Metabolism
Abstract
Given the central role of peroxisomes in lipid metabolism and redox homeostasis, we hypothesized that peroxisomal activity is critical for sustaining β cell function and identity. Pex5 deletion models were employed to investigate loss of peroxisomal function on glucose-stimulated insulin secretion (GSIS), oxidative stress, and β cell maturity markers. Peroxisome deficiency in male mice resulted in elevated GSIS. Glucose intolerance developed despite increased insulin secretion. Ion mobility mass spectrometry revealed oxidation of insulin proteins, and a truncated insulin 2-derived peptide, in islets from mice with a tissue-specific deficiency in peroxisomes. Peroxisome loss of function increased multiple markers of oxidative stress, including altered metabolite profiles, lipid peroxidation, and protein carbonylation. These findings reveal that increased secretion of oxidized insulin protein is insufficient to regulate whole-body glucose homeostasis. Peroxisome deficiency also reduced markers of β cell maturity. Based on these outcomes, we identified the peroxisome organelle as a key regulatory component of glucose homeostasis by protecting insulin from oxidative modification and degradation and by supporting maintenance of mature β cells.
Authors
J. Jason Collier, Caroline R. Cothern, Maggie P. Ducote, Thomas M. Martin, Melissa A. Linden, Robert C. Noland, David H. Burk, Samuel D. Dupuy, Michael D. Karlstad, Krisztian Stadler, Sarah S. Hirschbeck, Thanh D. Do, Anastasia Coldren, Marcela Brissova, Teayoun Kim, Kirk M. Habegger, Sujoy Ghosh, Zane A. Vickery, Qudus Sarumi, Shawn R. Campagna, Susan J. Burke
Abstract
It is necessary for naïve CD8 T cells to be actively maintained in a quiescent metabolic state in order to respond robustly to infection while avoiding inappropriate activation during homeostasis. With age this quiescent state is lost and the CD8 T cell response to infection decreases. The factors regulating metabolic quiescence of CD8 T cells and how this regulation is lost during aging are not completely understood. Herein, we identify the transcription factor AFF3 as a regulator of metabolic quiescence in naïve CD8 T cells. While naïve AFF3 deficient CD8 T cells are more metabolically active prior to infection, they have reduced accumulation in response to viral infection, and this is correlated with a poor capacity to engage glycolysis. During aging in both murine and human CD8 T cells, AFF3 expression is decreased. In mice, this is associated with a loss of metabolic quiescence and reduced capacity to accumulate following infection. Our data highlight the role of metabolic regulation in CD8 T cell quiescence and identifies a transcription factor that may be a target to reinvigorate CD8 T cell responses during aging.
Authors
Molly E. Lumnitzer, Stefanie F. Valbon, Stephanie A. Condotta, Allison E. Norlander, Sheng Liu, Jun Wan, Martin J. Richer
Abstract
Postnatal growth faltering is a pervasive problem among extremely preterm infants that is independently associated with adverse neurodevelopmental outcomes. We previously observed that preterm infants with poor postnatal growth have altered development of the intestinal microbiota relative to preterm infants with appropriate postnatal growth. Here, we used gnotobiotic mice to investigate whether these differences in microbiota development independently contribute to growth faltering. We found that colonization of neonatal mice with microbiotas from extremely preterm infants with poor growth reproduced postnatal growth impairment and induced a metabolic signature of enhanced lipolysis and fatty acid oxidation in the mice, characterized by elevated hepatic acylcarnitines and circulating ketones. In mice colonized at birth with microbiotas from infants with poor growth, postnatal treatment with microbiotas from infants with appropriate growth prevented growth impairment. These results indicate that altered development of the intestinal microbiota contributes to growth faltering in extremely preterm infants, and that microbiota modification can restore postnatal growth.
Authors
Kwai Tei Chan Poon, Se Hyang Han, Olga Ilkayeva, Michael J. Muehlbauer, Christopher B. Newgard, Charles M. Cotten, Patricia L. Ashley, Patrick C. Seed, John F. Rawls, Noelle E. Younge
Abstract
Antiviral immunity profoundly impacts host metabolism, which can, in turn, modulate immune responses and influence disease pathology. The liver orchestrates systemic bile acid (BA) metabolism, a pathway disrupted in chronic liver diseases such as viral hepatitis. BAs are increasingly recognized for their immunomodulatory properties. Thus, improved understanding of the interplay between immunity and BA metabolism may reveal novel therapeutic avenues. Using lymphocytic choriomeningitis virus (LCMV) as a model, we investigated the interplay between chronic virus infection, BA metabolism, and immunity. Chronic LCMV infection increased BA levels and shifted circulating and liver BA composition toward host-derived, conjugated BAs. Hepatic BA transport and synthesis genes were broadly downregulated, in part depending on CD8+ T cells. Pharmacological inhibition of the main hepatic transporter of conjugated BAs, NTCP (Slc10a1), increased hepatic damage, while combined genetic disruption of the BA transporters Slco1a1, Slco1a4, and Slco1b2, responsible for the hepatic reuptake of unconjugated BA, reduced liver pathology and impaired antiviral CD8+ T cell responses. These findings reveal a reciprocal interplay between BA metabolism and CD8+ T cells, expanding our understanding of adaptive immunity in viral hepatitis. They also highlight how immunometabolic changes in liver disease may affect adaptive immune responses against infections.
Authors
Felix Clemens Richter, Zsofia Keszei, Csilla Viczenczova, Maximilian Baumgartner, Henrique G. Colaço, Magdalena Siller, Lisa Holnsteiner, Hatoon Baazim, Anna Hofmann, Aubrey Burrett, Anna Schönbichler, Lukas Endler, Joel Xu En Wong, Laura Antonio-Herrera, Oleksandr Petrenko, Fabian Amman, Jakob-Wendelin Genger, Claudia D. Fuchs, Hubert Scharnagl, Hanns-Ulrich Marschall, Thomas Reiberger, Karl S. Lang, Clarissa Campbell, Michael Trauner, Andreas Bergthaler
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease caused by the selective loss of upper and lower motor neurons. There is a considerable variability in the disease progression of sporadic ALS, but the molecular basis for phenotypic heterogeneity remains largely unknown. ALS patients often manifest systemic metabolic abnormalities such as glucose intolerance and hypermetabolic state. We conducted reverse translational research to explore therapeutic targets in ALS based on the systemic metabolic alterations in patients and identified several metabolites associated with the disease progression, including metabolites involved in the expanded endocannabinoid system (ECS). In particular, the levels of N-acyl taurines (NATs) were correlated with the longitudinal change in the revised ALS functional rating scale and survival. Experiments with ALS cellular models, iPS cells derived from ALS patients and SOD1G93A transgenic mice revealed that PF-04457845, a fatty acid amide hydrolase inhibitor, upregulated the expanded ECS, particularly the levels of NATs and ameliorated motor neuron degeneration through the regulation of microglial environment, synapse plasticity, and neuronal development. These results collectively indicate that dysregulation of NATs is associated with ALS progression and PF-04457845 may represent a potential disease-modifying therapy for ALS.
Authors
Daisuke Ito, Madoka Iida, Yohei Iguchi, Atsushi Hashizume, Shinichiro Yamada, Yoshiyuki Kishimoto, Shota Komori, Kazuki Obara, Shuto Nishisaki, Satoshi Yokoi, Teppei Shimamura, Yuto Takemoto, Masahiro Nakatochi, Tomohiro Akashi, Kunihiko Hinohara, Hyeon-Cheol Lee-Okada, Yohei Okada, Junichi Niwa, Gen Sobue, Shinji Tanaka, Ken Takashina, Takehiko Yokomizo, Masahisa Katsuno
Abstract
While glucagon-like peptide-1 receptor agonists (GLP-1RAs) like semaglutide are effective in treating obesity, up to 45% of the resulting weight loss can be attributed to skeletal muscle loss. Given the critical role of skeletal muscle in health and mobility, this may have long-term adverse consequences. Herein we investigated whether oral ketone ester supplementation could prevent semaglutide-induced muscle loss and explored the underlying molecular mechanisms. Obese, glucose-intolerant mice received vehicle, semaglutide, or semaglutide plus a β-hydroxybutyrate–generating ketone ester for three weeks. Body composition, muscle strength, and endurance were assessed longitudinally. Semaglutide monotherapy reduced lean mass, impaired muscle strength, and suppressed mitochondrial gene expression while elevating atrophy-related genes in skeletal muscle samples. Co-administration with ketone ester preserved skeletal muscle mass and function without compromising fat loss. Mechanistically, ketone ester co-treatment prevented semaglutide-induced changes in mitochondrial and atrophy-related gene expression, suggesting mitochondrial defects and impaired ketone metabolism contribute to GLP-1RA-induced muscle loss. Together, these findings demonstrate that ketone ester supplementation can maintain muscle mass and performance during semaglutide-driven weight loss. These preclinical findings support ketone therapy as a promising strategy to counteract the sarcopenia-promoting effects of GLP-1RAs and warrant clinical evaluation to assess its translational potential.
Authors
Yasser Abuetabh, Mya A. Schmidt, Masaaki Naganuma, Ramana Vaka, Mahmoud A. El-Ghiaty, Shelly Braun, Ethan A. Kwan, Matthieu C.P. Zolondek, Darius Sahid, Laibah Khan, Rajat K. Shandal, Ashley L. Trudeau, Yaning Li, Sufyan O. Malik, Qiuyu Sun, Danica K. Roth, Daniela Y. Morales-Llamas, Jody L. Levasseur, Mourad Ferdaoussi, Richard P. Fahlman, Jason R.B. Dyck
Abstract
The composition of mitochondrial membrane lipids is crucial to cellular respiration, as seen in Barth syndrome (BTHS), a rare disease affecting skeletal muscle, heart, and neutrophils. In BTHS, mutations in the tafazzin (TAZ) gene reduce remodeling of the mitochondrial phospholipid, cardiolipin, causing mitochondrial dysfunction in skeletal muscle and heart. Here, we investigated effects of altering polyunsaturated fatty acid content in cardiolipin using preclinical models of BTHS. In vitro, the absence of TAZ did not impair omega-3 fatty acid incorporation into cardiolipin and resulted in increased turnover of these acyl chains. To examine this in a functional model, we generated a muscle-specific knockout mouse of TAZ (TAZ MKO), which recapitulated the human phenotype in skeletal muscle. Supplementing the diet of TAZ MKO with fish-oil-derived omega-3 fatty acids prevented lean mass loss, improved mitochondrial respiration, altered mitochondrial structure, and revealed moderate improvements in the stress response. Surprisingly, no diet-induced changes to cardiolipin species were observed in the TAZ MKO, but other phospholipids were altered by both genotype and diet, revealing complex regulation and potential compensation. Overall, this work provides evidence that omega-3 fatty acid supplementation is beneficial in muscle lacking TAZ to improve quality of life when added to current BTHS treatments.
Authors
Katharina B. Kuentzel, Ana Vranešević, Samuel A.J. Trammell, Fabian Finger, Jesper F. Havelund, Yvette L. Schooneveldt, Ivan Bradić, Nicoline R. Andersen, Anna S. Hassing, Katja T. Michler, Martin R. Larsen, Zachary Gerhart-Hines, Steven M. Claypool, Jonas T. Treebak, Andreas M. Fritzen, Matthew P. Gillum, Steen Larsen, Nils Færgeman, Trisha J. Grevengoed
Abstract
Cellular senescence is an irreversible stress response, which leads to loss of cellular function and remodelling of the cellular secretory profile. In humans, pancreatic β-cells undergo cellular senescence during the progression to type 2 diabetes (T2D). However, the mechanism linking β-cell senescence to islet dysfunction remains unknown and thus, the therapeutic potential of targeting senescent cells in T2D is not established. Herein, we identified a subpopulation of senescent β-cells expressing p21, which emerged early in the progression of T2D in humans and mice. Spatial transcriptomics, and proteomics analyses confirmed senescence and loss of cellular identity in this subpopulation in humans. Functional analysis revealed lack of glucose responsiveness, high basal insulin secretion, and transcription of senescence-associated secretory phenotype (SASP) factors. SASP factors from p21+ β-cells induced secondary senescence in neighbouring cells, characterized by dysfunction and loss of identity. Janus kinase inhibitors (JAKi) counteracted the induction of secondary senescence and restored β-cell function in islets from humans with T2D and in high-fat diet-fed mice. These findings reveal the critical role of p21+ β-cells in T2D pathogenesis and the therapeutic potential of targeting this pathophysiological process.
Authors
Kanako Iwasaki, Priscila Carapeto, Cristian Abarca, Francesko Hela, Stephanie Sanjines, Sebastian Pena, Sandra Le, Hui Pan, Maya Jackson, Christopher Cahill, Ayush Midha, Juliana Alcoforado Diniz, Dylan Baker, Sergii Domanskyi, Sara Espinoza, Alejandro Pena, Francisco G. Cigarroa, Jillian L. Woodworth, Jeffrey H. Chuang, Vesna D. Garovic, James L. Kirkland, Tamara Tchkonia, Nicolas Musi, George A. Kuchel, Paul Robson, Cristina Aguayo-Mazzucato
Abstract
Synovial hyperplasia is a hallmark of rheumatoid arthritis (RA), yet its mechanism remains unclear. RA synovium exhibits metabolic shift, characterized by upregulated glycolysis and enhanced lactate production. In this study, we elucidated the mechanism underlying the roles of lactate metabolism and protein lactylation in RA pathology. In patients with RA, both lactate production and protein lactylation were elevated and showed a positive correlation with clinical disease activity. These changes were further implicated in driving synovial proliferation. Among the lactylated proteins, Cysteine-rich intestinal protein 1 (CRIP1) exhibited a marked increase in modification and played a central role in promoting synovial proliferation. Mechanistically, CRIP1 underwent MOF-mediated lactylation in RA synovial fibroblasts. Lactylated CRIP1 hijacked the cell-cycle regulator p21, disrupting its interaction with cyclin-dependent kinase 2 (CDK2), thereby facilitating the G1/S phase transition. Functionally, AAV-mediated delivery of a lactylation-deficient CRIP1 K49R significantly reduced synovial proliferation compared with WT CRIP1. Peptide-based interventions targeting CRIP1 K49 lactylation effectively inhibited synovial hyperplasia and disease severity in both Collagen II–induced arthritis (CIA) and humanized NSG chimeric models. Collectively, CRIP1 protein lactylation drives synovial proliferation in RA by hijacking p21 from CDK2, thereby facilitating cell cycle progression. Targeting this pathway may serve as a promising strategy for RA.
Authors
Meican Ma, Yu Zhou, Qianlin Li, Zhao Wang, Shangqi Guan, Xiaoxue Wang, Han Zhao, Zhenke Wen, Ting Liu, Fenghong Yuan
Abstract
Central insulin action in the brain is thought to contribute to metabolic regulation, but the specific hypothalamic nuclei affected in type 2 diabetes (T2D) remain poorly characterized. We performed high-resolution functional MRI (fMRI) during intranasal insulin administration to assess nucleus-level hypothalamic responses in 21 Japanese men with T2D and 20 individuals acting as healthy controls. In controls, insulin rapidly suppressed fMRI signals within 5 minutes in the posterior hypothalamic nucleus; this early suppression was not observed in T2D, indicating impaired hypothalamic insulin responsiveness. In an independent older cohort, structural MRI further revealed decreased gray matter volume in the corresponding posterior hypothalamus in participants with diabetes. These converging functional and structural findings implicate the posterior hypothalamus as a candidate locus associated with brain insulin resistance in T2D, warranting longitudinal and interventional validation.
Authors
Hideyoshi Kaga, Akitoshi Ogawa, Takahiro Osada, Mai Kiya, Satoshi Oka, Yusuke Adachi, Mengping Yu, Shota Sakamoto, Saori Kakehi, Toshiki Kogai, Tsubasa Tajima, Hitoshi Naito, Naoaki Ito, Satoshi Kadowaki, Yuya Nishida, Ryuzo Kawamori, Seiki Konishi, Hirotaka Watada, Yoshifumi Tamura
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