bims-mimead 2025-01-05 papers

Issue of 2025–01–05
five papers selected by
Rachel M. Handy, University of Guelph

Nat Commun. 2025 Jan 02. 16(1): 122

Effects of seven days' fasting on physical performance and metabolic adaptation during exercise in humans.

Kristoffer J Kolnes, Emelie T F Nilsen, Steffen Brufladt, Allison M Meadows, Per B Jeppesen, Øyvind Skattebo, Egil I Johansen, Jesper B Birk, Kurt Højlund, Janne Hingst, Bjørn S Skålhegg, Rasmus Kjøbsted, Julian L Griffin, Anders J Kolnes, Stephen O'Rahilly, Jørgen F P Wojtaszewski, Jørgen Jensen.

Humans have, throughout history, faced periods of starvation necessitating increased physical effort to gather food. To explore adaptations in muscle function, 13 participants (7 males and 6 females) fasted for seven days. They lost 4.6 ± 0.3 kg lean and 1.4 ± 0.1 kg fat mass. Maximal isometric and isokinetic strength remained unchanged, while peak oxygen uptake decreased by 13%. Muscle glycogen was halved, while expression of electron transport chain proteins was unchanged. Pyruvate dehydrogenase kinase 4 (PDK4) expression increased 13-fold, accompanied by inhibitory pyruvate dehydrogenase phosphorylation, reduced carbohydrate oxidation and decreased exercise endurance capacity. Fasting had no impact on 5' AMP-activated protein kinase (AMPK) activity, challenging its proposed role in muscle protein degradation. The participants maintained muscle strength and oxidative enzymes in skeletal muscle during fasting but carbohydrate oxidation and high-intensity endurance capacity were reduced.

DOI: https://doi.org/10.1038/s41467-024-55418-0

J Obes Metab Syndr. 2024 Dec 30. 33(4): 275-288

Understanding Adipose Tissue Dysfunction.

Matthias Blüher.

Diseases affecting adipose tissue (AT) function include obesity, lipodystrophy, and lipedema, among others. Both a lack of and excess AT are associated with increased risk for developing diseases including type 2 diabetes mellitus, hypertension, obstructive sleep apnea, and some types of cancer. However, individual risk of developing cardiometabolic and other 'obesity-related' diseases is not entirely determined by fat mass. Rather than excess fat accumulation, AT dysfunction may represent the mechanistic link between obesity and comorbid diseases. There are people who remain metabolically healthy despite obesity, whereas people with normal weight or very low subcutaneous AT mass may develop typically obesity-related diseases. AT dysfunction is characterized by adipocyte hypertrophy, impaired subcutaneous AT expandability (ectopic fat deposition), hypoxia, a variety of stress, inflammatory processes, and the release of proinflammatory, diabetogenic, and atherogenic signals. Genetic and environmental factors might contribute to AT heterogeneity either alone or via interaction with intrinsic biological factors. However, many questions remain regarding the mechanisms of AT dysfunction initiation and whether and how it could be reversed. Do AT signatures define clinically relevant subtypes of obesity? Is the cellular composition of AT associated with variation in obesity phenotypes? What roles do environmental compounds play in the manifestation of AT dysfunction? Answers to these and other questions may explain AT disease mechanisms and help to define strategies for improving AT health. This review focuses on recent advances in our understanding of AT biology.

Keywords: Adipocytes; Adipokines; Adipose tissue; Inflammation; Lipedema; Lipodystrophy; Obesity

DOI: https://doi.org/10.7570/jomes24013

Nat Commun. 2025 Jan 02. 16(1): 170

Paracrine role of endothelial IGF-1 receptor in depot-specific adipose tissue adaptation in male mice.

During recent decades, changes in lifestyle have led to widespread nutritional obesity and its related complications. Remodelling adipose tissue as a therapeutic goal for obesity and its complications has attracted much attention and continues to be actively explored. The endothelium lines all blood vessels and is close to all cells, including adipocytes. The endothelium has been suggested to act as a paracrine organ. We explore the role of endothelial insulin-like growth factor-1 receptor (IGF-1R), as a paracrine modulator of white adipose phenotype. We show that a reduction in endothelial IGF-1R expression in the presence of high-fat feeding in male mice leads to depot-specific beneficial white adipose tissue remodelling, increases whole-body energy expenditure and enhances insulin sensitivity via a non-cell-autonomous paracrine mechanism. We demonstrate that increased endothelial malonate may be contributory and that malonate prodrugs have potentially therapeutically relevant properties in the treatment of obesity-related metabolic disease.

DOI: https://doi.org/10.1038/s41467-024-54669-1

EBioMedicine. 2024 Dec 27. pii: S2352-3964(24)00568-1. [Epub ahead of print]111 105532

Multi-omics profiling reveals altered mitochondrial metabolism in adipose tissue from patients with metabolic dysfunction-associated steatohepatitis.

Helena Castañé, Andrea Jiménez-Franco, Anna Hernández-Aguilera, Cristian Martínez-Navidad, Vicente Cambra-Cortés, Alina-Iuliana Onoiu, Juan Manuel Jiménez-Aguilar, Marta París, Mercè Hernández, David Parada, Carmen Guilarte, Antonio Zorzano, María Isabel Hernández-Alvarez, Jordi Camps, Jorge Joven.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe form steatohepatitis (MASH) contribute to rising morbidity and mortality rates. The storage of fat in humans is closely associated with these diseases' progression. Thus, adipose tissue metabolic homeostasis could be key in both the onset and progression of MASH.
METHODS: We conducted a case-control observational research using a systems biology-based approach to analyse liver, abdominal subcutaneous adipose tissue (SAT), omental visceral adipose tissue (VAT), and blood of n = 100 patients undergoing bariatric surgery (NCT05554224). MASH was diagnosed through histologic assessment. Whole-slide image analysis, lipidomics, proteomics, and transcriptomics were performed on tissue samples. Lipidomics and proteomics profiles were determined on plasma samples.
FINDINGS: Liver transcriptomics, proteomics, and lipidomics revealed interconnected pathways associated with inflammation, mitochondrial dysfunction, and lipotoxicity in MASH. Paired adipose tissue biopsies had larger adipocyte areas in both fat depots in MASH. Enrichment analyses of proteomics and lipidomics data confirmed the association of liver lesions with mitochondrial dysfunction in VAT. Plasma lipidomics identified candidates with high diagnostic accuracy (AUC = 0.919, 95% CI 0.840-0.979) for screening MASH.
INTERPRETATION: Mitochondrial dysfunction is also present in VAT in patients with obesity-associated MASH. This may cause a disruption in the metabolic equilibrium of lipid processing and storage, which impacts the liver and accelerates detrimental adaptative responses.
FUNDING: The project leading to these results has received funding from 'la Caixa' Foundation (HR21-00430), and from the Instituto de Salud Carlos III (ISCIII) (PI21/00510) and co-funded by the European Union.

Keywords: Interorgan crosstalk; Lipidomics; MASLD; Multi-omics; Multi-tissue

DOI: https://doi.org/10.1016/j.ebiom.2024.105532

Nat Metab. 2025 Jan 02.

A feeding-induced myokine modulates glucose homeostasis.

Xiaoliu Shi, Xiao Hu, Xinlei Fang, Liangjie Jia, Fangchao Wei, Ying Peng, Menghao Liu, Aibo Gao, Ke Zhao, Fengyi Chen, Xiaoli Hu, Jie Hong, Guang Ning, Yongfeng Song, Jiqiu Wang, Yiguo Wang.

Maintaining blood glucose homeostasis during fasting and feeding is crucial for the prevention of dysregulation that can lead to either hypo- or hyperglycaemia. Here we identified feimin, encoded by a gene with a previously unknown function (B230219D22Rik in mice, C5orf24 in humans), as a key modulator of glucose homeostasis. Feimin is secreted from skeletal muscle during feeding and binds to its receptor, receptor protein tyrosine kinase Mer (MERTK), promoting glucose uptake and inhibiting glucose production by activation of AKT. Administration of feimin and insulin synergistically improves blood glucose homeostasis in both normal and diabetic mice. Notably, a specific single nucleotide polymorphism (rs7604639, G>A) within the MERTK gene, causing an amino acid substitution (R466K) within the feimin-MERTK binding region, leads to reduced association with feimin and elevated postprandial blood glucose and insulin levels in humans. Our findings underscore a role of the feimin-MERTK signalling axis in glucose homeostasis, providing valuable insights into potential therapeutic avenues for diabetes.

DOI: https://doi.org/10.1038/s42255-024-01175-9