bims-mimead 2025-12-21 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–12–21
seven papers selected by
Rachel M. Handy, University of Guelph

Single cell transcriptomics of human weight loss links adipocyte NPY1R to control of lipolysis.
Role of FKBP5 in adipose tissue function: Implications for obesity and insulin sensitivity.
Natural daylight during office hours improves glucose control and whole-body substrate metabolism.
Impact of overweight and obesity on fasting insulin secretion in men and women without diabetes: effect sizes and mechanisms.
Acute Severe Hypoxia Impacts Whole-body Fat Oxidation and Muscle Desaturation Kinetics During Exercise: Intensity Matters.
Bovine adipose mitochondrial adaptation and a potential lactate-ketone toggle in early lactation.
The fate of pyruvate dictates cell growth by modulating cellular redox potential.

Mol Metab. 2025 Dec 16. pii: S2212-8778(25)00212-1. [Epub ahead of print] 102305

Single cell transcriptomics of human weight loss links adipocyte NPY1R to control of lipolysis.

Julius E R Grothen, Jaime M Martinez, Nikos Sidiropoulos, Lucas Massier, Danae Zareifi, Jiawei Zhong, Ida Davidsen, Jette W Platou, Jette Mandelbaum, Pia Rothe, Henning Hvid, Mads Grønborg, Christian Toft Madsen, Jens M Bruun, Mikael Rydén, Niklas Mejhert, Jørn W Helge, Zachary Gerhart-Hines, Thomas Å Pedersen.

BACKGROUND: Combination of increased physical exercise and hypocaloric diet has long been recognized to improve cardiometabolic health and adipose tissue function, including lipid turnover. How such lifestyle interventions mediate benefits at the cellular level remains unknown. Given the critical role of subcutaneous white adipose tissue (scWAT) to systemic metabolic homeostasis, we set out to interrogate how exercise and diet lifestyle intervention impacted scWAT in individuals living with obesity, with a particular focus on lipolytic capacity and cell-specific gene profiling.
METHODS: Single nuclei RNA sequencing (snRNAseq) was performed on cryopreserved scWAT biopsies originally collected before and after lifestyle intervention, involving regular exercise and hypocaloric diet in obese individuals. Findings on regulation of lipolysis in adipocytes were followed up with meta-analysis of clinical studies and pharmacological experiments in mature human adipocytes.
RESULTS: snRNAseq analysis revealed intervention-induced changes in all scWAT cell-types. In adipocytes genes linked to protein and organelle turnover, branch chain amino acid catabolism, and lipolytic control were most significantly regulated. We identified a cell autonomous brake on adipocyte lipolysis via the neuropeptide Y receptor 1 (NPY1R). Expression of adipocyte NPY1R was reduced after weight loss and correlated positively with body fat percentage and body mass index. Findings were confirmed in meta-analysis across 23 studies. Finally, we found a negative correlation between NPY1R and beta-adrenergic-induced lipolysis and that NPY dose-dependently attenuated lipolysis and cAMP-signaling in primary human subcutaneous adipocytes.
CONCLUSIONS: Our work suggests that decreases in adipocyte NPY1R during weight loss boost lipolytic capacity and contribute to improved systemic cardiometabolic health.

DOI: https://doi.org/10.1016/j.molmet.2025.102305
Mol Cell Endocrinol. 2025 Dec 13. pii: S0303-7207(25)00269-2. [Epub ahead of print] 112718

Role of FKBP5 in adipose tissue function: Implications for obesity and insulin sensitivity.

Rutger Laterveer, Susanne Hetty, Argyri Mathioudaki, Martin H Lundqvist, Maria K Svensson, Magnus Sundbom, Petros Katsogiannos, Jan W Eriksson, Maria J Pereira.

  FK506-binding protein 51 (FKBP51, encoded by FKBP5 gene) is a key regulator of glucocorticoid signaling and has been implicated in metabolism and insulin sensitivity, but its specific role in human adipose tissue remains unclear. This study investigated the role of FKBP51 in human adipose tissue and its impact on glucose metabolism and insulin signaling. FKBP5 was measured in paired subcutaneous (SAT) and omental (OAT) adipose tissue samples from 56 subjects with and without obesity, and in SAT from individuals with obesity during weight loss up to 104 weeks post-bariatric surgery. Furthermore, FKBP51 knockdown adipocytes were used to study its effects on insulin signaling and glucose uptake. FKBP5 gene expression, but not protein expression, was significantly lower in obese individuals in both SAT and OAT compared to lean and overweight subjects, and it inversely correlated with insulin resistance measured by homeostatic model assessment of insulin resistance (HOMA-IR). After bariatric surgery, FKBP5 expression in SAT increased to levels similar to those in non-obese controls. Knockdown of FKBP5 in human adipocytes reduced GLUT1 gene expression and insulin-stimulated AKT S473 phosphorylation, yet maximal insulin-stimulated glucose uptake rate remained unchanged. Our findings suggest that FKBP5 levels in adipose tissue are reduced in obesity, and this decrease impairs insulin signaling in adipocytes without altering maximal glucose capacity, indicating a limited effect on glucose uptake under the tested conditions.

Keywords:  FKBP5; Obesity; adiposity; glucocorticoids; metabolism; weight loss

DOI:  https://doi.org/10.1016/j.mce.2025.112718
Cell Metab. 2025 Dec 18. pii: S1550-4131(25)00490-5. [Epub ahead of print]

Natural daylight during office hours improves glucose control and whole-body substrate metabolism.

Jan-Frieder Harmsen, Ivo Habets, Andrew D Biancolin, Agata Lesniewska, Nicholas E Phillips, Loic Metz, Juan Sanchez-Avila, Marit Kotte, Merel Timmermans, Dzhansel Hashim, Soraya S de Kam, Gert Schaart, Johanna A Jörgensen, Anne Gemmink, Esther Moonen-Kornips, Daniel Doligkeit, Tineke van de Weijer, Mijke Buitinga, Florian Haans, Rebecca De Lorenzo, Hannah Pallubinsky, Marijke C M Gordijn, Tinh-Hai Collet, Achim Kramer, Patrick Schrauwen, Charna Dibner, Joris Hoeks.

  Because 80%-90% of our time is spent indoors and daylight is the main synchronizer of the central biological clock, the chronic lack of daylight is increasingly considered as a risk factor for metabolic diseases, such as type 2 diabetes. In a randomized crossover design (NCT05263232), 13 individuals with type 2 diabetes were exposed to natural daylight facilitated through windows vs. constant artificial lighting during office hours for 4.5 consecutive days. Continuous glucose monitoring revealed that participants spent more time in the normal glucose range, and whole-body substrate metabolism shifted toward a greater reliance on fat oxidation during daylight. Primary myotubes cultured from skeletal muscle biopsies displayed a phase advance after daylight exposure. Multi-omic analyses revealed daylight-induced differences in serum metabolites, lipids, and monocyte transcripts. Our findings suggest that natural daylight exposure has a positive metabolic impact on individuals with type 2 diabetes and could support the treatment of metabolic diseases.

Keywords:  artificial light; circadian clocks; daylight; glucose control; melatonin; multi-omics; skeletal muscle; type 2 diabetes

DOI:  https://doi.org/10.1016/j.cmet.2025.11.006
Diabetologia. 2025 Dec 18.

Impact of overweight and obesity on fasting insulin secretion in men and women without diabetes: effect sizes and mechanisms.

Martina Chiriacò, Domenico Tricò, John R Petrie, Rafael Gabriel, Amalia Gastaldelli, John Nolan, Nebojsa Lalic, Geltrude Mingrone, Andrea Mari, Andrea Natali.

   AIMS/HYPOTHESIS: Fasting hyperinsulinaemia is a key feature of obesity and is implicated in diabetes progression. However, the following aspects of insulin secretion remain unclear: (1) which index of obesity is most important; (2) what is the shape of the dose-response curve between obesity and insulin secretion; (3) what physiological mechanisms sustain insulin hypersecretion; (4) what are the underlying causes; and (5) whether sex-related differences exist.
METHODS: We analysed data from 1250 healthy participants (547 men, 703 women) of the EGIR-RISC cohort followed up for 3.5 years, with age 30-60 years and BMI 18.5-40.0 kg/m2. Assessments included body composition, insulin secretion, beta cell function modelling from an OGTT and clamp-derived insulin sensitivity. Endogenous glucose production (EGP) was measured in a subset of 368 participants. Multivariable regression models and stratifications for BMI, body fat per cent, WHR and fat mass were applied to evaluate the effect of obesity on insulin secretion and beta cell function.
RESULTS: The impact of obesity on fasting insulin secretion (FIS) was continuous across the full spectrum of BMI and WHR values and was greater in men than women. Among adiposity indices, fat mass (standardised β coefficient [Stβ] 0.27, p<0.0001) and waist circumference (Stβ 0.21, p<0.0001) were the strongest predictors of FIS. Insulin secretion increased 2.4-fold across BMI deciles, and adiposity-associated insulin hypersecretion appeared to be driven by the combination of hyperglycaemia and an increase in a specific beta cell function variable (insulin secretion rate at 5 mmol/l glucose [ISR@5]). In the follow-up cohort, weight gain (mean ± SD ∆ weight=+5.1 ± 3.8 kg) was associated with an increase in FIS and fasting glucose (+0.20 ± 0.63 mmol/l, p<0.03), whereas weight loss (-4.7 ± 2.8 kg) led to a reduction in FIS and fasting glucose (+0.06 ± 0.55 mmol/l, p<0.006). ISR@5 declined in both weight losers and those with stable weight (-0.17 ± 1.9 and -0.16 ± 1.0 U/h, respectively; p<0.002 for both) but not in weight gainers (-0.06 ± 1.1 U/h). Peripheral insulin resistance, plasma NEFA and leptin accounted for only part of obesity's effect on insulin secretion. Subset analysis of fasting and clamp EGP data suggested a rightwards shift in the dose-response curve across fat mass quintiles, indicating progressive hepatic glucose overproduction despite a preserved hepatic insulin response.
CONCLUSIONS/INTERPRETATION: The effect of body mass on insulin secretion is continuous, more pronounced in men, driven by fat mass and waist, sustained by hyperglycaemia and by an upregulation of beta cell insulin secretion and is only partially explained by typical hormonal and metabolic consequences of obesity. We suggest that hepatic glucose overproduction contributes to the fasting hyperinsulinaemia observed in individuals with obesity.

Keywords:  Adiposity; Beta cell function; Insulin; Obesity

DOI:  https://doi.org/10.1007/s00125-025-06643-9
Med Sci Sports Exerc. 2025 Dec 16.

Acute Severe Hypoxia Impacts Whole-body Fat Oxidation and Muscle Desaturation Kinetics During Exercise: Intensity Matters.

Johan Garcia, Paul Allender, Davide Malatesta.

   PURPOSE: The aim of this study was to investigate the effects of acute exposure to severe normobaric hypoxia vs. normoxia on whole-body fat oxidation and muscle desaturation kinetics over a wide range of identical relative and absolute intensities.
METHODS: Thirteen active men performed i) two maximal incremental tests to determine maximal oxygen uptake (V̇O2peak) in normobaric hypoxia [FiO2=13.2%, 3740 m] and normoxia [FiO2=20.7%, 375 m], and ii) two submaximal graded tests, after overnight fasting, to assess fat oxidation and muscle desaturation kinetics as a function of exercise intensity in each condition. Fat oxidation kinetics were measured using indirect calorimetry and characterized using a sinusoidal model. Vastus lateralis desaturation kinetics were measured using near-infrared spectroscopy and the tissue saturation index (TSI), and modeled through a double linear model.
RESULTS: Compared with the relative (%V̇O2peak) or absolute (%V̇O2peak,nomoxia) exercise intensity, absolute fat oxidation rates (g·min-1) were significantly higher in hypoxia than in normoxia, ranging from 55 to 85 %V̇O2peak (p≤0.023) and from 35 to 60 %V̇O2peak,normoxia (p≤0.027), respectively. The TSI was lower in hypoxia than in normoxia when compared at relative or absolute exercise intensity (p≤0.004), and muscle desaturation reached a maximal level only in hypoxia at high exercise intensity (p≤0.014).
CONCLUSIONS: Compared with normoxia, acute exposure to severe normobaric hypoxia enhanced fat oxidation pathways during moderate-to-high relative and low-to-moderate absolute exercise intensities while allowing greater and maximal muscle desaturation. These findings highlight the relevance of considering both relative and absolute intensities when comparing fat oxidation during exercise in hypoxia and normoxia and suggest that maximal muscle desaturation is not a limiting factor for fat oxidation during exercise.

Keywords:  ; EXERCISE INTENSITY; HYPOXIC EXPOSURE; MAXIMAL FAT OXIDATION; SUBSTRATE OXIDATION; TISSUE SATURATION INDEX

DOI:  https://doi.org/10.1249/MSS.0000000000003919
Front Vet Sci. 2025 ;12 1676955

Bovine adipose mitochondrial adaptation and a potential lactate-ketone toggle in early lactation.

Nial J O'Boyle, Miguel Chirivi, Ursula Abou-Rjeileh, David Salcedo-Tacuma, José M Dos Santos Neto, Crystal Prom, Jair Parales-Girón, Adam L Lock, Reinhard Stöger, Lisa Chakrabarti, G Andres Contreras.

  The periparturient period creates an intense energy demand due to the onset of lactation, which requires substantial glucose for milk synthesis, particularly in high producing cows, contributing to a high incidence of postpartum metabolic disease. We explored the transcriptomic adaptation of subcutaneous adipose tissue (AT), with a specific focus on metabolic gene networks and the mitochondrial component. Mitochondria coordinate cellular energy dynamics by linking the oxidation of nutrients to ATP synthesis via oxidative phosphorylation (OXPHOS). However, their role in postpartum metabolic disease is not clear. We therefore re-analysed a longitudinal RNA-seq dataset of subcutaneous AT from 12 healthy multiparous Holstein cows, sampled pre-calving and at two early-lactation time-points, to explore mitochondrial pathways. This analysis revealed downregulation of differentially expressed genes (DEGs), encoding components of the electron transport system and OXPHOS, in the postpartum phase, concurrent with a shift to DEGs associated with glycolysis. Given the observed glycolytic shift, an analysis of plasma lactate during the periparturient period was undertaken, to explore how this glycolysis-derived substrate fluctuates in this altered metabolic state. A postpartum decline in plasma lactate, alongside rising β-hydroxybutyrate, was further demonstrated in clinical ketotic cows, revealing a potential metabolic toggle between lactate and ketones; aligning with the concept that fuel sources will alter depending on redox and metabolic conditions. This supports the emerging view that ketones are not merely pathological markers but may serve as adaptive metabolic signals, warranting further investigation into their role in dairy cow metabolism. Further understanding of how mitochondria function during this energy-intensive postpartum phase of the dairy cow, may help elucidate how adipose tissue contributes to metabolic resilience or perturbation during early lactation.

Keywords:  adipose; bovine; ketone; lactate; mitochondria; peripartum; transcriptomics

DOI:  https://doi.org/10.3389/fvets.2025.1676955
Elife. 2025 Dec 16. pii: RP103705. [Epub ahead of print]13

The fate of pyruvate dictates cell growth by modulating cellular redox potential.

Ashish G Toshniwal, Geanette Lam, Alex J Bott, Ahmad A Cluntun, Rachel Skabelund, Hyuck-Jin Nam, Dona R Wisidagama, Carl S Thummel, Jared Rutter.

  Pyruvate occupies a central node in carbohydrate metabolism such that how it is produced and consumed can optimize a cell for energy production or biosynthetic capacity. This has been primarily studied in proliferating cells, but observations from the post-mitotic Drosophila fat body led us to hypothesize that pyruvate fate might dictate the rapid cell growth observed in this organ during development. Indeed, we demonstrate that augmented mitochondrial pyruvate import prevented cell growth in fat body cells in vivo as well as in cultured mammalian hepatocytes and human hepatocyte-derived cells in vitro. We hypothesize that this effect on cell size was caused by an increase in the NADH/NAD+ ratio, which rewired metabolism toward gluconeogenesis and suppressed the biomass-supporting glycolytic pathway. Amino acid synthesis was decreased, and the resulting loss of protein synthesis prevented cell growth. Surprisingly, this all occurred in the face of activated pro-growth signaling pathways, including mTORC1, Myc, and PI3K/Akt. These observations highlight the evolutionarily conserved role of pyruvate metabolism in setting the balance between energy extraction and biomass production in specialized post-mitotic cells.

Keywords:  D. melanogaster; cell biology; cell growth; genetics; hepatocytes; human; pyruvate metabolism; redox state; translation

DOI:  https://doi.org/10.7554/eLife.103705