bims-obesme 2024-08-04 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2024‒08‒04
ten papers selected by
Xiong Weng, University of Edinburgh

Lipid droplet-associated hydrolase mobilizes stores of liver X receptor sterol ligands and protects against atherosclerosis.
Single-nucleus transcriptomics identifies separate classes of UCP1 and futile cycle adipocytes.
Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging.
Loss of PPARα function promotes epigenetic dysregulation of lipid homeostasis driving ferroptosis and pyroptosis lipotoxicity in metabolic dysfunction associated Steatotic liver disease (MASLD).
Growth differentiation factor 15 alleviates diastolic dysfunction in mice with experimental diabetic cardiomyopathy.
mTORC1 activity oscillates throughout the cell cycle, promoting mitotic entry and differentially influencing autophagy induction.
Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation.
A microbial metabolite inhibits the HIF-2α-ceramide pathway to mediate the beneficial effects of time-restricted feeding on MASH.
Translational potential of mouse models of human metabolic disease.
Deficiency of protein phosphatase 5 resists osteoporosis in diabetic mice.

Nat Commun. 2024 Aug 02. 15(1): 6540

Lipid droplet-associated hydrolase mobilizes stores of liver X receptor sterol ligands and protects against atherosclerosis.

Young-Hwa Goo, Janeesh Plakkal Ayyappan, Francis D Cheeran, Sushant Bangru, Pradip K Saha, Paula Baar, Sabine Schulz, Todd A Lydic, Bernhard Spengler, Andreas H Wagner, Auinash Kalsotra, Vijay K Yechoor, Antoni Paul.

Foam cells in atheroma are engorged with lipid droplets (LDs) that contain esters of regulatory lipids whose metabolism remains poorly understood. LD-associated hydrolase (LDAH) has a lipase structure and high affinity for LDs of foam cells. Using knockout and transgenic mice of both sexes, here we show that LDAH inhibits atherosclerosis development and promotes stable lesion architectures. Broad and targeted lipidomic analyzes of primary macrophages and comparative lipid profiling of atheroma identified a broad impact of LDAH on esterified sterols, including natural liver X receptor (LXR) sterol ligands. Transcriptomic analyzes coupled with rescue experiments show that LDAH modulates the expression of prototypical LXR targets and leads macrophages to a less inflammatory phenotype with a profibrotic gene signature. These studies underscore the role of LDs as reservoirs and metabolic hubs of bioactive lipids, and suggest that LDAH favorably modulates macrophage activation and protects against atherosclerosis via lipolytic mobilization of regulatory sterols.

DOI: https://doi.org/10.1038/s41467-024-50949-y
Cell Metab. 2024 Jul 26. pii: S1550-4131(24)00276-6. [Epub ahead of print]

Single-nucleus transcriptomics identifies separate classes of UCP1 and futile cycle adipocytes.

Tongtong Wang, Anand Kumar Sharma, Chunyan Wu, Claudia Irene Maushart, Adhideb Ghosh, Wu Yang, Patrik Stefanicka, Zuzana Kovanicova, Jozef Ukropec, Jing Zhang, Myrtha Arnold, Manuel Klug, Katrien De Bock, Ulrich Schneider, Cristina Popescu, Bo Zheng, Lianggong Ding, Fen Long, Revati Sumukh Dewal, Caroline Moser, Wenfei Sun, Hua Dong, Martin Takes, Dominique Suelberg, Alexander Mameghani, Antonio Nocito, Christoph Johannes Zech, Alin Chirindel, Damian Wild, Irene A Burger, Michael R Schön, Arne Dietrich, Min Gao, Markus Heine, Yizhi Sun, Ariana Vargas-Castillo, Susanna Søberg, Camilla Scheele, Miroslav Balaz, Matthias Blüher, Matthias Johannes Betz, Bruce M Spiegelman, Christian Wolfrum.

  Adipose tissue can recruit catabolic adipocytes that utilize chemical energy to dissipate heat. This process occurs either by uncoupled respiration through uncoupling protein 1 (UCP1) or by utilizing ATP-dependent futile cycles (FCs). However, it remains unclear how these pathways coexist since both processes rely on the mitochondrial membrane potential. Utilizing single-nucleus RNA sequencing to deconvolute the heterogeneity of subcutaneous adipose tissue in mice and humans, we identify at least 2 distinct subpopulations of beige adipocytes: FC-adipocytes and UCP1-beige adipocytes. Importantly, we demonstrate that the FC-adipocyte subpopulation is highly metabolically active and utilizes FCs to dissipate energy, thus contributing to thermogenesis independent of Ucp1. Furthermore, FC-adipocytes are important drivers of systemic energy homeostasis and linked to glucose metabolism and obesity resistance in humans. Taken together, our findings identify a noncanonical thermogenic adipocyte subpopulation, which could be an important regulator of energy homeostasis in mammals.

Keywords:  energy homeostasis; futile cycling; human metabolism; single-nucleus RNA sequencing; thermogenesis

DOI:  https://doi.org/10.1016/j.cmet.2024.07.005
Nat Commun. 2024 Jul 28. 15(1): 6357

Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging.

James R Occean, Na Yang, Yan Sun, Marshall S Dawkins, Rachel Munk, Cedric Belair, Showkat Dar, Carlos Anerillas, Lin Wang, Changyou Shi, Christopher Dunn, Michel Bernier, Nathan L Price, Julie S Kim, Chang-Yi Cui, Jinshui Fan, Moitrayee Bhattacharyya, Supriyo De, Manolis Maragkakis, Rafael de Cabo, Simone Sidoli, Payel Sen.

DNA hydroxymethylation (5hmC), the most abundant oxidative derivative of DNA methylation, is typically enriched at enhancers and gene bodies of transcriptionally active and tissue-specific genes. Although aberrant genomic 5hmC has been implicated in age-related diseases, its functional role in aging remains unknown. Here, using mouse liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and restricts the magnitude of gene expression changes with age. Mechanistically, 5hmC decreases the binding of splicing associated factors and correlates with age-related alternative splicing events. We found that various age-related contexts, such as prolonged quiescence and senescence, drive the accumulation of 5hmC with age. We provide evidence that this age-related transcriptionally restrictive function is conserved in mouse and human tissues. Our findings reveal that 5hmC regulates tissue-specific function and may play a role in longevity.

DOI: https://doi.org/10.1038/s41467-024-50725-y
Front Mol Med. 2023 ;3 1283170

Loss of PPARα function promotes epigenetic dysregulation of lipid homeostasis driving ferroptosis and pyroptosis lipotoxicity in metabolic dysfunction associated Steatotic liver disease (MASLD).

Claudia Theys, Tineke Vanderhaeghen, Evelien Van Dijck, Cedric Peleman, Anne Scheepers, Joe Ibrahim, Ligia Mateiu, Steven Timmermans, Tom Vanden Berghe, Sven M Francque, Wim Van Hul, Claude Libert, Wim Vanden Berghe.

  Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) is a growing epidemic with an estimated prevalence of 20%-30% in Europe and the most common cause of chronic liver disease worldwide. The onset and progression of MASLD are orchestrated by an interplay of the metabolic environment with genetic and epigenetic factors. Emerging evidence suggests altered DNA methylation pattern as a major determinant of MASLD pathogenesis coinciding with progressive DNA hypermethylation and gene silencing of the liver-specific nuclear receptor PPARα, a key regulator of lipid metabolism. To investigate how PPARα loss of function contributes to epigenetic dysregulation in MASLD pathology, we studied DNA methylation changes in liver biopsies of WT and hepatocyte-specific PPARα KO mice, following a 6-week CDAHFD (choline-deficient, L-amino acid-defined, high-fat diet) or chow diet. Interestingly, genetic loss of PPARα function in hepatocyte-specific KO mice could be phenocopied by a 6-week CDAHFD diet in WT mice which promotes epigenetic silencing of PPARα function via DNA hypermethylation, similar to MASLD pathology. Remarkably, genetic and lipid diet-induced loss of PPARα function triggers compensatory activation of multiple lipid sensing transcription factors and epigenetic writer-eraser-reader proteins, which promotes the epigenetic transition from lipid metabolic stress towards ferroptosis and pyroptosis lipid hepatoxicity pathways associated with advanced MASLD. In conclusion, we show that PPARα function is essential to support lipid homeostasis and to suppress the epigenetic progression of ferroptosis-pyroptosis lipid damage associated pathways towards MASLD fibrosis.

Keywords:  MASLD; NAFLD; PPARα; bile acid metabolism; epigenetics; ferroptosis; lipid metabolism; pyroptosis

DOI:  https://doi.org/10.3389/fmmed.2023.1283170
Cell Rep. 2024 Jul 31. pii: S2211-1247(24)00902-1. [Epub ahead of print]43(8): 114573

Growth differentiation factor 15 alleviates diastolic dysfunction in mice with experimental diabetic cardiomyopathy.

Jordan S F Chan, Seyed Amirhossein Tabatabaei Dakhili, Maria Areli Lorenzana-Carrillo, Keshav Gopal, Serena M Pulente, Amanda A Greenwell, Kunyan Yang, Christina T Saed, Magnus J Stenlund, Sally R Ferrari, Indiresh A Mangra-Bala, Tanin Shafaati, Rakesh K Bhat, Farah Eaton, Michael Overduin, Sebastian Beck Jørgensen, Gregory R Steinberg, Erin E Mulvihill, Gopinath Sutendra, John R Ussher.

  Growth differentiation factor 15 (GDF15) is a peptide with utility in obesity, as it decreases appetite and promotes weight loss. Because obesity increases the risk for type 2 diabetes (T2D) and cardiovascular disease, it is imperative to understand the cardiovascular actions of GDF15, especially since elevated GDF15 levels are an established biomarker for heart failure. As weight loss should be encouraged in the early stages of obesity-related prediabetes/T2D, where diabetic cardiomyopathy is often present, we assessed whether treatment with GDF15 influences its pathology. We observed that GDF15 treatment alleviates diastolic dysfunction in mice with T2D independent of weight loss. This cardioprotection was associated with a reduction in cardiac inflammation, which was likely mediated via indirect actions, as direct treatment of adult mouse cardiomyocytes and differentiated THP-1 human macrophages with GDF15 failed to alleviate lipopolysaccharide-induced inflammation. Therapeutic manipulation of GDF15 action may thus have utility for both obesity and diabetic cardiomyopathy.

Keywords:  CP: Metabolism; GDF15; diabetic cardiomyopathy; diastolic dysfunction; inflammation; obesity; type 2 diabetes

DOI:  https://doi.org/10.1016/j.celrep.2024.114573
Cell Rep. 2024 Jul 26. pii: S2211-1247(24)00872-6. [Epub ahead of print]43(8): 114543

mTORC1 activity oscillates throughout the cell cycle, promoting mitotic entry and differentially influencing autophagy induction.

Jay N Joshi, Ariel D Lerner, Frank Scallo, Alexandra N Grumet, Paul Matteson, James H Millonig, Alexander J Valvezan.

  Mechanistic Target of Rapamycin Complex 1 (mTORC1) is a master metabolic regulator that is active in nearly all proliferating eukaryotic cells; however, it is unclear whether mTORC1 activity changes throughout the cell cycle. We find that mTORC1 activity oscillates from lowest in mitosis/G1 to highest in S/G2. The interphase oscillation is mediated through the TSC complex but is independent of major known regulatory inputs, including Akt and Mek/Erk signaling. By contrast, suppression of mTORC1 activity in mitosis does not require the TSC complex. mTORC1 has long been known to promote progression through G1. We find that mTORC1 also promotes progression through S and G2 and is important for satisfying the Chk1/Wee1-dependent G2/M checkpoint to allow entry into mitosis. We also find that low mTORC1 activity in G1 sensitizes cells to autophagy induction in response to partial mTORC1 inhibition or reduced nutrient levels. Together, these findings demonstrate that mTORC1 is differentially regulated throughout the cell cycle, with important phase-specific consequences for proliferating cells.

Keywords:  CDK1; CP: Cell biology; G2/M checkpoint; TSC complex; TSC2; autophagy; cell cycle; mTOR; mTORC1; mitosis

DOI:  https://doi.org/10.1016/j.celrep.2024.114543
Nat Commun. 2024 Jul 31. 15(1): 6438

Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation.

Meiyue Wang, Heinrich Flaswinkel, Abhinav Joshi, Matteo Napoli, Sergi Masgrau-Alsina, Julia M Kamper, Antonia Henne, Alexander Heinz, Marleen Berouti, Niklas A Schmacke, Karsten Hiller, Elisabeth Kremmer, Benedikt Wefers, Wolfgang Wurst, Markus Sperandio, Jürgen Ruland, Thomas Fröhlich, Veit Hornung.

Innate immune responses are linked to key metabolic pathways, yet the proximal signaling events that connect these systems remain poorly understood. Here we show that phosphofructokinase 1, liver type (PFKL), a rate-limiting enzyme of glycolysis, is phosphorylated at Ser775 in macrophages following several innate stimuli. This phosphorylation increases the catalytic activity of PFKL, as shown by biochemical assays and glycolysis monitoring in cells expressing phosphorylation-defective PFKL variants. Using a genetic mouse model in which PFKL Ser775 phosphorylation cannot take place, we observe that upon activation, glycolysis in macrophages is lower than in the same cell population of wild-type animals. Consistent with their higher glycolytic activity, wild-type cells have higher levels of HIF1α and IL-1β than PfklS775A/S775A after LPS treatment. In an in vivo inflammation model, PfklS775A/S775A mice show reduced levels of MCP-1 and IL-1β. Our study thus identifies a molecular link between innate immune activation and early induction of glycolysis.

DOI: https://doi.org/10.1038/s41467-024-50104-7
Cell Metab. 2024 Jul 23. pii: S1550-4131(24)00275-4. [Epub ahead of print]

A microbial metabolite inhibits the HIF-2α-ceramide pathway to mediate the beneficial effects of time-restricted feeding on MASH.

Yi Zhang, Xuemei Wang, Jun Lin, Jia Liu, Kai Wang, Qixing Nie, Chuan Ye, Lulu Sun, Yanpeng Ma, Ruize Qu, Yuejian Mao, Xuguang Zhang, Hua Lu, Pengyan Xia, Dongyu Zhao, Guang Wang, Zhipeng Zhang, Wei Fu, Changtao Jiang, Yanli Pang.

  Time-restricted feeding (TRF) is a potent dietary intervention for improving metabolic diseases, including metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis (MASLD/MASH). However, the mechanism of this efficacy has remained elusive. Here, we show that TRF improves MASLD, which is associated with a significant enrichment of Ruminococcus torques (R. torques). Mechanistically, R. torques suppresses the intestinal HIF-2α-ceramide pathway via the production of 2-hydroxy-4-methylpentanoic acid (HMP). We identify rtMor as a 4-methyl-2-oxopentanoate reductase that synthesizes HMP in R. torques. Finally, we show that either the colonization of R. torques or oral HMP supplementation can ameliorate inflammation and fibrosis in a MASH mouse model. These findings identify R. torques and HMP as potential TRF mimetics for the treatment of metabolic disorders.

Keywords:  MASLD/MASH; bacterial metabolites; gut microbiota; time-restricted feeding

DOI:  https://doi.org/10.1016/j.cmet.2024.07.004
Cell. 2024 Jul 24. pii: S0092-8674(24)00771-2. [Epub ahead of print]

Translational potential of mouse models of human metabolic disease.

I Sadaf Farooqi, Yong Xu.

  Obesity causes significant morbidity and mortality globally. Research in the last three decades has delivered a step-change in our understanding of the fundamental mechanisms that regulate energy homeostasis, building on foundational discoveries in mouse models of metabolic disease. However, not all findings made in rodents have translated to humans, hampering drug discovery in this field. Here, we review how studies in mice and humans have informed our current framework for understanding energy homeostasis, discuss their challenges and limitations, and offer a perspective on how human studies may play an increasingly important role in the discovery of disease mechanisms and identification of therapeutic targets in the future.

Keywords:  human; hypothalamus; mouse models; obesity; set-point

DOI:  https://doi.org/10.1016/j.cell.2024.07.011
Heliyon. 2024 Jul 15. 10(13): e34027

Deficiency of protein phosphatase 5 resists osteoporosis in diabetic mice.

Jun Wang, Changyu Zhao, Wenpeng Zhao, Songnan Li.

  Osteoporosis is a common diabetic consequence that negatively affects patients' health and quality of life. Nevertheless, there is mutual interference between clinical drugs intended to regulate blood glucose and bone metabolism. Therefore, it is crucial to look for new treatment targets that effectively control blood glucose and safely protect the bone health of patients with diabetes. In this study, mice given a high-fat diet were shown to be resistant to osteoporosis and diabetes when protein phosphatase 5 (PP5) knockout (KO) mice were used. Serum markers of bone remodeling show that PP5 KO mice are resistant to decreased bone formation and increased bone resorption brought on by diabetes. The absence of PP5 resists the reduction of osteoblast differentiation and the enhancement of osteoclast differentiation in diabetic mice, according to the in vitro osteoblast differentiation of bone mesenchymal stem cells and osteoclast differentiation of bone marrow-derived macrophages. Subsequent investigation revealed that PP5 deficiency increases the expression of the key regulator of osteoblast differentiation, runt-related transcription factor 2, and decreases the activity of the receptor activator of the nuclear factor-κB ligand/osteoprotegerin pathway, a crucial regulatory signaling pathway for osteoclast differentiation. In conclusion, we discovered that PP5 deficiency protects diabetic mice against osteoporosis for the first time.

Keywords:  Diabetes; High-fat diet; Osteoblast; Osteoclast; Osteoporosis; Protein phosphatase 5

DOI:  https://doi.org/10.1016/j.heliyon.2024.e34027