American journal of physiology. Endocrinology and metabolism最新文献

{"title":"Human skeletal muscle disuse atrophy has profound and negative effects on the muscle metabolome and lipidome.","authors":"Sean P Kilroe, Zachary D Von Ruff, Emily J Arentson-Lantz, Trevor B Romsdahl, Jennifer J Linares, Hanna Kalenta, Erik D Marchant, Elena Volpi, Douglas Paddon-Jones, William K Russell, Blake B Rasmussen","doi":"10.1152/ajpendo.00012.2025","DOIUrl":"10.1152/ajpendo.00012.2025","url":null,"abstract":"<p><p>We investigated how short-term muscle disuse altered the skeletal muscle metabolome, lipidome, and transcriptome in middle-aged adults. We report that the energy metabolism pathways: nicotinate and nicotinamide metabolism, glycolysis, and TCA cycle, were reduced after 7 days of muscle disuse. These changes in the metabolome were reflected by changes in the transcriptome where multiple genes involved in glycolysis and TCA pathways were reduced after short-term disuse. Phenylalanine, tyrosine, and tryptophan metabolism pathways showed the same response and were reduced after short-term disuse. The skeletal muscle lipidome showed a decrease in phosphatidylinositols but an increase in phosphatidylglycerols and diacylglycerols after short-term muscle disuse. We conclude that short-term muscle disuse in humans has profound and negative effects on the muscle metabolome and lipidome. These include significant downregulation of muscle glycolytic, amino acid, and TCA cycle intermediates. In contrast, skeletal muscle lipids had a divergent response to disuse (e.g., increased phosphatidylglycerols and diacylglycerols, but reduced phosphatidylinositols).<b>NEW & NOTEWORTHY</b> We present the first study that has applied a multiomic analysis (metabolomics, lipidomics, and transcriptomics) of short-term disuse in middle-aged adults. We identified an altered lipidomic and metabolic signature after disuse that included increases in lipids associated with lipotoxicity (e.g., sphingomyelin and diacylglycerol) and reductions in phosphatidylinositol. Energy pathway metabolites for glycolysis and the TCA cycle were reduced after short-term disuse. The lipidomics and metabolomics data were supported by changes in the associated gene expression.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E962-E978"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ketone body-supported respiration in murine isolated brain mitochondria is augmented by alpha-ketoglutarate and is optimized by neuronal SCOT expression.","authors":"Xin C Davis, Colin S McCoin, E Matthew Morris, Julie Allen, Harrison D Stierwalt, Edziu Franczak, Eric D Queathem, Kyle L Fulghum, Patrycja Puchalska, Peter A Crawford, John P Thyfault","doi":"10.1152/ajpendo.00058.2025","DOIUrl":"https://doi.org/10.1152/ajpendo.00058.2025","url":null,"abstract":"<p><p>Ketone bodies are increasingly examined as an alternative fuel source for the known decreases in glucose utilization that occur with neurodegeneration. Here, we established a protocol to maximize ketone body respiration in isolated brain mitochondria, while quantifying acetyl-CoA and energy charge via liquid chromatography-tandem mass spectrometry in control mice compared with mice with neuron-specific deletion of succinyl-CoA-3-oxoacid-CoA transferase (SCOT), required for CoA transfer from succinyl-CoA to acetoacetate (AcAc) to support its oxidation. Maximal ADP-dependent AcAc respiration occurred at 1 mM; however, the percent increase above basal was minimal (∼15%). Alpha-ketoglutarate (αKG) substantially increased AcAc-dependent respiration in isolated brain mitochondria, putatively through the generation of succinyl-CoA. Using mice with neuron-specific deletion of SCOT, we also examined brain mitochondrial respiration of AcAc and resulting acetyl CoA and energy charge (cellular energy availability via adenosine nucleotide ratios of ATP, ADP, and AMP). As expected, isolated brain mitochondria from SCOT-knockout (KO) mice had lower AcAc State 3 respiration than control mice. Surprisingly, we did not find differences in mitochondrial energy charge between SCOT control and neuron SCOT-KO mice despite decreased acetyl-CoA level in SCOT-KO mice when AcAc was used as the substrate. In conclusion, we show that αKG enhances ketone-supported respiration rate in isolated brain mitochondria and ketone metabolism in neurons affects acetyl-CoA level in brain mitochondria but not energy charge. Future work will determine whether diet, exercise, sex, or age impacts ketone-supported respiration rates in conjunction with differences in markers of brain health.<b>NEW & NOTEWORTHY</b> This paper established a protocol to maximize ketone body respiration in isolated brain mitochondria while quantifying acetyl-CoA and energy charge in control mice compared with mice with neuron-specific deletion of succinyl-CoA-3-oxoacid-CoA transferase (SCOT) enzyme, required for ketone body oxidation. Findings are that alpha-ketoglutarate substantially increased acetoacetate (AcAc)-dependent respiration and neuron SCOT-KO had lower AcAc state 3 respiration with a decreased acetyl-CoA level.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"328 6","pages":"E822-E832"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of ovarian function prevents exercise-induced activation of hepatic mitophagic flux.","authors":"Edziu Franczak, Benjamin A Kugler, Sebastian F Salathe, Julie A Allen, Mihaela E Sardiu, Colin S McCoin, Andrea L Hevener, E Matthew Morris, John P Thyfault","doi":"10.1152/ajpendo.00107.2025","DOIUrl":"10.1152/ajpendo.00107.2025","url":null,"abstract":"<p><p>Exercise effectively treats metabolic dysfunction-associated steatotic liver disease (MASLD) by enhancing hepatic mitochondria energy metabolism. However, the efficiency of exercise in treating MASLD in postmenopausal women may be reduced. Previously, we showed acute treadmill exercise activates hepatic mitophagy, the selective degradation of low-functioning mitochondria. Mitophagic flux is differentially regulated in female mice compared with males, possibly by estrogen. Here, we tested if loss of ovarian function via ovariectomy (OVX), which reduces estrogen, drives MASLD, and compromised hepatic mitochondrial energetics, would blunt activation of hepatic mitophagy induced by exercise. Following OVX, 12- to 15-wk-old female mice were placed on a low-fat diet (LFD) or high-fat diet (HFD) for 4 wk to induce MASLD, after which half of the mice performed a single acute bout of treadmill exercise to exhaustion or remained sedentary. Two hours post exercise, isolated hepatic mitochondria were examined via Western blotting and proteomics for accumulation of known mitophagy proteins. After exercise, reduced basal mitophagic flux in LFD-fed OVX was restored to levels found in sham mice. However, exercise possessed blunted capacity to promote mitochondrial recruitment of DRP1 (regulator of fission) and accumulation mitophagy-associated proteins (E3-ubiquitin ligase, ubiquitin, autophagy adaptor proteins, and autophagosome cargo receptors) in OVX versus sham mice on HFD. Mitochondrial H₂O₂ production, which putatively activates mitophagy, was elevated following exercise in all conditions except OVX + HFD. In summary, OVX reduces mitophagic flux, blunting the stimulatory effects of exercise on these factors. The impaired regulation of mitophagy following the cessation of ovarian function likely contributes to the pathogenesis of MASLD post menopause.<b>NEW & NOTEWORTHY</b> Loss of ovarian function reduces hepatic mitochondrial respiratory capacity, but mechanisms are unknown. Here, we leverage exercise-induced hepatic mitophagy activation to determine if loss of ovarian function impairs mitochondrial quality control mechanisms. Our data reveal that loss of ovarian function reduces both ubiquitin-mediated hepatic mitophagy and mitochondrial recruitment of Drp1 (mitochondrial fission protein) following acute exercise. These impairments to hepatic mitophagy coincided with alterations in hepatic mitochondrial respiratory capacity and mitochondrial-derived H₂O₂ production.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E869-E884"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evidence for the involvement of secondary bile acids on peripheral and central regulation of feed intake in rainbow trout.","authors":"Gabriel Pérez-Tierra, Jessica Calo, Sara Comesaña, Cristina Velasco, Ayelén M Blanco, José L Soengas","doi":"10.1152/ajpendo.00072.2025","DOIUrl":"https://doi.org/10.1152/ajpendo.00072.2025","url":null,"abstract":"<p><p>Recent studies suggest that secondary bile acids (SBAs) play a role in energy metabolism and feed intake regulation, but their effects in fish remain largely unknown. This study evaluates the impact of intragastric administration of the main SBAs [500 µM lithocholic acid (LCA), 1,500 µM deoxycholic acid (DCA), and their taurine conjugates: 1,000 µM T-LCA and 600 µM T-DCA] on feed intake, regulatory pathways, and bile acid-related elements in rainbow trout. Results show that all tested SBAs influenced bile acid transporters [apical sodium-dependent bile acid transporter (Asbt), Na+ taurocholate co-transporting polypeptide (Ntcp), organic solute transporter α and β (Ostα, and Ostβ)] and receptors [farnesoid X receptor like-α and β (Fxrα, Fxrβ), and Takeda G protein-coupled receptor 5 (Tgr5)], with DCA and T-DCA mainly affecting the gastrointestinal tract and LCA modulating hypothalamic pathways, suggesting a putative orexigenic role. Plasma analysis confirmed SBA absorption from the gastrointestinal tract into the bloodstream. This study provides the first evidence in fish of SBAs modulating gene and protein expression linked to appetite regulation, underscoring their role in gut-brain communication. Although all SBAs influenced fxr expression, gpbar1 remained unaffected, differing from mammals where BAs suppress appetite. Notably, despite taurine-conjugated SBAs being the most abundant in rainbow trout, only nonconjugated LCA showed significant effects. Taken together, these results provide new information on the emerging importance of SBA in feed intake regulation and bile acid mechanisms.<b>NEW & NOTEWORTHY</b> This study determined for the first time in teleost fish (specifically in rainbow trout): <i>1</i>) the role of secondary bile acids in the regulation of feed intake and associated signaling pathways, highlighting a putative orexigenic role of lithocholic acid (LCA); <i>2</i>) the response of Asbt and Ostα transporters and Tgr5 receptor in hypothalamus after LCA administration; and <i>3</i>) the reabsorption of LCA, DCA, and their taurine conjugates from the gastrointestinal tract into the bloodstream.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"328 6","pages":"E787-E803"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of TFEB protects against diabetic vascular calcification by improving autophagic flux and activating Nrf2 antioxidant system.","authors":"Xue-Jiao Sun, Sheng-Jue Xiao, Wen-Qi Ma, Hong Jin, Li-Qun Ren, Yu-Yu Yao, Zheng-Dong Chen, Xiao-Xue Li, Tian Chen, Nai-Feng Liu","doi":"10.1152/ajpendo.00161.2023","DOIUrl":"10.1152/ajpendo.00161.2023","url":null,"abstract":"<p><p>Autophagic flux blockade and excessive oxidative stress play important roles in the pathogenesis of diabetic vascular calcification (VC). Transcription factor EB (TFEB) is an important regulator of many autophagy-lysosomal related components, which is mainly involved in promoting autophagy process in cells. Nuclear factor erythroid-2 related factor 2 (Nrf2) antioxidant system is considered as one of the key pathways in response to intracellular oxidative stress. Periostin (POSTN), a matrix protein, is widely involved in regulating the formation and maintenance of organs such as bones, teeth, heart valves, and tendons. We have previously reported that POSTN interfered with autophagic flux in an oxidative stress-dependent manner in vascular smooth muscle cells (VSMCs) to aggravate the development of diabetic VC. However, how POSTN interfered with autophagic flux by regulating oxidative stress has not been clarified. This study aims to further explore the roles of TFEB, POSTN, autophagy, and Nrf2 antioxidant system in the development of diabetic VC. Our experimental results revealed that activation of TFEB attenuated diabetic VC by improving autophagic flux and activating Nrf2 antioxidant system, whereas POSTN reduced the autophagic degradation of Kelch-like ECH-associated protein 1 (KEAP1) by inhibiting lysosomal function, thus inhibiting the activation of the Nrf2 antioxidant system, and ultimately abolishing the protective effect of TFEB against diabetic VC. In conclusion, this study uncovers that TFEB play an important role in alleviating diabetic VC by improving autophagic flux and activating Nrf2 antioxidant system, suggesting that TFEB may be a new target for the prevention and treatment of diabetic VC.<b>NEW & NOTEWORTHY</b> This study is the first to suggest the protective effect of activation of transcription factor EB (TFEB) against diabetic vascular calcification (VC), emphasizing that activation of TFEB alleviated diabetic VC by improving the autophagic flux and activating the Nuclear factor erythroid-2 related factor 2 (Nrf2) antioxidant system in vascular smooth muscle cells (VSMCs), and revealing that periostin (POSTN) partially abolished the protective effect of TFEB on diabetic VC by inhibiting the autophagic degradation of Kelch-like ECH-associated protein 1 (KEAP1).</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E924-E939"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bile acid regulation of xenobiotic nuclear receptors on the expressions of orosomucoids in the liver.","authors":"Ji Ho Suh, Inyoung Cheon, Hyun-Jung Jung, Sung Ho Lee, Mi Jeong Heo, Matthew DeBerge, Clavia Ruth Wooton-Kee, Kang Ho Kim","doi":"10.1152/ajpendo.00417.2024","DOIUrl":"10.1152/ajpendo.00417.2024","url":null,"abstract":"<p><p>The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic nuclear receptors activated by various xenobiotics, drugs, hormones, and bile acids (BAs). Upon activation, these nuclear receptors play critical roles in regulating systemic energy homeostasis. However, precise mechanisms through which CAR and PXR influence systemic metabolism remain incompletely understood. Here, we investigated the impact of CAR and PXR on the liver-secreted hormone (i.e., hepatokine) expressions in response to BA stress, such as cholic acid (CA) feeding. Our analysis revealed that several BA-activated genes, including the well-known CAR/PXR target, aldo-keto reductase family 1, member B7 (<i>Akr1b7</i>), were commonly increased by CAR- and PXR-agonist treatments. Notably, we identified a gene cluster encoding new BA-regulated hepatokines, orosomucoids (ORMs), as direct transcriptional targets of CAR and PXR. The <i>Orm1</i> and <i>Orm2</i> expressions were completely abolished in the absence of both CAR and PXR following CA feeding. In addition, we found that <i>Orm</i> transcriptions are dynamically regulated under various metabolic conditions, proposing a potential contribution of CAR/PXR. In conclusion, our study demonstrated that BA stress activates CAR and PXR, which play a key role in regulating hepatokine expression, including ORMs. This suggests a potential link between hepatic BA signaling, CAR/PXR activity, and systemic metabolic effects.<b>NEW & NOTEWORTHY</b> Hepatic bile acid signaling plays a crucial role in coordinating systemic metabolism between the liver and other peripheral tissues. Our report demonstrates that, under bile acid-enriched conditions, activation of nuclear receptors CAR and PXR stimulate the expression of several putative hepatokines, including the orosomucoid gene family, which may exert regulatory effects in the liver and adipose tissue against metabolic disorders.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E940-E951"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CYP1A1/1A2 enzymes mediate glucose homeostasis and insulin secretion in mice in a sex-specific manner.","authors":"Ma Enrica Angela Ching, Myriam P Hoyeck, Lahari Basu, Rayanna Merhi, Emilia Poleo-Giordani, Erin van Zyl, Angela M Crawley, Jennifer E Bruin","doi":"10.1152/ajpendo.00284.2024","DOIUrl":"10.1152/ajpendo.00284.2024","url":null,"abstract":"<p><p>The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that controls the expression of several downstream targets including xenobiotic metabolism enzymes, cytochrome P450 1A1 and 1A2 (<i>Cyp1a1/1a2</i>). Besides xenobiotic metabolism, AhR also mediates responses to other stressors including high-fat diets (HFDs). Although global deletion or downregulation of AhR protects against metabolic dysfunction in HFD-fed mice, the role of <i>Cyp1a1/1a2</i> in glucose homeostasis remains unclear. We demonstrated that <i>Cyp1a1</i> expression is induced in mouse pancreatic islets not only by xenobiotic exposure but also by HFD feeding. Since CYP1A1/1A2 enzymes can produce reactive oxygen intermediates, we hypothesized that chronic CYP1A1/1A2 activation may contribute to HFD-induced metabolic dysfunction in mice, and thus, deleting these enzymes may be protective. We fed 29- to 31-wk-old male and female global <i>Cyp1a1/1a2</i> knockout (<i>Cyp</i>^KO) and wild-type (<i>Cyp</i>^WT) mice a 45% HFD or standard chow for 14 wk. <i>Cyp</i>^KO females were partially protected from HFD-induced glucose intolerance, and chow-fed <i>Cyp</i>^KO females had lower plasma insulin and suppressed insulin secretion in isolated islets compared with <i>Cyp</i>^WT females. Meanwhile, <i>Cyp</i>^KO males exhibited HFD-induced hyperinsulinemia later than <i>Cyp</i>^WT males. HFD feeding elevated <i>Cyp1a1</i> and other stress genes in <i>Cyp</i>^WT male islets but not in <i>Cyp</i>^KO islets, indicating that CYP1A1 mediates islet stress responses. Liver pathology, adiposity, and adipose inflammation were primarily affected by diet, not genotype, in both sexes. Our study highlights a novel sex-dependent role for <i>Cyp1a1/1a2</i> in shaping the systemic metabolic response to HFD feeding, suggesting that CYP1A1/1A2 enzymes are involved in glucose homeostasis, insulin secretion, and islet stress responses.<b>NEW & NOTEWORTHY</b> Cytochrome P450 (CYP)1A1/1A2 enzymes have sex-specific roles in glucose homeostasis in mice. In females, global <i>Cyp1a1/1a2</i> deletion partially protects from glucose intolerance in high-fat diet (HFD)-fed mice and lowers plasma insulin in chow-fed mice. In males, <i>Cyp1a1/1a2</i> deletion delays HFD-induced hyperinsulinemia in vivo and inhibits HFD-induced islet stress responses. Genotype-driven differences were only seen in islets, suggesting a novel role for islet CYP1A1/1A2 enzymes in responding to metabolic stress.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E885-E898"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of reducing sedentary behavior on liver insulin sensitivity, liver fat content, and liver enzyme levels: a six-month randomized controlled trial.","authors":"Saara Laine, Tanja Sjöros, Taru Garthwaite, Miikka-Juhani Honka, Eliisa Löyttyniemi, Jooa Norha, Olli Eskola, Mikko Koivumäki, Henri Vähä-Ypyä, Harri Sievänen, Tommi Vasankari, Jussi Hirvonen, Kirsi Laitinen, Noora Houttu, Kari K Kalliokoski, Virva Saunavaara, Juhani Knuuti, Ilkka H A Heinonen","doi":"10.1152/ajpendo.00446.2024","DOIUrl":"10.1152/ajpendo.00446.2024","url":null,"abstract":"<p><p>Metabolic syndrome increases the risk of developing noncommunicable diseases such as metabolic dysfunction-associated steatotic liver disease. The aim was to investigate the effects of sedentary behavior (SB) reduction on liver glucose uptake (LGU), endogenous glucose production (EGP), liver fat content (LFC), and liver enzyme levels [alanine aminotransferase (ALT), aspartate aminotransferase, and γ-glutamyltransferase]. Forty-four sedentary (daily SB time ≥ 10 h), physically inactive middle-aged adults with metabolic syndrome were randomized into intervention (INT; <i>n</i> = 23, 21 completed) and control (CON; <i>n</i> = 21, 19 completed) groups. For 6 mo, INT aimed to limit SB by 1 h/day, whereas CON aimed to maintain usual habits. SB and physical activity (PA) were measured continuously with hip-worn accelerometers. Before and at the end of the intervention, LGU was measured using positron emission tomography during the hyperinsulinemic-euglycemic clamp. EGP was calculated, and LFC was measured by magnetic resonance spectroscopy. INT reduced SB by 51 [95% confidence interval (CI): 22, 78] min/day and increased moderate-to-vigorous physical activity (MVPA) by 22 (95% CI: 12, 33) min/day, with no significant change in CON. Differences in liver health markers between the groups were not significant. However, according to the exploratory analyses among participants who successfully reduced SB, ALT decreased (-1.1 [95% CI: 0.93, 1.36] U/L) compared with the continuously sedentary participants (+0.8 [95% CI: 0.65, 1.05] U/L) (group × time, <i>P</i> = 0.006). To enhance liver health, reducing SB for longer durations and/or increasing the intensity of PA may be necessary. However, successfully reducing SB may lead to better levels of circulating ALT liver enzymes.<b>NEW & NOTEWORTHY</b> Aiming to reduce sedentary behavior (SB) by 1 h/day did not significantly influence liver health markers, suggesting that more substantial reductions or a different approach might be necessary to see improvements. However, achieving the desired behavioral change could lead to improvements in ALT levels. This study is the first to analyze how reducing SB and replacing it with nonguided physical activity impacts liver health in adults with metabolic syndrome, offering insights for future intervention strategies.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"328 6","pages":"E756-E771"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A dietary intervention following incretin analog treatment restores adipose tissue functions in diet-induced obese mice.","authors":"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","doi":"10.1152/ajpendo.00010.2025","DOIUrl":"https://doi.org/10.1152/ajpendo.00010.2025","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144155503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut lactate increases circulating L-Lac-Phe and key metabolites linked to GLP-1 and human health.","authors":"Emaan Ghias, Mette Glavind Bülow Pedersen, Camilla Bak Nielsen, Louise Vase Bech, Ida Marie Modvig, Natasa Brkovic Zubanovic, Jacob Marthinsen Seefeldt, Roni Nielsen, Esben Søndergaard, Kim Frisch, Jakob Hansen, Jens Juul Holst, Niels Møller, Nikolaj Rittig, Mogens Johannsen","doi":"10.1152/ajpendo.00037.2025","DOIUrl":"https://doi.org/10.1152/ajpendo.00037.2025","url":null,"abstract":"<p><p>Lactate, a small organic acid related to short-chain fatty acids (SFCAs), is emerging as a key energy metabolite, although much remains unknown about its actions in the gut. In the current study, we specifically tested how oral (PO) and parenteral (IV) lactate affects lactoylation of amino acids (Lac-AA) in humans and whether these clinical results could be reproduced in a perfused rat intestine model. Furthermore, using targeted and untargeted metabolomics we globally investigated how PO and IV lactate impact the circulating metabolome to delineate potential circulating messengers and obtain additional mechanistic insight into how oral lactate may potentially induce GLP-1 secretion as well as alternative metabolites correlated to human health. Our findings provide a better understanding of the general effects of lactate in the gut and how it potentially signals to increase satiety in humans.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}