12,13-diHOME protects against the age-related decline in cardiovascular function via attenuation of CaMKII

Nature Communications · 2025-08-02 · 6 citations

Aging poses significant challenges to cardiovascular health necessitating novel therapeutic approaches. This study investigates the potential of the brown adipose tissue (BAT) derived lipokine 12,13-diHOME to mitigate age-induced impairments in cardiovascular function. Analysis of human and rodent plasma signaling lipids reveals a decline in 12,13-diHOME levels with age. Transplantation of BAT or sustained upregulation of 12,13-diHOME effectively preserved cardiac function in aged male and female mice. Bulk RNA-Seq of hearts from aged mice reveals significant increases in pathways involved in ER stress and fibrosis which were partially attenuated by BAT transplantation or sustained upregulation of 12,13-diHOME. Mechanistically, in vivo and in vitro models demonstrate that 12,13-diHOME alleviated ER stress through CaMKII inhibition, particularly in males. These findings underscore 12,13-diHOME as a promising candidate for combating age-related cardiovascular dysfunction, offering insights into potential therapeutic strategies for addressing cardiovascular diseases in aging populations.

Ingestion of a lipid-rich meat matrix blunts the postexercise increase of myofibrillar protein synthesis rates in healthy adults: a randomized controlled trial

American Journal of Clinical Nutrition · 2025-09-07 · 1 citations

Exercise Training Induces a Hepatic Memory Associated with Improved Glucose Control and Hepatic Secretory Function

Physiology · 2025-05-01

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a global healthcare challenge. While increasing physical activity through exercise is considered a powerful therapy against MAFLD, its long-term effects on liver function remain unclear. This study aimed to investigate how exercise elicits hepatic memory, hypothesizing that exercise training cycles enhance long-term liver function and metabolic health, which persist after exercise cessation and are amplified with retraining. Here, 8-week-old male mice were fed a control diet and assigned to endurance-(voluntary wheel running; VWR) or resistance-based training (progressive weighted wheel running; PoWeR), or were sedentary (SED) and monitored throughout successive training (4 weeks), detraining (4 weeks), and retraining cycles (4 weeks). In vivo glucose homeostasis and hepatic function were assessed at each time point. We proposed that resistance-based training would yield superior metabolic outcomes. Both endurance (VWR) and resistance training (PoWeR) groups maintained lower body weight throughout training cycles, compared to SED, and following retraining, both training modalities resulted in fat mass reductions and increased lean mass, with PoWeR showing superior effects. While VWR only improved glucose tolerance (GTT) after retraining, PoWeR training robustly enhanced glucose (GTT) and pyruvate tolerance (PTT, and indirect marker of hepatic function) following training and retraining. Next, we studied the hepatic transcriptional adaptations (RNA-seq) and identified an upregulation of genes associated with hepatic secretory functions (Herpes simplex) following retraining including ~70 zinc finger protein (Zfp). Moreover, we identified that endurance retraining induced a group of hepatic carboxylesterases ( Ces2b, Ces3b, Ces4a ), which play a key role in complex lipid clearance from circulation. Greater liver expression of carboxylesterases was associated with higher serum carboxylesterase enzymatic activity (assessed by substrate cleavage). Additionally, PoWeR mice showed higher hepatic Ces2b expression and CES activity, particularly after training, further supporting the role of exercise in enhancing hepatic secretary function. Our findings indicate that exercise induces a hepatic memory that is potentiated by retraining and may be associated with glucose regulation and lipid metabolism. Notably, resistance-based training persistently enhanced the hepatic glucoregulatory function. Our study highlights the powerful effect of exercise as a targeted intervention for improving long-term metabolic health in MAFLD. Funding was provided by the Campus Research Board at the University of Illinois Urbana-Champaign. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

BPS2025 - Diet-induced obesity modulates close-packing of triacylglycerols in lipid droplets of adipose tissue

Biophysical Journal · 2025-02-01

Interplay Between Pulmonary Membrane Properties and Lung Disease: A Study of Seven Bottlenose Dolphins

bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-19 · 1 citations

Abstract Pneumonia is the leading cause of morbidity and mortality of bottlenose dolphins Tursiops truncatus . We investigate a series of rare and opportunistic samples of pulmonary surfactant membranes (PSMs) extracted from lungs of seven dolphins in the care of the U.S. Navy Marine Mammal Program. We found a striking correlation between PSM structure, lipidome, and mechanical properties with the severity of lung injury. Specifically, lipidomics reveals exacerbated contents of cardiolipins, confirming a result obtained for terrestrial mammals afflicted by experimental pneumonia. Employing a battery of X-ray scattering, atomic force, and electron microscopy, we evaluate how the altered lipid composition impairs the structural integrity of the PSM and leads to dehydration and enhanced rigidity. Our findings demonstrate that the function of pulmonary surfactant membranes goes far beyond lowering alveolar surface tension, regulating their biochemical and biophysical properties with lung pathology progression. This knowledge will be useful to the development of future diagnostics and therapeutics of respiratory diseases targeting lung membranes.

Muscle memory of exercise optimizes mitochondrial metabolism to support skeletal muscle growth

American Journal of Physiology-Cell Physiology · 2025-09-12 · 3 citations

Here we provide evidence that exercise memory in skeletal muscle fine-tunes mitochondrial metabolism to respond to dietary challenges and support muscle growth. Using physiological, RNA sequencing, and biochemical approaches, we show that exercise retraining optimizes mitochondrial metabolism to increase fatty acid oxidative capacity. These findings enhance our understanding of how prior exercise primes muscle for enhanced adaptations, offering insights into strategies to promote healthy aging.

Deleting adipose FXR exacerbates metabolic defects and induces endocannabinoid lipid, 2-oleoyl glycerol, in obesity

Journal of Lipid Research · 2025-02-10 · 5 citations

The nutrient sensor farnesoid X receptor (FXR) transcriptionally regulates whole-body lipid and glucose homeostasis. Several studies examined targeting FXR as a modality to treat obesity with varying conflicting results, emphasizing the need to study tissue-specific roles of FXR. We show that deletion of adipocyte Fxr results in increased adipocyte hypertrophy and suppression of several metabolic genes that is akin to some of the changes noted in high-fat diet (HFD)-fed control mice. Moreover, upon HFD challenge, these effects are worsened in adipocyte-specific Fxr knockout mice. We uncover that FXR regulates fatty acid amide hydrolase (Faah) such that its deletion lowers Faah expression. Conversely, FXR activation by its ligand, chenodeoxycholic acid, induces Faah transcription. Notably, HFD results in the reduction of adipose Faah expression in control mice and that Faah inhibition or deletion is linked to obesity. We report that the adipocyte FXR-Faah axis controls local 2-oleoyl glycerol and systemic N-acyl ethanolamine levels. Taken together, these findings show that loss of adipose FXR may contribute to the pathogenesis of obesity and subsequent metabolic defects.

Transplantation of committed pre-adipocytes from brown adipose tissue improves whole-body glucose homeostasis

iScience · 2024-01-21 · 12 citations

Obesity and its co-morbidities including type 2 diabetes are increasing at epidemic rates in the U.S. and worldwide. Brown adipose tissue (BAT) is a potential therapeutic to combat obesity and type 2 diabetes. Increasing BAT mass by transplantation improves metabolic health in rodents, but its clinical translation remains a challenge. Here, we investigated if transplantation of 2-4 million differentiated brown pre-adipocytes from mouse BAT stromal fraction (SVF) or human pluripotent stem cells (hPSCs) could improve metabolic health. Transplantation of differentiated brown pre-adipocytes, termed "committed pre-adipocytes" from BAT SVF from mice or derived from hPSCs improves glucose homeostasis and insulin sensitivity in recipient mice under conditions of diet-induced obesity, and this improvement is mediated through the collaborative actions of the liver transcriptome, tissue AKT signaling, and FGF21. These data demonstrate that transplantation of a small number of brown adipocytes has significant long-term translational and therapeutic potential to improve glucose metabolism.

Diet-Induced Obesity Modulates Close-Packing of Triacylglycerols in Lipid Droplets of Adipose Tissue

Journal of the American Chemical Society · 2024-12-07 · 8 citations

Adipose-derived lipid droplets (LDs) are rich in triacylglycerols (TAGs), which regulate essential cellular processes, such as energy storage. Although TAG accumulation and LD expansion in adipocytes occur during obesity, how LDs dynamically package TAGs in response to excessive nutrients remains elusive. Here, we found that LD lipidomes display a remarkable increase in TAG acyl chain saturation under calorie-dense diets, turning them conducive to close-packing. Using high-resolution X-ray diffraction, solid-state NMR, and imaging, we show that beyond size expansion LDs from mice under varied obesogenic diets govern fat accumulation by packing TAGs in different crystalline polymorphs. Consistently, LDs and tissue stiffen for high-calorie-fed mice with more than a 2-fold increase in elastic moduli compared to normal diet. Our data suggest that in addition to expanding, adipocyte LDs undergo structural remodeling by close-packing rigid and highly saturated TAGs in response to caloric overload, as opposed to liquid TAGs in a low-calorie diet. This work provides insights into how lipid packing within LDs can allow for the rapid and optimal expansion of fat during the initial stages of obesity.

Aging amplifies a gut microbiota immunogenic signature linked to heightened inflammation

Aging Cell · 2024-05-09 · 37 citations

Aging is associated with low-grade inflammation that increases the risk of infection and disease, yet the underlying mechanisms remain unclear. Gut microbiota composition shifts with age, harboring microbes with varied immunogenic capacities. We hypothesized the gut microbiota acts as an active driver of low-grade inflammation during aging. Microbiome patterns in aged mice strongly associated with signs of bacterial-induced barrier disruption and immune infiltration, including marked increased levels of circulating lipopolysaccharide (LPS)-binding protein (LBP) and colonic calprotectin. Ex vivo immunogenicity assays revealed that both colonic contents and mucosa of aged mice harbored increased capacity to activate toll-like receptor 4 (TLR4) whereas TLR5 signaling was unchanged. We found patterns of elevated innate inflammatory signaling (colonic Il6, Tnf, and Tlr4) and endotoxemia (circulating LBP) in young germ-free mice after 4 weeks of colonization with intestinal contents from aged mice compared with young counterparts, thus providing a direct link between aging-induced shifts in microbiota immunogenicity and host inflammation. Additionally, we discovered that the gut microbiota of aged mice exhibited unique responses to a broad-spectrum antibiotic challenge (Abx), with sustained elevation in Escherichia (Proteobacteria) and altered TLR5 immunogenicity 7 days post-Abx cessation. Together, these data indicate that old age results in a gut microbiota that differentially acts on TLR signaling pathways of the innate immune system. We found that these age-associated microbiota immunogenic signatures are less resilient to challenge and strongly linked to host inflammatory status. Gut microbiota immunogenic signatures should be thus considered as critical factors in mediating chronic inflammatory diseases disproportionally impacting older populations.