bims-mimead 2026-07-05 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2026–07–05
eight papers selected by
Rachel M. Handy, University of Guelph and Universiteit Mastricht

Effect of adipose tissue insulin resistance on substrate utilization during low-intensity exercise: a pilot study in young men.
GIP contributes to postprandial regulation of splanchnic blood supply in humans with type 2 diabetes: a randomised, single-blinded, placebo-controlled, crossover study.
Nitrate and resveratrol supplementation selectively enhances hepatic adaptations to aerobic exercise in high-fat fed male mice.
Low oxygen availability induces a metabolic shift towards enhanced glucose utilization in non-lipid-loaded and lipid-loaded HepG2 cells.
Maximal fat oxidation assessment in active postmenopausal females: A novel relative power FATmax test.
Ablation of microglial estrogen receptor alpha predisposes male mice to diet-induced obesity.
Females Are Completely Resistant to Semaglutide-Induced Muscle Loss in ob/ob Mice.
Effects of exercise and exercise timing on energy intake and appetite control: a randomised crossover trial in people with overweight or obesity with and without type 2 diabetes.

J Phys Ther Sci. 2026 Jul;38(7): 288-295

Effect of adipose tissue insulin resistance on substrate utilization during low-intensity exercise: a pilot study in young men.

Shigeharu Numao, Ryota Uchida, Masaki Nakagaichi.

  [Purpose] Impaired insulin-mediated suppression of adipocyte lipolysis, adipose tissue insulin resistance (ATIR), may influence lipolysis and substrate utilization during exercise. This pilot study aimed to investigate the effects of ATIR on metabolic responses and substrate utilization during exercise in young men. [Participants and Methods] Twenty-four young men were divided into two groups based on their ATIR index (Adipo-IR): low Adipo-IR (LA) and high Adipo-IR (HA). The participants performed 40 min of aerobic exercise at an intensity corresponding to 40% peak oxygen uptake. Venous blood samples were collected at baseline and immediately after exercise to measure hormones and metabolite levels. Expired gas was collected during the exercise to estimate substrate oxidation. [Results] After adjusting for whole-body insulin resistance, circulating free fatty acid (FFA) levels at baseline and immediately after exercise were significantly higher in the HA group than in the LA group. The HA group demonstrated significantly lower carbohydrate oxidation and significantly higher fat oxidation than the LA group. Adipo-IR and FFA levels were significantly correlated with parameters of substrate utilization during exercise. [Conclusion] ATIR was associated with substrate utilization during exercise, independent of whole-body insulin resistance. ATIR may play a distinct role in the regulation of substrate utilization during exercise.

Keywords:  Lipolysis; Respiratory exchange ratio; Substrate utilization

DOI:  https://doi.org/10.1589/jpts.38.288
Diabetologia. 2026 Jul 02.

GIP contributes to postprandial regulation of splanchnic blood supply in humans with type 2 diabetes: a randomised, single-blinded, placebo-controlled, crossover study.

Rasmus S Rasmussen, Sophie W Nielsen, Lotte Alstrup, Tanne S W Larsson, Jonathan K Hansen, Rune P Pedersen, Mark B Vestergaard, Bryan Haddock, Helle H Johannesen, Henrik B W Larsson, Jens J Holst, Bolette Hartmann, Mette M Rosenkilde, Ali Asmar, Ulrik B Andersen, Lærke S Gasbjerg.

   AIMS/HYPOTHESIS: In healthy lean humans, endogenous glucose-dependent insulinotropic polypeptide (GIP) contributes significantly to the postprandial increase in arteria mesenterica superior blood flow. The vascular biology related to activation of the GIP receptor is markedly impaired in individuals with type 2 diabetes and is sometimes absent. In this population, we investigated the role of endogenous GIP on postprandial splanchnic blood flow by using the GIP receptor antagonist, GIP(3-30)NH2. The primary outcome of this study was the changes in blood flow in arteria mesenterica superior during oral glucose with or without GIP receptor antagonist infusion.
METHODS: Ten participants with type 2 diabetes (age 20-80 years, BMI 20-35 kg/m2, and HbA1c >48 mmol/mol and <75 mmol/mol) were investigated in a randomised, placebo-controlled, crossover study. On four separate occasions, participants received the following treatment: oral glucose + i.v. GIP(3-30)NH2; oral glucose + i.v. saline (154 mmol/l NaCl); oral water + i.v. GIP(3-30)NH2; oral water + i.v. saline. Participants were randomly assigned to intervention groups using (random.org). Participants were unaware of allocation, while investigators were aware. No additional allocation concealment procedures were used. During all four interventions, splanchnic blood flow was measured using phase-contrast MRI in the arteria mesenterica superior, truncus coeliacus and vena portae during oral glucose (75 g) or water ingestion. The study was conducted at Rigshospitalet, Copenhagen. Liver volume and oxygenation, as well as gallbladder volume, were assessed. Blood samples were collected and analysed for insulin, C-peptide, GIP, glucagon and glucose.
RESULTS: Oral glucose alone increased mean blood flow in arteria mesenterica superior by 57% (95% CI 26, 88) and this was 15% (95% CI -2, 32) lower during concomitant GIP receptor antagonist infusion, p=0.012. Infusion of GIP receptor antagonist during oral glucose treatment did also result in lower insulin secretion, C-peptide and C-peptide/glucose ratio compared with saline infusion, whereas glucagon levels and plasma glucose were unaffected. Oral water did not affect any outcomes.
CONCLUSIONS/INTERPRETATION: Endogenous GIP contributes to postprandially increased splanchnic blood flow in people with type 2 diabetes.
TRIAL REGISTRATION: ClinicalTrials.gov NCT06426823 FUNDING: This work was supported by the Novo Nordisk Foundation.

Keywords:  Endocrinology; GIP; Gut hormones; Haemodynamic; Incretin hormones; Postprandial metabolism

DOI:  https://doi.org/10.1007/s00125-026-06788-1
Am J Physiol Endocrinol Metab. 2026 Jul 01.

Nitrate and resveratrol supplementation selectively enhances hepatic adaptations to aerobic exercise in high-fat fed male mice.

Rachel M Handy, Geneviève J DesOrmeaux, Sandra Guga, Katarzyna Hodun-Bielska, Anna E Kupraty, Sara M Frangos, Fasih A Rahman, Adrian Chabowski, Henver S Brunetta, Graham P Holloway.

  Aerobic exercise training (AET) and numerous dietary interventions, including nitrate and resveratrol supplementation, display overlapping mechanisms affecting mitochondrial bioenergetics and metabolism in diverse tissues. However, it remains unclear if a combination of these interventions results in additive benefits for the prevention of obesity-related co-morbidities. To investigate this, C57Bl/6N mice consumed a high-fat diet and remained sedentary (HFD) or performed AET for 6 weeks in the absence (HFD+AET) or presence of nitrate+resveratrol supplementation (HFD+AET+NR). As expected, AET attenuated body weight gain, reduced adipocyte cross-sectional area and markers of cellular stress/inflammation within white adipose tissue, and increased mitochondrial respiratory capacity and decreased lipid content within skeletal muscle independent of supplementation. While AET alone was sufficient to improve glucose tolerance, the addition of +NR provided modest liver-specific enhancements including increased mitochondrial respiratory capacity, reduced reactive lipid accumulation, and a unique proteomic signature associated with altered amino acid metabolism, corresponding to further reductions in systemic fasting blood glucose levels. These data suggest that while AET remains a primary lifestyle intervention to drive metabolic improvements during high-fat feeding, targeted dietary supplementation may provide tissue-specific enhancements, particularly within the liver, that complement exercise adaptations.

Keywords:  Mitochondria; dietary supplementation; exercise; glucose homeostasis; high-fat diet; lipid/glucose metabolism; obesity; reactive lipids

DOI:  https://doi.org/10.1152/ajpendo.00529.2025
Am J Physiol Endocrinol Metab. 2026 Jul 02.

Low oxygen availability induces a metabolic shift towards enhanced glucose utilization in non-lipid-loaded and lipid-loaded HepG2 cells.

Geng Li, Ludwig J Dubois, Rianne Biemans, Gijs H Goossens, Ruth C R Meex.

  Liver function is impaired in metabolic dysfunction-associated fatty liver disease. Previous studies demonstrated that oxygen availability in the tissue microenvironment affects adipose tissue and skeletal muscle function, but its hepatic effects remain unclear. This study aimed to investigate the impact of oxygen levels on metabolic pathways in HepG2 cells. Non-lipid-loaded and lipid-loaded HepG2 cells, were exposed to different physiological O2 levels (5% and 10%) or standard laboratory conditions (21% O2) for 24h. Thereafter, we determined lipid content, gene expression of metabolic markers, glycogen content and glucose release. Furthermore, mitochondrial respiration and glycolytic activity were assessed by measuring the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), respectively. Exposure to 5% O₂ increased the expression of the gluconeogenic gene G6PC1 in both non-lipid-loaded and steatotic HepG2 cells compared to 21% O2 (p<0.001). Furthermore, 5% O2 decreased the expression of lipogenic genes (SREBP1C, ACC2 and FASN) in non-lipid-loaded and/or steatotic cells (all p<0.05), while genes involved in fatty acid oxidation (PPARGC1A, p<0.001; PPARA, p=0.038) were downregulated in steatotic cells. Low oxygen exposure increased glycogen content in non-lipid-loaded and steatotic cells (both p<0.001) and reduced glucose release (p<0.05). Finally, low oxygen exposure reduced OCR (p<0.05) and increased glycolysis (p<0.001) in both non-lipid-loaded and steatotic cells compared to 21%. In conclusion, our findings demonstrate that reduced oxygen availability in the microenvironment has marked effects on metabolic pathways in non-lipid-loaded and steatotic hepatocytes, inducing a metabolic shift to enhanced reliance on glucose as energy source.

Keywords:  Glucose metabolism; glycolysis; hypoxia; lipid metabolism; liver

DOI:  https://doi.org/10.1152/ajpendo.00095.2026
Physiol Rep. 2026 Jul;14(13): e70991

Maximal fat oxidation assessment in active postmenopausal females: A novel relative power FATmax test.

Jordi Monferrer-Marín, Ainoa Roldán, Jørn Wulff Helge, Cristina Blasco-Lafarga.

  This study compared a novel relative-to-body-mass FATmax test (RFT; 0.15 W/kg/4 min from 0.45 W/kg) with a traditional absolute power FATmax test (AFT; 10 W/3min15sec from 30 W) in postmenopausal females. The aim was to determine whether the RFT protocol would improve fat oxidation kinetics during exercise, in females with lower maximal fat oxidation (MFO). It was hypothesized that the longer duration and the lower workload increments would result in higher fat oxidation values than AFT. Seventeen active postmenopausal females (69.2 ± 5.1 years) performed both protocols in a randomized order and were divided into above (H-MFO) or below (L-MFO) 0.3 g/min MFO. Groups were equal in age and body composition. Overall, time to MFO was delayed during the RFT protocol (765 ± 621 vs. 401 ± 262 s) without MFO differences. Both groups displayed longer time to MFO in RFT, whilst significantly only for L-MFO (420 ± 280 s vs. 317 ± 232). Although no statistical differences, moderate effect sizes were observed in the L-MFO group during RFT for both MFO (0.22 ± 0.04 vs. 0.19 ± 0.06 g/min, d = 0.65) and VO2 (12.8 ± 3.8 vs. 15.4 ± 5.5 mL/min/kg, d = -0.53). RFT may improve the determination of substrate oxidation kinetics in postmenopausal females with reduced fat oxidation capacity, while facilitating complementary analyses requiring longer recordings and stability (efficiency and Heart Rate Variability).

Keywords:  aging; energy expenditure; metabolic flexibility; relative power; respiratory exchange

DOI:  https://doi.org/10.14814/phy2.70991
Metabolism. 2026 Jul 02. pii: S0026-0495(26)00200-3. [Epub ahead of print] 156689

Ablation of microglial estrogen receptor alpha predisposes male mice to diet-induced obesity.

Inmaculada Velasco, Jeremy M Frey, Vladislav Baglaev, Tristan Jafari, Thomas Huang, Sophia Schwie, Olivia D Santiago, Rachael D Fasnacht, Joshua P Thaler, Mauricio D Dorfman.

  Estrogen receptor alpha (ERα) signaling has metabolic and anti-inflammatory properties in addition to its impact on reproductive function. Compared to females, male mice generally exhibit greater inflammatory activation of microglia and increased susceptibility to diet-induced obesity (DIO). Given the established metabolic protective effects of estrogen, these observations raise the possibility that sex differences in microglial estrogen signaling contribute to this sexual dimorphism. In this study, we assessed metabolic and CNS histopathological properties in a mouse model with inducible microglia-specific ablation of ERα (MG-ERαKO). Male MG-ERαKO mice developed increased weight gain and insulin resistance relative to controls during high-fat diet (HFD) feeding. Indirect calorimetry and food intake analysis revealed that reduced energy expenditure, coupled with an inadequate compensatory reduction in food intake, was the primary driver of the obese phenotype. In contrast, female MG-ERαKO mice fed HFD developed mild insulin resistance, with no change in body weight gain compared to controls, despite a similar reduction in energy expenditure. Immunohistochemical analyses of the microglial activation marker IBA1 in the mediobasal hypothalamus (MBH) revealed that female MG-ERαKO mice had an increased number of microglia without showing morphological signs of activation. In contrast, MBH microglial number was unchanged in MG-ERαKO male mice, but the cells adopted more activated morphological profiles. Finally, HFD-fed MG-ERαKO male mice had increased POMC neuron-microglia interactions but fewer overall hypothalamic POMC neurons, suggesting microglia may disrupt POMC neuron integrity to promote DIO. Together, these findings indicate that sex-specific actions of estrogen in microglia limit the metabolic complications of HFD feeding.

Keywords:  Estrogen receptor alpha; Microglia; Neuroinflammation; Obesity; POMC neurons

DOI:  https://doi.org/10.1016/j.metabol.2026.156689
Diabetes. 2026 Jul 02. pii: db260229. [Epub ahead of print]

Females Are Completely Resistant to Semaglutide-Induced Muscle Loss in ob/ob Mice.

Subhasmita Rout, Takuya Karasawa, Shinya Watanabe, Amandine Chaix, Micah J Drummond, Katsuhiko Funai, Ran Hee Choi.

ARTICLE HIGHLIGHTS: Female C57BL/6 J mice are relatively resistant to weight gain, which complicates the study of sex-specific metabolic responses. So, we used ob/ob mice to examine semaglutide-induced weight loss in both sexes. We wanted to determine whether semaglutide-induced weight loss produces sex-specific effects on skeletal muscle mass and function in ob/ob mice. Semaglutide had minimal effects on skeletal muscle mass and strength in ob/ob mice. In particular, females were completely resistant to loss of muscle mass. These findings reveal that semaglutide exerts sex-specific effects, highlighting a need for further research into the molecular mechanisms driving these distinct protective outcomes.

DOI: https://doi.org/10.2337/db26-0229
EBioMedicine. 2026 Jul 01. pii: S2352-3964(26)00236-7. [Epub ahead of print]129 106353

Effects of exercise and exercise timing on energy intake and appetite control: a randomised crossover trial in people with overweight or obesity with and without type 2 diabetes.

Natja Poder Launbo, Lea Jalking, Marie Møller Jensen, Kristine Beaulieu, Graham Finlayson, Martin Bæk Blond, Astrid Wiggers, Jørgen Rungby, Malin Nilsson, Nicolai J Wewer Albrechtsen, Marina Kjærgaard Gerstenberg, Hanne Enghoff Pedersen, Kristine Færch, Louise Groth Grunnet, Jonas Salling.

   BACKGROUND: This randomised crossover trial (ClinicalTrials.gov: NCT05768958) examined how high-intensity interval exercise (HIIE) vs. rest and time of day affect ad libitum energy intake, subjective appetite, and metabolic markers, and whether responses differ by type 2 diabetes (T2D) status.
METHODS: Fifty-eight adults with overweight/obesity (with and without T2D) completed four laboratory visits (HIIE or rest in the morning or late afternoon). Participants were randomised using a balanced incomplete block design; blinding was not feasible. The primary outcome was ad libitum energy intake; secondary outcomes included 24-h post-visit energy intake, subjective appetite, satiety quotient and metabolic markers (including glucose, insulin, ghrelin, Glucagon-Like Peptide-1, Fibroblast Growth Factor 21 (FGF21), and Growth Differentiation Factor 15 (GDF15)).
FINDINGS: Energy intake was lower after HIIE than rest (-361 kJ (95% CI: -520: -202), p < 0.001) with no compensation over the next 24 h. Appetite ratings were lower after HIIE, accompanied by reduced ghrelin and increased FGF21 and GDF15. Time of day did not affect outcomes; however, only participants without T2D consumed less after morning than late afternoon HIIE. FGF21 and GDF15 increased after exercise compared to rest independent of time of day. GDF15 showed a significantly greater response and higher concentrations in participants with T2D. In participants with T2D, morning HIIE elicited higher FGF21 concentrations than late afternoon HIIE. Other time-of-day effects were minimal. No serious adverse events occurred.
INTERPRETATION: In conclusion, acute HIIE suppresses energy intake and elevates GDF15 and FGF21 in people with overweight/obesity, with modest timing effects that differ by diabetes status.
FUNDING: Novo Nordisk A/S.

Keywords:  Acute exercise; Ad libitum meal; Appetite control; Obesity; Overweight; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.ebiom.2026.106353