bims-mimead 2025-06-01 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–06–01
thirteen papers selected by
Rachel M. Handy, University of Guelph

Personalized molecular signatures of insulin resistance and type 2 diabetes.
The skeletal muscle response to high-intensity training assessed by single-nucleus RNA-sequencing is blunted in individuals with type 2 diabetes.
PI3K in the VMH Attenuates Diet-Induced Obesity and Participates in the Effects of E2 on Energy Expenditure in Mice.
Changes in Inflammatory Markers Following Bariatric Surgery and the Impact of the Surgical Procedure: A 12-Month Longitudinal Study.
Hepatic steatosis is associated with impaired hepatic glucose uptake under hyperglycemic conditions, a dynamic whole-body 18F-FDG PET approach.
The potential role of mitochondria in age-related health benefits conferred by moderate hypoxia.
Molecular landscape of sex- and modality-specific exercise adaptation in human skeletal muscle through large-scale multi-omics integration.
Optimizing Measures of Insulin-Regulated Lipolysis in Humans.
Genetic depletion of adipose-derived Isthmin-1 causes hepatic steatosis.
Antioxidant supplementation blunts the proteome response to 3 weeks of sprint interval training preferentially in human type 2 muscle fibres.
A dietary intervention following incretin analog treatment restores adipose tissue functions in diet-induced obese mice.
CoQ imbalance drives reverse electron transport to disrupt liver metabolism.
Modeling Hepatic Glucose Tracer Kinetics from Isotope Dilution Technique and Deuterium Metabolic Imaging in Post-Bariatric-Surgery and Non-Operated Individuals.

Cell. 2025 May 21. pii: S0092-8674(25)00515-X. [Epub ahead of print]

Personalized molecular signatures of insulin resistance and type 2 diabetes.

Jeppe Kjærgaard, Ben Stocks, John Henderson, Jordana B Freemantle, David Rizo-Roca, Michele Puglia, Maria Madrazo Montoya, Daniel Andersson, Jesper Bäckdahl, Daniel Eriksson-Hogling, Jacob V Stidsen, Michael Wierer, Simon Rasmussen, Kei Sakamoto, Kurt Højlund, Mikael Rydén, Juleen R Zierath, Anna Krook, Atul S Deshmukh.

  Insulin resistance is a hallmark of type 2 diabetes, which is a highly heterogeneous disease with diverse pathology. Understanding the molecular signatures of insulin resistance and its association with individual phenotypic traits is crucial for advancing precision medicine in type 2 diabetes. Utilizing cutting-edge proteomics technology, we mapped the proteome and phosphoproteome of skeletal muscle from >120 men and women with normal glucose tolerance or type 2 diabetes, with varying degrees of insulin sensitivity. Leveraging deep in vivo phenotyping, we reveal that fasting proteome and phosphoproteome signatures strongly predict insulin sensitivity. Furthermore, the insulin-stimulated phosphoproteome revealed both dysregulated and preserved signaling nodes-even in individuals with severe insulin resistance. While substantial sex-specific differences in the proteome and phosphoproteome were identified, molecular signatures of insulin resistance remained largely similar between men and women. These findings emphasize the necessity of incorporating disease heterogeneity into type 2 diabetes care strategies.

Keywords:  disease heterogeneity; glucose metabolism; phosphoproteomics; sex differences; signaling; skeletal muscle

DOI:  https://doi.org/10.1016/j.cell.2025.05.005
J Physiol. 2025 May 25.

The skeletal muscle response to high-intensity training assessed by single-nucleus RNA-sequencing is blunted in individuals with type 2 diabetes.

Maria Hansen, Julius E R Grothen, Anders Karlsen, Jaime M Martinez, Nikos Sidiropoulos, Jørn W Helge, Thomas Å Pedersen, Flemming Dela.

  Training can improve insulin sensitivity in individuals with type 2 diabetes, but a clear understanding of the mechanisms remains elusive. To further our knowledge in this area, we aimed to examine the effect of type 2 diabetes and of high-intensity interval training (HIIT) on the nuclear transcriptional response in skeletal muscle. We performed single-nucleus RNA-sequencing (snRNA-seq) and immunofluorescence analysis on muscle biopsies from the trained and the untrained legs of participants with and without type 2 diabetes, after 2 weeks of one-legged HIIT on a cycle ergometer. Surprisingly, the type 2 diabetes condition only seemed to have a minor effect on transcriptional activity in myonuclei related to major metabolic pathways when comparing the untrained legs. However, while in particular the type IIA myonuclei in the control group displayed a considerable metabolic response to HIIT, with increases in genes related to glycogen breakdown and glycolysis primarily in the type IIA myonuclei of the trained leg, this response was blunted in the diabetes group, despite a marked increase in glucose clearance in both groups. Additionally, we observed that fibre type distribution assessed by immunofluorescence significantly correlated with the proportion of myonuclei in the snRNA-seq analysis. In conclusion, the type 2 diabetes condition blunts the metabolic transcriptional response to HIIT in the type IIA myonuclei without affecting the improvement in insulin sensitivity. Additionally, our results indicate that snRNA-seq can be used as a surrogate marker for fibre type distribution in sedentary middle-aged adults. KEY POINTS: The study utilized single-nucleus RNA sequencing (snRNA-seq) to analyse 38 skeletal muscle biopsies, revealing distinct transcriptional profiles in myonuclei from individuals with and without type 2 diabetes (T2D) after 2 weeks of HIIT. snRNA-seq identified significant differences in gene expression, with 14 differentially expressed genes (DEGs) in type IIA myonuclei of the control group, specifically related to glycogen breakdown and glycolysis, which were blunted in the T2D group. In the control group, HIIT induced a substantial transcriptional response in type IIA myonuclei, enhancing metabolic pathways associated with insulin sensitivity, while the T2D group showed minimal transcriptional changes despite improved insulin sensitivity. The T2D group exhibited a blunted response in metabolic gene expression, indicating that the training effect on muscle adaptation was significantly impaired compared to healthy controls. Overall, the findings highlight the differential impact of HIIT on muscle metabolism, emphasizing the need for tailored exercise interventions for individuals with T2D.

Keywords:  HIIT; glucose metabolism; snRNA‐seq; training; type 2 diabetes

DOI:  https://doi.org/10.1113/JP288368
J Endocr Soc. 2025 Jul;9(7): bvaf080

PI3K in the VMH Attenuates Diet-Induced Obesity and Participates in the Effects of E2 on Energy Expenditure in Mice.

Aline Alves de Jesus, Raoni Conceição Dos-Santos, Isabelle Rodrigues-Santos, Hellen Veida-Silva, Milene Mantovani Mata, Rafaella Eduarda Volpi, Gabriel Henrique Marques Gonçalves, Luiz Carlos Navegantes, Carol Fuzeti Elias, José Antunes-Rodrigues, Lucila Leico Kagohara Elias.

  Obesity is associated with the development of several illnesses, such as diabetes mellitus, cancer, and cardiovascular diseases. Elucidating the mechanisms of body weight control is important for the development of effective therapeutic strategies against obesity. In response to the action of hormones such as leptin and 17β-estradiol (E2), the ventromedial hypothalamus (VMH) plays an essential role in protection against diet-induced obesity (DIO) through the regulation of food intake and energy expenditure. However, little is known about the intracellular mechanisms involved in these effects. To assess the role of phosphoinositide 3-kinase (PI3K) signaling in neurons that express steroidogenic factor 1 (SF1) in the VMH in energy homeostasis, we used Cre-lox technology to generate male and female mice with specific disruption of the catalytic subunit P110α in SF1 neurons in the VMH. We demonstrated that the conditional knockout of P110α in SF1 neurons in the VMH affects body weight, energy expenditure, and thermogenesis in animals fed a high-fat diet. In addition, we demonstrated that female mice with genetic disruption of PI3K activity in VMH neurons exhibited greater weight gain than their male counterparts. Furthermore, inhibition of PI3K activity in the VMH partially blocked the effects of E2 on body weight regulation, stimulation of energy expenditure, and thermogenesis in female ovariectomized mice. Collectively, our results indicate that PI3K activity in VMH neurons plays a relevant role in protecting against DIO and contributes to the effects of estradiol on energy expenditure in females.

Keywords:  17β estradiol; PI3K; SF1; VMH; diet-induced obesity; energy expenditure

DOI:  https://doi.org/10.1210/jendso/bvaf080
Obes Surg. 2025 May 27.

Changes in Inflammatory Markers Following Bariatric Surgery and the Impact of the Surgical Procedure: A 12-Month Longitudinal Study.

Rasmus Tanderup Jensen, Anne Cathrine Baun Thuesen, Yun Huang, Sara Elizabeth Stinson, Helene Bæk Juel, Sten Madsbad, Flemming Bendtsen, Torben Hansen, Julie Steen Pedersen.

BACKGROUND: Obesity is associated with an increased risk of cardiometabolic morbidity and mortality, which may be attributable to systemic low-grade inflammation. The impact of bariatric surgery-induced weight loss on low-grade inflammation has not yet thoroughly been described. We investigated the effect of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) on the plasma levels of cytokines, chemokines, and cytokine receptors prior to surgery (baseline), and then three and 12 months after surgery.
METHODS: We recruited 68 individuals (41 females, 27 males) with severe obesity (42.84 ± 6.28) who had been referred for bariatric surgery (RYGB: n = 29, SG: n = 39). Blood samples were collected after an overnight fast at baseline (immediately before surgery), 3 and 12 months after surgery. Eleven patients without obesity or cardiometabolic disease served as controls at baseline. Ninety-two plasma proteins were measured using an Olink Target 96 inflammation panel.
RESULTS: We used a linear mixed model to test differences in inflammatory markers at baseline, across time points and between groups. At baseline, 36 cytokines were found to be differentially expressed between the bariatric surgery patients and controls. Of these cytokines, 13 had significantly decreased three months after bariatric surgery and 27 had significantly decreased 12 months after surgery, compared with baseline. Two cytokines (CCL25 and CCL28) increased markedly after 12 months. Only one cytokine (CCL25) was significantly different between the procedures performed, where it increased in the RYGB group 12 months after surgery.
CONCLUSION: Individuals with severe obesity have increased expression of plasma inflammatory cytokines compared to controls, but low-grade inflammation improves following bariatric surgery, regardless of whether it is RYGB or SG.

DOI: https://doi.org/10.1007/s11695-024-07629-z
Diabetes Res Clin Pract. 2025 May 28. pii: S0168-8227(25)00302-X. [Epub ahead of print] 112288

Hepatic steatosis is associated with impaired hepatic glucose uptake under hyperglycemic conditions, a dynamic whole-body 18F-FDG PET approach.

Jeremy Basset-Sagarminaga, Tineke van de Weijer, Evi Koene, Yvonne M H Op den Kamp-Bruls, Esther Phielix, Kim Brouwers, Sam Springer, Edvin Johansson, Lars Johansson, Fotis Kotasidis, Paul Deak, Joachim E Wildberger, Roel Wierts, Iina Laitinen, Patricia Iozzo, Patrick Schrauwen, Vera B Schrauwen-Hinderling.

   OBJECTIVE: Accumulation of fat in the liver is associated with hepatic insulin resistance, as evidenced by a reduced insulin-induced suppression of endogenous glucose production (EGP). However, suppression of EGP has been proposed to be mainly a reflection of indirect insulin action.Hepatic glucose uptake in the postprandial state is another aspect of hepatic insulin sensitivity, which is seldom investigated. Here we sought to examine if hepatic steatosis is associated with a reduced hepatic glucose uptake under conditions of hyperglycemia and hyperinsulinemia.
METHODS: In this cross-sectional study, 15 participants with a range of liver fat content (0.9-18 %) as assessed by 1H-MRSwere recruited. Whole-body insulin sensitivity and insulin-induced suppression of EGP were measured by a two-step euglycemic-hyperinsulinemic clamp. A hyperglycemic-hyperinsulinemic clamp was used to measure hepatic and tissue-specific glucose uptake using a dynamic whole-body 18F-FDG PET protocol.
RESULTS: Under conditions of hyperglycemic-hyperinsulinemia, hepatic glucose uptake correlated strongly and inversely with liver fat content (r = -0.756, p < 0.001). Hepatic glucose uptake also correlated with insulin-stimulated EGP suppression (r = 0.616, p = 0.015). Adipose tissue insulin sensitivity was negatively associated with liver fat content and positively with hepatic, skeletal muscle, and adipose tissue glucose uptake.
CONCLUSION: We show that another aspect of hepatic insulin resistance, namely the ability of insulin to stimulate hepatic glucose uptake under hyperglycemic conditions, is negatively associated with hepatic fat content. This suggests that hepatic glucose uptake is another factor that may be important in Metabolic dysfunction Associated Steatotic Liver Disease (MASLD) and the risk for type 2 diabetes, and needs further investigation.

Keywords:  18F-FDG PET imaging; Adipose tissue insulin sensitivity; Endogenous glucose production (EGP); Hepatic fat content; Hepatic glucose uptake; Hepatic insulin resistance; Hyperglycemic-hyperinsulinemic clamp; Metabolic dysfunction Associated Steatotic Liver Disease (MASLD); Tissue-specific glucose uptake; Type 2 diabetes risk

DOI:  https://doi.org/10.1016/j.diabres.2025.112288
Gerontology. 2025 May 26. 1-14

The potential role of mitochondria in age-related health benefits conferred by moderate hypoxia.

Johannes Burtscher, Kamilla Woznica Miskowiak, Katharina Hüfner, Hannelore Ehrenreich, Martin Kopp.

Background Mitochondrial integrity and efficiency deteriorate with age and are linked to cellular senescence. Mitochondria are highly responsive to reduced oxygen availability (hypoxia), which for example occurs when exposed to altitude. We hypothesize that mitochondria are involved in the observed health benefits at moderate altitude. Because the experimental evidence on mitochondrial changes at moderate altitude is limited, we also evaluate dose-response associations of oxygen transport and mitochondrial functions derived from measurements at normoxia and severe hypoxia. Summary We summarize the effects of environmental oxygen availability and changes in cellular oxygen demand/supply on mitochondrial functions and assess, how this may influence aging. Hypotheses are presented how mild hypoxia at moderate altitude (1000 - 2500 m) could improve mitochondrial function and possibly explain the reported lower levels of mortality from several age-related diseases. Key messages It is unknown, whether continuous or intermittent types of hypoxia exposure are more effective in improving mitochondrial functions and promoting healthy aging. The combination of tissue-specific oxygen demand (for example during physical exercise) with mild reductions of ambient oxygen availability may enable the reported health benefits associated with moderate altitude residence.

DOI: https://doi.org/10.1159/000546478
Cell Rep. 2025 May 28. pii: S2211-1247(25)00521-2. [Epub ahead of print]44(6): 115750

Molecular landscape of sex- and modality-specific exercise adaptation in human skeletal muscle through large-scale multi-omics integration.

Macsue Jacques, Shanie Landen, Adam P Sharples, Andrew Garnham, Ralf Schittenhelm, Joel Steele, Aino Heikkinen, Elina Sillanpää, Miina Ollikainen, James Broatch, Navabeh Zarekookandeh, Ola Hanson, Ola Ekström, Olof Asplund, Séverine Lamon, Sarah E Alexander, Cassandra Smith, Carlie Bauer, Mary N Woessner, Itamar Levinger, Andrew E Teschendorff, Linn Gillberg, Ida Blom, Jørn Wulff Helge, Nicholas R Harvey, Larisa M Haupt, Lyn R Griffiths, Atul S Deshmukh, Kirsi H Pietiläinen, Päivi Piirilä, Robert A E Seaborne, Marie Klevjer, Anja Bye, Ulrik Wisløff, Bernadette Jones-Freeman, Nir Eynon.

  We investigated the molecular mechanisms of exercise adaptations in human muscle by integrating genome, methylome, transcriptome, and proteome data from over 1,000 participants (2,340 muscle samples). We identified distinctive signatures associated with maximal oxygen consumption (VO2max), and multi-omics integration uncovered five key genes as robust exercise markers across layers, with transcription factors functioning as activators, synergizing with DNA methylation to regulate gene expression. Minimal sex differences were observed, while modality-specific analysis highlighted distinct pathways for aerobic and resistance exercise, contrasting with muscle disuse patterns. Finally, we created a webtool, OMAx, featuring our individual omics and integration analysis. These findings provide a comprehensive multi-omics framework for understanding exercise-induced molecular adaptations, offering insights into muscle health, cardiorespiratory fitness, and their roles in aging and disease prevention.

Keywords:  CP: Metabolism; DNA methylation; Multi Omics; VO(2 max); epigenetics; exercise; gene expression; proteomic; skeletal muscle; transcriptomic

DOI:  https://doi.org/10.1016/j.celrep.2025.115750
Am J Physiol Endocrinol Metab. 2025 May 24.

Optimizing Measures of Insulin-Regulated Lipolysis in Humans.

Yilin Song, Kelli A Lytle, Michael D Jensen.

  The goals of these studies were to test for errors in measuring the insulin concentration resulting in 50% suppression from baseline free fatty acid palmitate rate of appearance (FFApalmitate IC50) when measured with a two-step, euglycemic, hyperinsulinemic clamp (EHC). We also determined the reproducibility of FFApalmitate IC50 in weight stable adults and assessed the magnitude of the change in FFApalmitate IC50in response to weight loss. To accomplish this we analyzed data from 46 studies of 27 volunteers enrolled in two ongoing clinical research studies that included weight loss by lifestyle intervention or bariatric surgery. FFA palmitate kinetics were measure using an intravenous infusion of [U-13C]palmitate under basal (fasting) and a two-step EHC. For 40 of 46 studies, calculating FFApalmitate IC50 using data from both steps of a EHC overestimated FFApalmitate IC50 compared with the first (low) dose, which suppressed palmitate Ra by > 50%. FFApalmitate IC50 did not change and was reproducible after 4 months (r = 0.70, P = 0.02) for 10 weight stable volunteers. Weight loss by either intervention reduced FFApalmitate IC50 and the reduction was correlated with fat loss and change in adipocyte size. We conclude that, although a 2-step EHC (with an initial low dose) allows accurate assessment of FFApalmitate IC50, careful scrutiny of each set of study data is needed. These data will improve the ability of investigators to design studies that can detect small, but important differences or changes in adipose tissue insulin action.

Keywords:  euglycemic hyperinsulinemic clamp; free fatty acid; lipolysis; weight loss

DOI:  https://doi.org/10.1152/ajpendo.00078.2025
Mol Metab. 2025 May 26. pii: S2212-8778(25)00079-1. [Epub ahead of print] 102172

Genetic depletion of adipose-derived Isthmin-1 causes hepatic steatosis.

Saranya C Reghupaty, Laetitia Coassolo, Meng Zhao, Ramya Lakshmi Narasimhan, Aayan Patel, Jameel Lone, Ewa Bielczyk-Maczynska, Niels Banhos Danneskiold-Samsoee, Taylor Brown, Zewen Jiang, Veronica L Li, Katrin J Svensson.

   OBJECTIVE: Adipose tissue plays a critical role in obesity, as its dysfunction can impair lipid homeostasis and result in lipid overflow and ectopic lipid deposition in the liver. We previously demonstrated that Isthmin-1 (Ism1) regulates glucose uptake into the adipose tissue and suppresses hepatic steatosis, but the role of adipose-derived Ism1 is unknown. Here, we investigate the role of adipose-derived Ism1 in metabolic health and its impact on hepatic steatosis and lipid metabolism.
METHODS: In this study, we employed both a genetic knockout approach, selectively deleting Ism1 in adipose tissue of mice (AdipoQ-Ism1-KO), and a pharmacological approach by administering recombinant Ism1 protein to mice. These mice were subjected to a high fat-high fructose diet to simulate conditions that promote Metabolic-dysfunction Associated Steatotic Liver Disease (MASLD).
RESULTS: AdipoQ-Ism1-KO are of normal weight, but prone to severe hepatic steatosis in response to high fat-high fructose feeding. Lipidomic profiling through untargeted analyses in both gain-of-function and loss-of-function models was used to assess changes in hepatic lipid homeostasis. These results provide in vivo genetic support for the role of Ism1 as a regulator of the adipose-hepatic axis.
CONCLUSIONS: Collectively, these data demonstrate that loss of adipose-derived Ism1 disrupts lipid homeostasis and accelerates the development of hepatic steatosis. This study provides a genetic basis for Ism1's involvement in metabolic regulation, suggesting a potential therapeutic target for treating metabolic disorders.

Keywords:  Adiposity; Isthmin-1 (Ism1); Lipidomics; Metabolic-dysfunction Associated Steatohepatitis (MASH); Metabolic-dysfunction Associated Steatotic Liver Disease (MASLD)

DOI:  https://doi.org/10.1016/j.molmet.2025.102172
J Physiol. 2025 May 28.

Antioxidant supplementation blunts the proteome response to 3 weeks of sprint interval training preferentially in human type 2 muscle fibres.

Victoria L Wyckelsma, Marta Murgia, Sigitas Kamandulis, Stefano Gastaldello, Marius Brazaitis, Audrius Snieckus, Nerijus Eimantas, Mati Pääsuke, Sebastian Edman, William Apro, Daniel C Andersson, Håkan Westerblad, Tomas Venckunas.

  Sprint interval training (SIT) is a time-efficient type of endurance training that involves large type 2 muscle fibre recruitment. Effective antioxidant supplementation may mitigate positive training adaptations by limiting the oxidant challenge. Our aim was to test whether SIT affects type 2 more than type 1 muscle fibres, and whether the muscular training response is mitigated by antioxidant treatment. Young men performed three weekly SIT sessions (4-6 × 30 s all-out cycling) for 3 weeks while treated with antioxidants (vitamin C, 1 g day-1; vitamin E, 235 mg day-1) or placebo. Vastus lateralis biopsies were taken to measure (i) activation of genes for reactive oxygen/nitrogen species (ROS) sensors and inflammatory mediators with quantitative RT-PCR and (ii) fibre type-specific proteome adaptations using MS-based proteomics. Vitamin treatment decreased the upregulation of genes for ROS sensors and inflammatory regulators during the first SIT session. The 3 weeks of SIT caused generally larger proteome adaptations in type 2 than in type 1 fibres, and this included larger increases in abundance of proteins involved in mitochondrial energy production. Vitamin treatment blunted the SIT-induced proteome adaptations, whereas it did not affect the training-induced improvement in maximal cycling performance. In conclusion, (i) the large type 2 fibre recruitment and resulting proteome adaptations are instrumental to the effectiveness of SIT and (ii) antioxidant supplementation counteracts positive muscular adaptations to SIT, which would blunt any improvement in submaximal endurance performance, whereas it does not affect the improvement in maximal cycling performance, where O2 delivery to muscle would be limiting. KEY POINTS: Sprint interval training (SIT) is a time-efficient type of endurance training that involves large recruitment of fast-twitch muscle fibres. Treatment with antioxidants may mitigate the positive effects of endurance training. Fibre type-specific proteomics performed on muscle biopsies obtained from young men before and after 3 weeks of SIT showed larger training effects in fast- than in slow-twitch fibres. Antioxidant treatment in the form of vitamin C and E pills counteracted the positive muscular adaptations to the 3 weeks of SIT. These results increase our understanding of why SIT is an effective endurance training regime and provide further evidence against the common belief that antioxidant supplements are beneficial in a physical exercise context.

Keywords:  antioxidants; muscle fibre types; proteomics; reactive oxygen/nitrogen species; skeletal muscle; sprint interval training

DOI:  https://doi.org/10.1113/JP288638
Am J Physiol Endocrinol Metab. 2025 May 28.

A dietary intervention following incretin analog treatment restores adipose tissue functions in diet-induced obese mice.

Joke Seuntjens, Jente De Gols, Bethan K Davies, Fien Van Looy, Ingrid Stockmans, Karen Moermans, Geert Carmeliet, Christophe Matthys, Roman Vangoitsenhoven, Bart Van Der Schueren, Steve Stegen, Mitsugu Shimobayashi.

  Obesity is associated with the development of type 2 diabetes. In recent years, incretin analogs are prescribed at a high rate for treatment of obesity and diabetes due to their potent effects on lowering bodyweight and improving glucose homeostasis. However, many patients do not stay on incretin analog therapy and thereby rapidly regain bodyweight. The non-compliance of patients to incretin analog therapy is not only due to drug shortage but also insufficient knowledge on the long-term effects of the therapy. To address this knowledge gap, we examined the effects of incretin analog treatment and withdrawal on adipose tissue functions in high fat diet (HFD)-induced obese mice. Our transcriptome data suggest that incretin analog treatment restored most of obesity-mediated deregulated gene expression in adipose tissue. However, genes encoding lipogenic enzymes, downregulated by HFD, were not restored by incretin analog treatment. Interestingly, a dietary intervention with normal chow diet (ND) feeding, but not calorie-matched HFD feeding, restored the expression of lipogenic enzymes. Upon incretin therapy withdrawal, mice displayed rapid bodyweight regain, impaired adipose tissue function, and glucose intolerance. In contrast, a ND intervention following incretin analog therapy withdrawal restored lipogenic gene expression in adipose tissue, maintained glucose homeostasis, and minimized body weight regain. This study revealed the effects of incretin analog therapy and therapy withdrawal on adipose tissue and highlights the importance of the dietary composition during and after incretin analog therapy. Thus, our findings may contribute to the development of long-term therapy guidelines of incretin analog therapy for patients with obesity.

Keywords:  adipose tissue; de novo lipogenesis; dietary intervention; incretin analogs; obesity

DOI:  https://doi.org/10.1152/ajpendo.00010.2025
Nature. 2025 May 28.

CoQ imbalance drives reverse electron transport to disrupt liver metabolism.

Renata L S Goncalves, Zeqiu Branden Wang, Jillian K Riveros, Güneş Parlakgül, Karen E Inouye, Grace Yankun Lee, Xiaorong Fu, Jani Saksi, Clement Rosique, Sheng Tony Hui, Mar Coll, Ana Paula Arruda, Shawn C Burgess, Isabel Graupera, Gökhan S Hotamışlıgil.

Mitochondrial reactive oxygen species (mROS) are central to physiology1,2. Excess mROS production has been associated with several disease states2,3; however, the precise sources, regulation and mechanism of generation in vivo remain unclear, which limits translational efforts. Here we show that in obesity, hepatic coenzyme Q (CoQ) synthesis is impaired, which increases the CoQH2 to CoQ (CoQH2/CoQ) ratio and drives excessive mROS production through reverse electron transport (RET) from site IQ in complex I. Using multiple complementary genetic and pharmacological models in vivo, we demonstrate that RET is crucial for metabolic health. In patients with steatosis, the hepatic CoQ biosynthetic program is also suppressed, and the CoQH2/CoQ ratio positively correlates with disease severity. Our data identify a highly selective mechanism for pathological mROS production in obesity, which can be targeted to protect metabolic homeostasis.

DOI: https://doi.org/10.1038/s41586-025-09072-1
Am J Physiol Endocrinol Metab. 2025 May 26.

Modeling Hepatic Glucose Tracer Kinetics from Isotope Dilution Technique and Deuterium Metabolic Imaging in Post-Bariatric-Surgery and Non-Operated Individuals.

Alessandro Brunasso, Chiara Dalla Man, Simone Poli, Jeanine J Prompers, David Herzig, Roland Kreis, Lia Bally, Michele Schiavon.

  Despite extensive research on liver metabolism, mathematical models describing hepatic glucose kinetics are currently limited due to the lack of organ-level data. Here, we propose a model of postprandial hepatic glucose kinetics exploiting liver Deuterium Metabolic Imaging (DMI) data combined with plasma isotope dilution analysis in humans. We used data from 10 individuals who had previously undergone Roux-en-Y Gastric Bypass surgery (RYGB) and 10 healthy controls (HC). The experimental setting included a labeled Oral Glucose Tolerance Test consisting of 60g of [6,6'-2H2]-glucose in combination with liver DMI at 7T. The hepatic glucose tracer signal was frequently quantified over 150 min, while peripheral plasma insulin and glucose tracer concentrations were measured in venous blood. The model was able to describe both liver and peripheral glucose tracer data well and provided estimates of postprandial glucose appearance and disposal in both the liver and the systemic circulation. The model predicted that almost all the ingested glucose had appeared in the liver in RYGB, but not in HC (89.0% vs. 64.0%, p=0.008) after 150 min, while total hepatic disposal (RYGB=26.4% vs. HC=29.7%) and first-pass extraction (RYGB=10.7% vs. HC=11.4%) were similar between populations. The fraction of glucose eliminated in the periphery was greater in RYGB (49.9% vs. 25.3%, p=0.003). Lastly, no differences were observed in hepatic blood flow and GLUT2 transport rates. Although further studies are needed to validate and extend the model to include endogenous glucose production and disposal, it can be used to quantify parameters, and possibly reveal defects, of hepatic glucose handling.

Keywords:  RYGB; deuterium metabolic imaging; glucose metabolism; liver; mathematical modeling

DOI:  https://doi.org/10.1152/ajpendo.00511.2024