bims-mimead 2026-03-22 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2026–03–22
eight papers selected by
Rachel M. Handy, University of Guelph

Acute metabolic and molecular responses to sprint interval versus moderate-intensity continuous exercise in healthy young men.
Siah2 Regulates Lipid Uptake in Adipose Tissue Macrophages.
Adipose-Specific GHR Knockout Confers Multidimensional Anti-Aging Advantages via Adipose Tissue Remodelling and Enhanced Metabolic Elasticity.
Oxidative phosphorylation and mitochondrial dynamics are regulated by Sestrin2 to maintain cellular function.
Weight loss with GLP-1 medicines does not result in a disproportionate loss of muscle mass or function in obese mice and humans.
A Long-Term Human Adipocyte Organoid Model Reveals Aging-Associated Responses to Intermittent Hypoxia.
Aerobic glycolysis drives differentiation of unilocular adipocytes.
Extracellular matrix signals promote actin-dependent mitochondrial elongation and activity.

Am J Physiol Endocrinol Metab. 2026 Mar 14.

Acute metabolic and molecular responses to sprint interval versus moderate-intensity continuous exercise in healthy young men.

Enda Murphy, Claire Laurens, Laurie Frances, Marie-Adeline Marquès, François Crampes, Isabelle de Glisezinski, Javier Monedero, Helena Kenny, Noel McCaffrey, Francis M Finucane, Cedric Moro, Donal J O'Gorman.

  Background: Exercise intensity is a key determinant of the physiological responses in skeletal muscle that lead to improvements in human health. Whether a bout of brief supramaximal acute exercise has similar effects on muscle physiology and metabolic health to a longer bout of continuous acute exercise remains unclear. Methods: In a randomized crossover design, 12 healthy young recreationally active men completed single acute bouts of either sprint interval exercise (SIE; seven repeated 30-s maximal sprints at 130% over 35 mins) or moderate-intensity continuous exercise (MICE; cycling at 65% effort over 60 minutes), or a non-exercise control session (CON), on separate days. Acute changes in skeletal muscle insulin sensitivity were measured with a hyperinsulinemic euglycemic clamp. Muscle biopsies were performed to quantify changes in muscle glycogen content and insulin signaling proteins. Results: Despite a six-fold lower total mechanical work in SIE versus MICE, SIE elicited greater and more prolonged increases in whole-body insulin sensitivity, with greater pre-clamp muscle glycogen depletion and glycogen repletion during the clamp. We found reduced glycogen synthase and glycogen synthase kinase-3β phosphorylation, with no differences in Akt Thr308/Ser473 phosphorylation. Conclusions: A single session of sprint interval exercise elicits more pronounced effects on several measures of skeletal muscle insulin sensitivity than a single bout of moderate-intensity continuous exercise, despite substantially lower mechanical work and time commitment. These findings indicate that exercise intensity is a key mediator of acute skeletal muscle metabolic adaptations to exercise and suggest that sprint interval exercise represents a highly time-efficient stimulus for improving skeletal muscle insulin responsiveness.

Keywords:  exercise intensity; insulin sensitivity; metabolism; moderate intensity exercie; sprint interval exercise

DOI:  https://doi.org/10.1152/ajpendo.00548.2025
J Biol Chem. 2026 Mar 17. pii: S0021-9258(26)00250-4. [Epub ahead of print] 111380

Siah2 Regulates Lipid Uptake in Adipose Tissue Macrophages.

Bhaswati Ghosh, Pradip R Panta, Matthew C Scott, Jessica Taylor, Robbie Beyl, Krisztian Stadler, Z Elizabeth Floyd.

  In obesity, adipose tissue macrophages (ATMs) reprogram their metabolism to influence adipose tissue remodeling and function. Ubiquitin ligases are critical in modulating degradation of key proteins implicated in macrophage lipid metabolism. Yet, the role of ubiquitin ligases in ATM lipid metabolism is largely unexplored. Previously, we reported that the ubiquitin ligase Siah2 is crucial in mediating adipogenic pathways and adipose tissue inflammation. Here, we co-cultured bone marrow-derived macrophages with adipose tissue as an ex vivo model of bone marrow-derived ATMs to investigate Siah2's role in ATM lipid metabolism. We found that adipose tissue- induced lipid accumulation in ATMs was exacerbated by Siah2 deficiency via increased CD36-mediated lipid uptake and reduced lipid delivery to lysosomes. Together, these changes contributed to excessive lipid accumulation, lipid peroxidation and an inflammatory phenotype. Our data reveals a central role for Siah2 as a lipid uptake sensor in maintaining the balance between lipid influx and degradation in ATMs.

Keywords:  Adipose tissue macrophages; CD36; Inflammation; Lipid metabolism; Lipolysis; Lysosome; PPARγ; Siah2; Ubiquitin ligase

DOI:  https://doi.org/10.1016/j.jbc.2026.111380
Diabetes Obes Metab. 2026 Mar 18.

Adipose-Specific GHR Knockout Confers Multidimensional Anti-Aging Advantages via Adipose Tissue Remodelling and Enhanced Metabolic Elasticity.

Rui Ma, Liyuan Ran, Jinyang Geng, Yue Zhang, Jie Liu, Zichao Yu, Bin Liang, Li Qiang, Yingjie Wu.

   OBJECTIVE: Global growth hormone receptor knockout (GHR-/-) extends lifespan but also causes adverse effects. As a key target of growth hormone (GH), adipose tissue may mediate aging, though the underlying mechanisms remain unclear. We investigated how adipose-specific GHR ablation influences multisystem aging, with a focus on metabolic health and cognitive function.
METHODS: We generated adipose-specific GHR knockout (Ad-GHRKO) mice and assessed healthspan parameters including cognitive function, musculoskeletal integrity and metabolic profiles. Adipose tissue remodelling and inflammation were examined by histology and protein analysis. Subcutaneous white adipose transcriptomics identified gene expression changes. The role of the AMPK-SIRT1-Ac-PPARγ pathway in metabolic elasticity and aging was elucidated by Western blot and in vitro assays.
RESULTS: Ad-GHRKO mice exhibited extended healthspan, with enhanced cognitive performance, improved muscle strength and bone mass and a lifespan increase trend. Mechanistically, GHR ablation remodelled adipose tissue, reducing age-related lipid redistribution, restoring glucose homeostasis and creating a low-inflammation, high-plasticity depot. This reprogramming boosted systemic metabolic elasticity primarily via AMPK-SIRT1-Ac-PPARγ activation. AMPK inhibition abolished benefits, confirming its pivotal role.
CONCLUSION: Our findings identify adipose-specific GH signalling antagonism as a regulatory switch that recalibrates the local balance between GH and IGF-1 actions, thereby reprogramming adipose tissue to promote coordinated systemin metabolic resilience during aging. This tissue-targeted strategy circumvents the developmental and endocrine limitations associated with global GH/IGF-1 suppression. Rather than merely extending lifespan, adipose-specific GHR ablation supports healthier aging by preserving metabolic homeostasis, maintaining multisystem functional integrity and reducing age-associated inflammatory and fibrotic remodelling. Collectively, these results highlight a potentially translatable approach for mitigating age-related metabolic and cognitive decline.

Keywords:  adipose tissue; adipose tissue remodelling; aging; growth hormone receptor; metabolic elasticity

DOI:  https://doi.org/10.1111/dom.70655
FEBS J. 2026 Mar 19.

Oxidative phosphorylation and mitochondrial dynamics are regulated by Sestrin2 to maintain cellular function.

Ivo F Machado, Carlos M Palmeira, Anabela P Rolo.

  The stress-inducible protein Sestrin2 (SESN2) has recently emerged as an orchestrator of mitochondrial signaling. The regulation of mitochondria-related pathways, such as aerobic respiration, is thought to be mediated by SESN2, but the underlying mechanisms are not fully understood. Here, we characterized mitochondria in Sesn2-knockdown myoblasts under physiological conditions using oxygen consumption rate measurements, fluorescence microscopy, and protein content analysis. We discovered that SESN2 is essential for sustaining oxidative phosphorylation and maintaining the mitochondrial network organization. SESN2 loss diminished ATP production, decreased the levels of nuclear- and mitochondrial-encoded complex IV subunits, and increased superoxide generation. Moreover, the assessment of mitochondrial distribution in Sesn2-knockdown cells revealed a more fragmented network. This was associated with an increased ratio of short to long optic atrophy 1 (OPA1) forms. Remarkably, disruption of mitochondrial signaling suppressed cellular proliferation and altered both cell and nuclear morphology. In summary, our findings suggest that SESN2 plays an important role in maintaining cellular homeostasis, partly through its impact on mitochondrial function.

Keywords:  SESN2; mitochondria; mitochondrial dynamics; mitophagy; oxidative phosphorylation

DOI:  https://doi.org/10.1111/febs.70497
Cell Rep Med. 2026 Mar 17. pii: S2666-3791(26)00082-0. [Epub ahead of print]7(3): 102665

Weight loss with GLP-1 medicines does not result in a disproportionate loss of muscle mass or function in obese mice and humans.

Henning Tim Langer, Natalie K Gilmore, Christopher M T Hayden, Julien Roux, Bruno Bariohay, Thaïs Rouquet, Manar Awada, Julie Marcotorchino, Lorrine Bournot, Elizabeth Nunn, Paul M Titchenell, Daniela Liskiewicz, Timo D Müller, Oluwaseun Anyiam, Philip J Atherton, Iskandar Idris, Andreas Hentschel, Andreas Roos, Natalie Haritonow, Kristina Norman, Ursula Müller-Werdan, Keith Baar.

  The large decrease in body weight with glucagon-like peptide-1 (GLP-1) medicines raises concern about a loss of lean body mass (LBM) and skeletal muscle. In this work, we present four pre-clinical studies and a proof-of-concept clinical trial that address this issue. We report that in obese mice, GLP-1 medicines predominantly reduce body fat alongside a small but significant decrease in LBM. Among lean tissues, loss of liver mass exceeds change in muscle mass. While absolute muscle mass and strength decrease, relative muscle mass and strength improve, resulting in better running performance. Interestingly, while atrophy is similar during immobilization, GLP-1 medicines have a distinct effect on the muscle proteome compared to calorie restriction. Patients with obesity on GLP-1 medicines improve their body composition without negatively affecting strength. Overall, in middle-aged mice and men, GLP-1 medicines slightly decrease absolute muscle values but positively impact body composition and mobility. The clinical trial is registered on clinicaltrials.gov (NCT05606471).

Keywords:  GLP-1; atrophy; function; incretins; muscle loss; muscle mass; obesity; wasting; weight loss

DOI:  https://doi.org/10.1016/j.xcrm.2026.102665
Am J Physiol Cell Physiol. 2026 Mar 18.

A Long-Term Human Adipocyte Organoid Model Reveals Aging-Associated Responses to Intermittent Hypoxia.

Yunzhou Dong, Jingjing Wang, Feifei Feng, Isra H Ali, Lida Chen, Shahid Karim, Joshua M Bock, Virend K Somers.

  Obstructive sleep apnea (OSA), characterized by recurrent intermittent hypoxia (IH), is increasingly recognized as a driver of adipose tissue dysfunction, insulin resistance, and accelerated aging. However, current in vitro models inadequately recapitulate the long-term effects of IH on human adipocytes. Here, we developed a robust long-term human adipocyte organoid culture system that models IH-induced adipocyte aging in vitro. Human stromal vascular fraction (SVF) cells isolated from subcutaneous abdominal adipose tissue were embedded in Matrigel and seeded into Biofloat U-bottom 96-well plates. Using a 1:1 Matrigel-cell mixture and optimized seeding volumes (5-20 µL), adipocyte organoids formed within 10-12 days and maintained stable morphology and viability for more than 90 days. Matrigel was essential for structural integrity, whereas gelatin and low-melting agarose failed to support organoid formation. Subcutaneous preadipocyte medium supplemented with 10% FBS supported more robust adipogenic differentiation and long-term maintenance than Advanced/F12K medium. To model OSA-associated hypoxic stress, organoids were exposed to programmable IH. IH suppressed adipogenesis, as evidenced by reduced lipid accumulation, downregulation of adipogenic markers (PPARγ, adiponectin, FABP4), and reduced lipid droplets. Transmission electron microscopy revealed IH-induced ultrastructural abnormalities, including endoplasmic reticulum fragmentation, mitochondrial disruption, nuclear enlargement, and heterochromatin accumulation-features consistent with cellular senescence. IH further upregulated HIF1α, H2AX, repressive histone methylation marks (H3K9me3, H3K79me3, H4K20me3), and extracellular matrix remodeling proteins (fibronectin, LOX), while impairing insulin signaling as demonstrated by reduced PI3K and AKT phosphorylation. Collectively, these findings establish a physiologically relevant human adipocyte organoid platform for investigating IH-induced adipocyte dysfunction and aging.

Keywords:  Fat organoid aging model; Human adipocyte organoids; OSA; cellular aging; intermittent hypoxia

DOI:  https://doi.org/10.1152/ajpcell.00020.2026
J Lipid Res. 2026 Mar 16. pii: S0022-2275(26)00049-0. [Epub ahead of print] 101023

Aerobic glycolysis drives differentiation of unilocular adipocytes.

Alice Maestri, Min Cai, Ruby Schipper, Julia Backman, Alana Vannay, Anneli Olsson, Ewa Ehrenborg, Roland Nilsson, Carolina E Hagberg.

  The hallmark of white adipocytes is a single, large lipid droplet, yet this unilocular morphology has remained challenging to reproduce in vitro due to limited understanding of its molecular drivers. Here, we identify metabolic reprogramming as the key determinant of adipocyte unilocularity in human 3D cultures. Transcriptomic and metabolomic profiling revealed unilocularity to be primarily characterized by enhanced aerobic glycolysis and reduced mitochondrial content. Importantly, this mirrored the metabolic pattern of freshly isolated human white adipocytes but contrasted that of preadipocytes and 2D cultures. We demonstrate that aerobic glycolysis in adipocytes activates AMP-activated protein kinase (AMPK) that then enhances CD36-mediated fatty acid uptake. Pharmacological inhibition of aerobic glycolysis reduced fatty acid uptake and led to a more multilocular phenotype, which could be rescued by re-activating AMPK. Importantly, limiting mitochondrial activity or activating AMPK in multilocular 3D cultures was enough to promote their unilocularity. These findings establish aerobic glycolysis as a key driver of white adipocyte lipid droplet morphology and size. They also underscore the influence of cellular microenvironment on shaping adipocyte metabolism and function. Taken together, the study provides important insights of adipocyte lipid droplet biology that can be used to improve human adipocyte functionality and prevent disease.

Keywords:  Adipocyte; aerobic glycolysis; lipid droplet; metabolism; unilocularity

DOI:  https://doi.org/10.1016/j.jlr.2026.101023
iScience. 2026 Mar 20. 29(3): 115171

Extracellular matrix signals promote actin-dependent mitochondrial elongation and activity.

Priya Gatti, Pritha Mukherjee, Priyanka Dey Talukdar, Wesley Freppel, Anahita Kasmaie, Joseph Kanou, Laurent Chatel-Chaix, Urmi Chatterji, Marc Germain.

  Mitochondria are crucial metabolic organelles regulated by both intracellular and extracellular cues. The extracellular matrix (ECM) is a key component of the cellular environment that controls cellular behavior and metabolic activity. Here, we determined how ECM signaling regulates mitochondrial structure and activity. To distinguish mitochondrial regulation from general ECM-regulated survival cues, we used mammospheres derived from breast cancer cells because of their ability to grow in suspension culture in the absence of ECM. Using this system, we demonstrate that the association of mammospheres with the ECM results in dramatic mitochondrial elongation, along with enhanced mitochondrial respiration and ATP production. This remodeling occurs independently of DRP1 activity but relies on integrin signaling and actin polymerization. Therefore, our findings demonstrate that ECM-driven actin polymerization plays a crucial role in remodeling mitochondrial networks to promote OXPHOS, which represents a vital step for migrating cells to enhance cellular adhesion and facilitate cell growth.

Keywords:  Biological sciences; Cell biology; Integrative aspects of cell biology; Organizational aspects of cell biology; Specialized functions of cells

DOI:  https://doi.org/10.1016/j.isci.2026.115171