American journal of physiology. Endocrinology and metabolism最新文献

{"title":"Pompe disease, a new approach to clearing out the trash.","authors":"Ann Louise Olson","doi":"10.1152/ajpendo.00379.2024","DOIUrl":"10.1152/ajpendo.00379.2024","url":null,"abstract":"","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387265","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":"Class B1 GPCRs: insights into multireceptor pharmacology for the treatment of metabolic disease.","authors":"Panjamaporn Sangwung, Joseph D Ho, Tessa Siddall, Jerry Lin, Alejandra Tomas, Ben Jones, Kyle W Sloop","doi":"10.1152/ajpendo.00371.2023","DOIUrl":"10.1152/ajpendo.00371.2023","url":null,"abstract":"<p><p>The secretin-like, class B1 subfamily of seven transmembrane-spanning G protein-coupled receptors (GPCRs) consists of 15 members that coordinate important physiological processes. These receptors bind peptide ligands and use a distinct mechanism of activation that is driven by evolutionarily conserved structural features. For the class B1 receptors, the C-terminus of the cognate ligand is initially recognized by the receptor via an N-terminal extracellular domain that forms a hydrophobic ligand-binding groove. This binding enables the N-terminus of the ligand to engage deep into a large volume, open transmembrane pocket of the receptor. Importantly, the phylogenetic basis of this ligand-receptor activation mechanism has provided opportunities to engineer analogs of several class B1 ligands for therapeutic use. Among the most accepted of these are drugs targeting the glucagon-like peptide-1 (GLP-1) receptor for the treatment of type 2 diabetes and obesity. Recently, multifunctional agonists possessing activity at the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, such as tirzepatide, and others that also contain glucagon receptor activity, have been developed. In this article, we review members of the class B1 GPCR family with focus on receptors for GLP-1, GIP, and glucagon, including their signal transduction and receptor trafficking characteristics. The metabolic importance of these receptors is also highlighted, along with the benefit of polypharmacologic ligands. Furthermore, key structural features and comparative analyses of high-resolution cryogenic electron microscopy structures for these receptors in active-state complexes with either native ligands or multifunctional agonists are provided, supporting the pharmacological basis of such therapeutic agents.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562433","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":"Metabolic shifts in ratio of ucOcn to cOcn towards bone resorption contribute to age-dependent bone loss in male mice.","authors":"Matthew Bernhard, Obinna Okorie, Wei-Ju Tseng, Mengcun Chen, Julia Danon, Mingshu Cui, Elisabeth Lashbrooks, Yanmei Yang, Bin Wang","doi":"10.1152/ajpendo.00294.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00294.2024","url":null,"abstract":"<p><p>The study of the senile osteoporosis in men still lags significantly behind in women. The changes of protein molecule levels and their relationships with bone loss remain poorly understood. In the present study, we used C57BL/6J male mice at ages from 3 to 24 months to delineate the mechanisms of aging effects on bone loss. We employed the micro-computed tomography, mechanical testing, histomorphometry assays, and detection of serum levels of undercarboxylated osteocalcin (ucOcn) and carboxylated osteocalcin (cOcn) to assess bone mass changes and their relationships with ratios of ucOcn to cOcn in mice from different age groups. The results showed that mouse trabecular bone mass reduced gradually with age while cortical bone loss and mechanical property changes mostly occurred in advanced age. Our findings further demonstrated that the increase in osteoclast activity and the decrease in osteoblast function were significantly corelated with blood levels of ucOcn and cOcn, respectively. The dynamic metabolic changes of ucOcn to cOcn ratio were correlated with age-dependent bone loss in mice. In summary, metabolic shifts in ratio of ucOcn to cOcn towards bone resorption from young adult to elderly mice contribute to the pathogenesis of age-related bone loss. Simultaneously monitoring blood ratios of ucOcn to cOcn may be useful to predict the status of bone mass <i>in vivo</i>.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492943","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":"Postnatal surge of adipose-secreted leptin is a robust predictor of fat mass trajectory in mice.","authors":"Olga Horakova, Petra Janovska, Ilaria Irodenko, Jana Buresova, Inge van der Stelt, Sara Stanic, Eliska Haasova, Nivasini Shekhar, Tatyana Kobets, Jaap Keijer, Petr Zouhar, Martin Rossmeisl, Jan Kopecky, Kristina Bardova","doi":"10.1152/ajpendo.00237.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00237.2024","url":null,"abstract":"<p><p>The transient postnatal increase in circulating leptin levels, known as leptin surge, may increase later susceptibility to diet-induced obesity in rodents. However, the source of leptin during the surge needs to be better characterized, and the long-term effects of leptin are contradictory. Characterization of the interaction of leptin with the genetic background, sex, and other factors is required. Here, we focused on the impact of circulating leptin levels and several related variables, measured in 2- and 4-week-old (i) obesity-prone C57BL/6 (B6) and (ii) obesity-resistant A/J mice. In total, 264 mice of both sexes were used. Posttranscriptionally controlled leptin secretion from subcutaneous white adipose tissue, the largest adipose tissue depot in mice pups, was the primary determinant of plasma leptin levels. When the animals were randomly assigned standard chow or high-fat diet (HFD) between 12 - 24 weeks of age, the obesogenic effect of HFD-feeding was observed in B6 but not A/J mice. Only leptin levels at 2 weeks, i.e., close to the maximum in the postnatal leptin surge, correlated with both body weight (BW) trajectory throughout the life and adiposity of the 24-week-old mice. Leptin surge explained 13 and 7 % of the variance in BW and adiposity of B6 mice and 9 and 35 % of the variance in these parameters in A/J mice, with a minor role of sex. Our results prove the positive correlation between the leptin surge and adiposity in adulthood, reflecting the fundamental biological role of leptin. This role could be compromised in obese subjects.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492944","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":"Metabolic Effects of Medium-Chain Triacylglycerol Consumption are Preserved in Obesity.","authors":"Josephine M Kanta, Anne-Marie Lundsgaard, Jesper F Havelund, Sarah L Amour, Ole Bæk, Duc Ninh Nguyen, Erik A Richter, Jakob G Knudsen, Maximilian Kleinert, Nils Faergeman, Andreas M Fritzen, Bente Kiens","doi":"10.1152/ajpendo.00234.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00234.2024","url":null,"abstract":"<p><p>Several health beneficial effects are associated with intake of medium-chain triacylglycerol (MCT), however, the underlying mechanisms are unknown. Furthermore, it remains uncertain whether the acute metabolic effects of MCT differ between lean individuals and individuals with obesity - and whether these effects are sustained following chronic intake. This study aimed to elucidate the postprandial physiological and metabolic effects of MCT before and after eight days intake compared to intake of energy-matched triacylglycerol consisting of long-chain fatty acids (LCT) using a randomized cross-over design in lean individuals (n=8) and individuals with obesity (n=8). The study revealed that consumption of MCT increased ketogenesis and metabolic rate, while lowering blood glucose levels over five hours. The hypoglycemic action of MCT intake was accompanied by a concomitant transient increase in plasma insulin and glucagon levels. Interestingly, the effects on ketogenesis, metabolic rate, and glycemia were preserved in individuals with obesity and sustained after eight days of daily supplementation. Lipidomic plasma analysis in lean individuals (n=4) showed that a part of the ingested MCT bypasses the liver and entered the systemic circulation as medium-chain fatty acids (MCFA). The findings suggest that MCFA, along with ketone bodies from the liver, may act as signaling molecules and/or substrates in the peripheral tissues, thereby contributing to the effects of MCT intake. In summary, these findings underscore the health benefits of MCT in metabolically compromised individuals after daily supplementation. Moreover, we uncover novel aspects of MCFA biology, providing insights into how these fatty acids orchestrate physiological effects in humans.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492942","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":"Endothelial Beta 1 Integrins are Necessary for Microvascular Function and Glucose Uptake.","authors":"Nathan C Winn, Deborah A Roby, Penn Mason McClatchey, Ian M Williams, Deanna P Bracy, Michelle N Bedenbaugh, Louise Lantier, Erin Plosa, Ambra Pozzi, Roy Zent, David H Wasserman","doi":"10.1152/ajpendo.00322.2024","DOIUrl":"10.1152/ajpendo.00322.2024","url":null,"abstract":"<p><p>Microvascular insulin delivery to myocytes is rate limiting for the onset of insulin-stimulated muscle glucose uptake. The structural integrity of capillaries of the microvasculature is regulated, in part, by a family of transmembrane adhesion receptors known as integrins, which are composed of an α and β subunit. The integrin β1 (itgb1) subunit is highly expressed in endothelial cells (EC). EC itgb1 is necessary for the formation of capillary networks during embryonic during development and its knockdown blunts the reactive hyperemia that manifests during ischemia reperfusion. We investigated the contribution of EC itgb1 in microcirculatory function and glucose uptake with emphasis in skeletal muscle. We hypothesized that loss of EC itgb1 would impair microvascular hemodynamics and glucose uptake during insulin stimulation, creating 'delivery'-mediated insulin resistance. An itgβ1 knockdown mouse model was developed to avoid lethality of embryonic gene knockout and the deteriorating health resulting from early post-natal inducible gene deletion. Mice with (itgb1^fl/flSCLcre) and without (itgb1^fl/fl) tamoxifen inducible stem cell leukemia cre recombinase (SLCcre) expression at 10 days post cre induction had comparable exercise tolerance and pulmonary and cardiac functions. Using robust in vivo experimental platforms (i.e., intravital microscopy and hyperinsulinemic-euglycemic clamp), we show that itgb1^fl/flSCLcre mice compared to itgb1^fl/fl littermates have, i) deficits in capillary flow rate, flow heterogeneity, and capillary density; ii) impaired insulin-stimulated glucose uptake despite sufficient transcapillary insulin efflux; and iii) reduced insulin-stimulated glucose uptake due to perfusion-limited glucose delivery. Thus, EC itgb1 is necessary for microcirculatory function and to meet the metabolic challenge of insulin stimulation.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492941","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":"The Acute and Chronic influence of Exercise on Mitochondrial Dynamics in Skeletal Muscle.","authors":"Elya Janis Ritenis, Camila S Padilha, Matthew B Cooke, Christos George Stathis, Andrew Philp, Donny M Camera","doi":"10.1152/ajpendo.00311.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00311.2024","url":null,"abstract":"<p><p>Exercise and nutritional modulation are potent stimuli for eliciting increases in mitochondrial mass and function. Collectively, these beneficial adaptations are increasingly recognized to coincide with improvements to skeletal muscle health. Mitochondrial dynamics of fission and fusion are increasingly implicated as having a central role in mediating aspects of key organelle adaptions that are seen with exercise. Exercise-induced mitochondrial adaptations that dynamics have been implicated in are: 1) Increases to mitochondrial turnover, resulting from elevated rates of mitochondrial synthesis (biogenesis) and degradative (mitophagy) processes. 2) Morphological changes to the 3D tubular network, known as the mitochondrial reticulum, that mitochondria form in skeletal muscle. Notably, mitochondrial fission has also been implicated in coordinating increases in mitophagy, following acute exercise. Further, increased fusion following exercise training promotes increased connectivity of the mitochondrial reticulum and is associated with improved metabolism and mitochondrial function. However, the molecular basis and fashion in which exercise infers beneficial mitochondrial adaptations through mitochondrial dynamics remains poorly understood. This review attempts to highlight recent developments investigating the effects of exercise on mitochondrial dynamics, while attempting to offer a perspective of the methodological refinements and potential variables, such as substrate/glycogen availability, which should be considered going forward.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492945","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":"Arginine vasopressin induces analgesic effects and inhibits pyramidal cells in the anterior cingulate cortex in spared nerve injured mice.","authors":"Huaxing Si, Xiaodie Liu, Chaoyi Sun, Shanming Yang, Han Zhao, Xianxia Yan, Tao Chen, Pan Wang","doi":"10.1152/ajpendo.00361.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00361.2024","url":null,"abstract":"<p><p>Neuropathic pain (NP) is a severe disease caused by a primary disease or lesion affecting the somatosensory nervous system. It`s reported that NP is related to the increased activity of glutamatergic pyramidal cells and changed neural oscillations in the anterior cingulate cortex (ACC). Arginine vasopressin (AVP), a neurohypophyseal hormone, has been shown to cause pain-alleviating effects when applied to peripheral system. However, the extent to which, and the mechanisms by which, AVP induces analgesic effects in the central nervous system remain unclear. In the present study, we observed that intranasal delivery of AVP inhibited mechanical pain, thermal pain and spontaneous pain sensitivity in mice with spared nerve injury. Meanwhile, AVP application exclusively reduced the FOS expression in the pyramidal cells but not interneurons in the ACC. <i>In vivo</i> electrophysiological recording of the ACC further showed that AVP application not only inhibited the theta oscillation in local field potential analysis, but also reduced the firing rate of spikes of pyramidal cells in the ACC in neuropathic pain mice. In summary, AVP induce analgesic effects by inhibiting neural theta oscillations and the spiking of pyramidal cells of the ACC in mice with neuropathic pain, which should provide new potential noninvasive methods for clinical treatment of chronic pain.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492940","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":"Alterations of urine microRNA-7977/G6PD level in patients with diabetic kidney disease and its association with dysfunction of albumin-induced autophagy in proximal epithelial tubular cells.","authors":"Zhenzhen Shi, Xinran Li, Liyi Zhang, Jinlan Xie, Feifei Zhong, Zhenhong Guo, Zhongai Gao, Jingyu Wang, Roshan Kumar Mahto, Yuan Li, Shenglan Wang, Baocheng Chang, Robert C Stanton, Juhong Yang","doi":"10.1152/ajpendo.00399.2023","DOIUrl":"10.1152/ajpendo.00399.2023","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Diabetic kidney disease (DKD) remains as one of the leading long-term complications of type 2 diabetic mellitus (T2DM). Studies have shown that decreased expression of glucose-6-phosphate dehydrogenase (G6PD) plays an important role in DKD. However, the upstream and downstream pathways of G6PD downregulation leading to DKD have not been elucidated. We conducted a series of studies including clinical study, animal studies, and in vitro studies to explore this. First, a total of 90 subjects were evaluated including 30 healthy subjects, 30 patients with T2DM, and 30 patients with DKD. The urinary G6PD activity and its association with the clinical markers were analyzed. Multivariate linear regression analysis was used to analyze the risk factors of urinary G6PD in these patients. Then, microRNAs that were differentially expressed in urine and could bind and degrade G6PD were screened and verified in patients with DKD. After that, high glucose (HG)-cultured human kidney cells (HK-2) and Zucker diabetic fatty (ZDF) rats were used to test the roles of miR-7977/G6PD/albumin-induced autophagy in DKD. Beclin and P62 were used as markers of kidney autophagy indicators. A dual-luciferase reporter assay system was used to test the binding of G6PD by mir-7977. The plasma and urinary G6PD activity were decreased significantly in patients with DKD, accompanied by increased urinary mir-7977 level. The fasting plasma glucose (FPG), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and urinary albumin excretion were independent predictors of urinary G6PD activity, according to multiple linear regression analysis. The increased expression of miR-7977 and decreased expression of G6PD were also found in the kidney of ZDF rats with early renal tubular damage. The correlation analysis showed that beclin protein expression levels were positively correlated with kidney G6PD activity, whereas P62 protein expression was negatively correlated with kidney G6PD activity in rats. In HK-2 cells cultured with normal situation, a low level of albumin could induce autophagy along with the stimulation of G6PD, although this was impaired under high glucose. Overexpression of G6PD reversed albumin-induced autophagy in HK-2 cells under high glucose. Further study revealed that G6PD was a downstream target of miR-7977. Inhibition of miR-7977 expression led to significantly increased expression of G6PD and reversed the effects of high glucose on albumin-induced autophagy. In conclusion, our study supports a new mechanism of G6PD downregulation in DKD. Therapeutic measures targeting the miR-7977/G6PD/autophagy signaling pathway may help in the prevention and treatment of DKD.&lt;b&gt;NEW & NOTEWORTHY&lt;/b&gt; This study provides new evidence that reduced glucose-6-phosphate dehydrogenase (G6PD) may damage the endocytosis of renal tubular epithelial cells by reducing albumin-induced autophagy. More importantly, for the first time, our study has provided evidence from humans that ","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intermittent fasting increases fat oxidation and promotes metabolic flexibility in lean mice but not obese type 2 diabetic mice.","authors":"Meghan O Conn, Daniel M Marko, Jonathan D Schertzer","doi":"10.1152/ajpendo.00255.2024","DOIUrl":"10.1152/ajpendo.00255.2024","url":null,"abstract":"<p><p>Obesity and type 2 diabetes (T2D) are associated with metabolic inflexibility, characterized by an impaired ability to switch between substrate storage and utilization pathways. Metabolic inflexibility during obesity is typified by lower engagement of fatty acid metabolism despite an ample supply of stored lipids. Intermittent fasting (IF) can promote metabolic flexibility. However, it is not clear how obesity and T2D alter metabolic flexibility after repeated IF. Male obese <i>db/db</i> and control <i>db/+</i> mice were fasted for 24 h twice a week for 10 wk. This 5:2 IF regimen did not alter body mass, body composition, food intake, or physical activity in <i>db/db</i> or <i>db/+</i> mice. After IF, <i>db/db</i> mice had lower fatty acid oxidation and higher carbohydrate oxidation in the fed state, indicating metabolic inflexibility to metabolize lipids. After IF, control <i>db/+</i> mice had higher fatty acid oxidation and lower carbohydrate oxidation in the fed state, characteristic of metabolic flexibility, and increased engagement of lipid metabolism. In the fasted state, IF lowered carbohydrate oxidation and increased fatty acid oxidation in control <i>db/+</i> mice but not in obese <i>db/db</i> mice. After IF, <i>db/db</i> mice also had lower serum β-hydroxybutyrate than control <i>db/+</i> mice. Ten weeks of IF decreased adipocyte size in visceral adipose tissue of control <i>db/+</i> mice, but this IF regimen did not change adipocyte size in obese <i>db/db</i> mice. Therefore, IF increases fatty acid oxidation and metabolic flexibility in lean mice, but this adaptation is absent in a mouse model of obesity and type 2 diabetes.<b>NEW & NOTEWORTHY</b> We show that a 5:2 intermittent fasting regimen can increase lipid oxidation without altering body mass in lean mice. Therefore, repeated intermittent fasting can increase metabolic flexibility without the need for (or prior to) weight loss. Intermittent fasting did not increase lipid oxidation in mice with obesity and type 2 diabetes, highlighting that obesity and/or type 2 diabetes limit changes in metabolic flexibility and mitigate increased fatty acid oxidation without weight loss during intermittent fasting.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085901","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}