.celrep.2026.117061

Nat Commun. 2026 Mar 03.

GPR146 in adipose tissue drives adipose-liver crosstalk and promotes hepatic steatosis in mice.

The limited therapeutic options for metabolic dysfunction-associated steatotic liver disease (MASLD) underscore the need for deeper mechanistic insight and new treatment strategies. Here, we identify the orphan G protein-coupled receptor GPR146 as a regulator of hepatic steatosis through adipose-liver crosstalk. Human genetic analyses link the GPR146 locus to circulating markers of liver injury and inflammation. In mice, both constitutive and acute GPR146 depletion protect against diet-induced obesity and hepatic steatosis. Notably, adipose-specific, but not liver-specific, GPR146 deletion reduces hepatic lipid accumulation by limiting free fatty acid (FFA) influx. Mechanistically, GPR146 promotes adipogenesis in preadipocytes via Gαq-PKC-AKT signaling, increasing lipid storage capacity, and enhances lipolysis in mature adipocytes through ERK activation, elevating circulating FFA. Together, these coordinated actions increase FFA delivery to the liver, promoting triglyceride accumulation. Our findings establish GPR146 as a pleiotropic regulator of adipose tissue biology and a potential therapeutic target for MASLD.

DOI: https://doi.org/10.1038/s41467-026-70136-5