bims-mimead 2025-02-09 papers

bims-mimead

Biomed News

on Mitochondrial metabolism in ageing and metabolic disease

Issue of 2025–02–09
eight papers selected by
Rachel M. Handy, University of Guelph

Fetuin B is related to cytokine/chemokine and insulin signaling in adipose tissue and plasma in humans.
Cellular deconstruction of the human skeletal muscle microenvironment identifies an exercise-induced histaminergic crosstalk.
Visceral adipose tissue area and proportion provide distinct reflections of cardiometabolic outcomes in weight loss; pooled analysis of MRI-assessed CENTRAL and DIRECT PLUS dietary randomized controlled trials.
The Twin Cycle Hypothesis of type 2 diabetes aetiology: From concept to national NHS programme.
THE REGULATION OF CELL METABOLISM BY HYPOXIA AND HYPERCAPNIA.
Metabolic Messengers: small extracellular vesicles.
Purified adipose tissue-derived extracellular vesicles facilitate adipose organoid vascularization through coordinating adipogenesis and angiogenesis.
Piezo2 in sensory neurons regulates systemic and adipose tissue metabolism.

J Clin Endocrinol Metab. 2025 Feb 07. pii: dgaf073. [Epub ahead of print]

Fetuin B is related to cytokine/chemokine and insulin signaling in adipose tissue and plasma in humans.

Esther J Kemper, Gijs H Goossens, Ellen E Blaak, Michiel E Adriaens, Ruth C R Meex.

   OBJECTIVE: Fetuin B is a steatosis-responsive hepatokine that induces glucose intolerance in mice. Recently, we found that fetuin B in white adipose tissue was positively associated with peripheral insulin resistance in mice and a small study population, possibly through a fetuin B-induced inflammatory response in adipocytes. This translational study aimed to investigate the link between plasma fetuin B and the adipose tissue transcriptome and plasma proteome in a large cohort of humans.
METHODS: Continuous linear regression analysis in R was applied to investigate the link between plasma fetuin B and the adipose tissue transcriptome (n=207) and plasma proteome (n=558) in humans, after adjustment for sex, age and study centre (model 1), model 1 + BMI (model 2) and model 2 + insulin sensitivity (MATSUDA-index) (model 3).
RESULTS: Plasma fetuin B was associated with >100 genes in white adipose tissue, belonging to pathways related to cytokine/chemokine signaling (models 1 and 2) and insulin signaling (all models), and with >146 plasma proteins, involved in pathways related to metabolic processes and insulin signaling (all models).
CONCLUSION: Plasma fetuin B is related to adipose tissue genes and plasma proteins involved in metabolic processes and insulin signaling. Our findings provide evidence for the involvement of white adipose tissue in fetuin B-induced insulin resistance.

Keywords:  Fetuin B; glucose homeostasis; inflammation; insulin resistance; inter-organ crosstalk

DOI:  https://doi.org/10.1210/clinem/dgaf073
Cell Metab. 2025 Feb 03. pii: S1550-4131(24)00493-5. [Epub ahead of print]

Cellular deconstruction of the human skeletal muscle microenvironment identifies an exercise-induced histaminergic crosstalk.

Thibaux Van der Stede, Alexia Van de Loock, Guillermo Turiel, Camilla Hansen, Andrea Tamariz-Ellemann, Max Ullrich, Eline Lievens, Jan Spaas, Nurten Yigit, Jasper Anckaert, Justine Nuytens, Siegrid De Baere, Ruud Van Thienen, Anneleen Weyns, Laurie De Wilde, Peter Van Eenoo, Siska Croubels, John R Halliwill, Pieter Mestdagh, Erik A Richter, Lasse Gliemann, Ylva Hellsten, Jo Vandesompele, Katrien De Bock, Wim Derave.

  Plasticity of skeletal muscle is induced by transcriptional and translational events in response to exercise, leading to multiple health and performance benefits. The skeletal muscle microenvironment harbors myofibers and mononuclear cells, but the rich cell diversity has been largely ignored in relation to exercise adaptations. Using our workflow of transcriptome profiling of individual myofibers, we observed that their exercise-induced transcriptional response was surprisingly modest compared with the bulk muscle tissue response. Through the integration of single-cell data, we identified a small mast cell population likely responsible for histamine secretion during exercise and for targeting myeloid and vascular cells rather than myofibers. We demonstrated through histamine H1 or H2 receptor blockade in humans that this paracrine histamine signaling cascade drives muscle glycogen resynthesis and coordinates the transcriptional exercise response. Altogether, our cellular deconstruction of the human skeletal muscle microenvironment uncovers a histamine-driven intercellular communication network steering muscle recovery and adaptation to exercise.

Keywords:  crosstalk; exercise; glycogen; histamine; macrophages; mast cells; metabolism; muscle fibers; skeletal muscle; transcriptomics

DOI:  https://doi.org/10.1016/j.cmet.2024.12.011
BMC Med. 2025 Feb 04. 23(1): 57

Visceral adipose tissue area and proportion provide distinct reflections of cardiometabolic outcomes in weight loss; pooled analysis of MRI-assessed CENTRAL and DIRECT PLUS dietary randomized controlled trials.

Hadar Klein, Hila Zelicha, Anat Yaskolka Meir, Ehud Rinott, Gal Tsaban, Alon Kaplan, Yoash Chassidim, Yftach Gepner, Matthias Blüher, Uta Ceglarek, Berend Isermann, Michael Stumvoll, Ilan Shelef, Lu Qi, Jun Li, Frank B Hu, Meir J Stampfer, Iris Shai.

   BACKGROUND: Visceral adipose tissue (VAT) is well established as a pathogenic fat depot, whereas superficial subcutaneous adipose tissue (SAT) is associated with either an improved or neutral cardiovascular state. However, it is unclear to what extent VAT area (VATcm2) and its proportion of total abdominal adipose tissue (VAT%) are distinguished in predicting cardiometabolic status and clinical outcomes during weight loss.
METHODS: We integrated magnetic resonance imaging (MRI) measurements of VAT, deep-SAT, and superficial-SAT from two 18-month lifestyle weight loss clinical trials, CENTRAL and DIRECT PLUS (n = 572).
RESULTS: At baseline, the mean VATcm2 was 144.8cm2 and VAT% = 28.2%; over 18 months, participants lost 28cm2 VATcm2 (- 22.5%), and 1.3 VAT% units. Baseline VATcm2 and VAT% were similarly associated with metabolic syndrome, hypertension, and diabetes status, while VAT% better classified hypertriglyceridemia. Conversely, higher VATcm2 was associated with elevated high-sensitivity C-reactive protein (hsCRP), while VAT% was not. After 18 months of lifestyle intervention, both VATcm2 and VAT% loss were significantly associated with decreased triglycerides, HbA1c, ferritin, and liver enzymes, and increased HDL-c levels beyond weight loss (FDR < 0.05). Only VATcm2 loss was correlated with decreased HOMA-IR, chemerin, and leptin levels.
CONCLUSIONS: MRI follow-up of 572 participants over 18 months of weight loss intervention suggests that although increased VATcm2 and VAT% exhibit similar clinical manifestations, it might be preferable to examine VAT% when exploring lipid status, while VATcm2 may better reflect inflammatory and glycemic states.
TRIAL REGISTRATION: CENTRAL (Clinical-trials-identifier: NCT01530724); DIRECT PLUS (Clinical-trials-identifier: NCT03020186).

Keywords:  Diabetes; Metabolic syndrome; Subcutaneous adipose tissue; Visceral adipose tissue; Weight loss

DOI:  https://doi.org/10.1186/s12916-025-03891-9
Exp Physiol. 2025 Feb 03.

The Twin Cycle Hypothesis of type 2 diabetes aetiology: From concept to national NHS programme.

Roy Taylor.

  The development of magnetic resonance methods for quantifying intra-organ metabolites has permitted advances in the understanding of fasting and post-prandial carbohydrate and lipid handling in people with and without type 2 diabetes. Insulin resistance in the liver was shown to be related to excess intra-organ fat and was able to be returned to normal by weight loss. The practical effect of having muscle insulin sensitivity in the lower part of the wide normal range resulted in the obligatory shunting of carbohydrates via de novo lipogenesis into saturated fat. These observations provided the basis for the Twin Cycle Hypothesis of the aetiology of type 2 diabetes. Subsequent studies on people with type 2 diabetes confirmed the postulated pathophysiological abnormalities and demonstrated their reversibility by dietary weight loss of 10-15 kg. Overall, the fundamental understanding of the mechanisms causing type 2 diabetes has bridged physiological and clinical perspectives. Large population-based randomised controlled trials confirmed the practical clinical application of the method of achieving substantial weight loss, and an NHS programme is now in place offering potential remission to people within 6 years of diagnosis.

Keywords:  Twin Cycle Hypothesis; clinical applications; dietary weight loss; type‐2 diabetes

DOI:  https://doi.org/10.1113/EP092009
J Biol Chem. 2025 Feb 04. pii: S0021-9258(25)00099-7. [Epub ahead of print] 108252

THE REGULATION OF CELL METABOLISM BY HYPOXIA AND HYPERCAPNIA.

Ben Reddan, Eoin P Cummins.

Every cell in the body is exposed to a certain level of CO2 and O2. Hypercapnia and hypoxia elicit stress signals to influence cellular metabolism and function. Both conditions exert profound yet distinct effects on metabolic pathways and mitochondrial dynamics, highlighting the need for cells to adapt to changes in the gaseous microenvironment. The interplay between hypercapnia and hypoxia signalling is key for dictating cellular homeostasis as microenvironmental CO2 and O2 levels are inextricably linked. Hypercapnia, characterized by elevated pCO₂, introduces metabolic adaptations within the aerobic metabolism pathways, affecting TCA cycle flux, lipid, and amino acid metabolism, OXPHOS and the ETC. Hypoxia, defined by reduced oxygen availability, necessitates a shift from OXPHOS to anaerobic glycolysis to sustain ATP production, a process orchestrated by the stabilisation of HIF-1α. Given that hypoxia and hypercapnia are present in both physiological and cancerous microenvironments, how might the coexistence of hypercapnia and hypoxia influence metabolic pathways and cellular function in physiological niches and the tumor microenvironment?

DOI: https://doi.org/10.1016/j.jbc.2025.108252
Nat Metab. 2025 Feb 07.

Metabolic Messengers: small extracellular vesicles.

Theresa V Rohm, Karina Cunha E Rocha, Jerrold M Olefsky.

Small extracellular vesicles (sEVs) are signalling molecules and biomarkers of cell status that govern a complex intraorgan and interorgan communication system through their cargo. Initially recognized as a waste disposal mechanism, they have emerged as important metabolic regulators. They transfer biological signals to recipient cells through their cargo content, and microRNAs (miRNAs) often mediate their metabolic effects. This review provides a concise overview of sEVs, specifically in the context of obesity-associated chronic inflammation and related metabolic disorders, describing their role as metabolic messengers, identifying their key sites of action and elucidating their mechanisms. We highlight studies that have shaped our understanding of sEV metabolism, address critical questions for future exploration, discuss the use of miRNAs as disease biomarkers and provide insights into the therapeutic potential of sEVs or specific miRNAs for treating metabolic diseases and related disorders in the future.

DOI: https://doi.org/10.1038/s42255-024-01214-5
Biofabrication. 2025 Feb 05.

Purified adipose tissue-derived extracellular vesicles facilitate adipose organoid vascularization through coordinating adipogenesis and angiogenesis.

Congxiao Zhu, Zonglin Huang, Hongru Zhou, Xuefeng Han, Lei Li, Ningbei Yin.

  One of the major challenges in the way of better fabricating vascularized adipose organoids is the destructive effect of adipogenic differentiation on preformed vasculature, which probably stems from the discrepancy between the in vivo physiological microenvironment and the in vitro culture conditions. As an intrinsic component of adipose tissue (AT), adipose tissue-derived extracellular vesicles (AT-EVs) have demonstrated both adipogenic and angiogenic ability in recent studies. However, whether AT-EVs could be employed to coordinate the angiogenesis and adipogenesis in the vascularization of adipose organoids remains largely unexplored. Herein, we present an efficient method for isolating higher-purity AT-EV preparations from lipoaspirates, and verify the superiority of AT-EV preparations' angiogenic and adipogenic capabilities over those from unpurified lipoaspirates. Next, in the spheroid culture model, it was discovered that the addition of AT-EVs could effectively improve the aggregation through enhancing intercellular adhesion of monoculture spheroids composed of human umbilical vascular endothelial cells (HUVECs), and helped produce vascularized adipose organoids with proper lipolysis and glucose uptake ability in the coculture spheroids comprised of adipose-derived stem cells (ADSCs) and HUVECs. Subsequently, it was observed that AT-EVs could exert a retaining effect on the vasculature of prevascularized coculture spheroids cultured in an adipogenic environment, compared to the reduced vascular networks where AT-EVs were absent. Altogether, these results indicate that AT-EVs, by means of releasing bioactive molecules that emulate the in vivo microenvironment, can modify non-replicative in vitro microenvironments, coordinate in vitro adipogenesis and angiogenesis, and facilitate the fabrication of vascularized adipose organoids.&#xD.

Keywords:  Adipogenesis; Adipose tissue; Adipose tissue-derived extracellular vesicles; Angiogenesis; Lipoaspirate; Vascularized adipose organoids

DOI:  https://doi.org/10.1088/1758-5090/adb2e7
Cell Metab. 2025 Jan 29. pii: S1550-4131(24)00526-6. [Epub ahead of print]

Piezo2 in sensory neurons regulates systemic and adipose tissue metabolism.

Fabian S Passini, Bavat Bornstein, Sarah Rubin, Yael Kuperman, Sharon Krief, Evi Masschelein, Tevie Mehlman, Alexander Brandis, Yoseph Addadi, Shira Huri-Ohev Shalom, Erik A Richter, Tal Yardeni, Amir Tirosh, Katrien De Bock, Elazar Zelzer.

  Systemic metabolism ensures energy homeostasis through inter-organ crosstalk regulating thermogenic adipose tissue. Unlike the well-described inductive role of the sympathetic system, the inhibitory signal ensuring energy preservation remains poorly understood. Here, we show that, via the mechanosensor Piezo2, sensory neurons regulate morphological and physiological properties of brown and beige fat and prevent systemic hypermetabolism. Targeting runt-related transcription factor 3 (Runx3)/parvalbumin (PV) sensory neurons in independent genetic mouse models resulted in a systemic metabolic phenotype characterized by reduced body fat and increased insulin sensitivity and glucose tolerance. Deletion of Piezo2 in PV sensory neurons reproduced the phenotype, protected against high-fat-diet-induced obesity, and caused adipose tissue browning and beiging, likely driven by elevated norepinephrine levels. Finding that brown and beige fat are innervated by Runx3/PV sensory neurons expressing Piezo2 suggests a model in which mechanical signals, sensed by Piezo2 in sensory neurons, protect energy storage and prevent a systemic hypermetabolic phenotype.

Keywords:  PIEZO2; Runx3/PV sensory neurons; body composition; brown and beige adipose tissues; glucose tolerance; insulin sensitivity; mechanosensing; metabolic diseases; norepinephrine; systemic metabolism

DOI:  https://doi.org/10.1016/j.cmet.2024.12.016