American journal of physiology. Endocrinology and metabolism最新文献

{"title":"Novel link between plasma bilirubin and anti-inflammatory miRNA profiles in follicular fluid of IVF patients.","authors":"Natascha Berger, Anna Rieder, Katharina Brugger, Bettina Amtmann, Martina Kollmann, Irmgard Oreskovic, Slave Trajanoski, Ursula Hiden, Herbert Fluhr","doi":"10.1152/ajpendo.00479.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00479.2024","url":null,"abstract":"<p><p>Maternal metabolic factors are increasingly recognized as critical pre-conceptional determinants of fertility outcomes. To investigate how metabolic health influences female fertility, we investigated the molecular composition of follicular fluid (FF), with a focus on microRNA (miRNA) expression. Blood and FF samples from 15 women undergoing controlled ovarian stimulation were examined in a pilot study. Clinical traits (glucometabolic markers, lipid profiles, liver function markers, inflammatory cytokines, and hormonal parameters) and oocyte outcomes were measured and recorded. Elevated plasma bilirubin levels were associated with a distinct miRNA profile in FF, characterized by an enrichment of anti-inflammatory miRNAs, including miR-146a-5p, miR-146b-5p, miR-487b-3p, and miR-21-5p. Bioinformatic analysis revealed that these miRNAs directly target key inflammatory mediators, including IL6, COX2, TLR4, IRAK1, and NFKB1, suggesting a regulatory role in intra-follicular inflammation. Furthermore, patients with a fertilization rate of ≤50% exhibited higher transcript levels of miRNAs associated with elevated plasma bilirubin. Our findings provide a novel perspective on the growing body of evidence supporting bilirubin's regulatory properties, including anti-oxidative and anti-inflammatory effects and highlight the relationship between plasma bilirubin and FF miRNA expression. The observed associations between bilirubin levels, follicular fluid miRNA composition, and oocyte quality underscore the critical influence of metabolic factors on reproductive outcomes. This exploratory work provides a foundation for further studies to investigate the functional role of plasma bilirubin in follicular physiology and its potential as a biomarker to optimize fertility treatments.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952626","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":"Systemic effect of combined functional overload and endurance-type swimming exercise on whole body metabolism in mice.","authors":"Takanaga Shirai, Kazuki Uemichi, Ryoto Iwai, Hayato Shinkai, Tomohiro Iwata, Riku Tanimura, Shunsuke Sugiyama, Tohru Takemasa","doi":"10.1152/ajpendo.00433.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00433.2024","url":null,"abstract":"<p><p>In this study, we examined the effects of concurrent functional overload and endurance exercise on muscle hypertrophy, mitochondrial function, and systemic adaptations in male mice. The mice were assigned to three groups: Sham (Sham), overload-induced hypertrophy (OL), and overload with concurrent 60-min free swimming (5 times/wk) (OL + Swim), for 4 wk. Although OL promoted muscle hypertrophy and protein synthesis through the Akt/mammalian/mechanistic target of rapamycin (mTOR) signaling pathway, the addition of swimming (OL + Swim) attenuated these effects, resulting in less pronounced muscle growth and a smaller increase in myofiber cross-sectional area. Notably, the OL + Swim group exhibited enhanced mitochondrial activity and glycogen content compared with the OL group. Both the OL and OL + Swim groups showed elevated rates of protein synthesis, with a significant upregulation of AMP-activated kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in the OL + Swim group, suggesting enhanced mitochondrial biogenesis and adaptation. Concurrent training also resulted in systemic benefits, including reduced inguinal and epididymal white adipocyte size, improved mitochondrial enzyme activities in adipose and liver tissues, and higher levels of fibronectin type III domain containing protein 5 (FNDC5), fibroblast growth factor 21 (FGF21), and brain-derived neurotrophic factor (BDNF) in serum, which contributed to enhanced muscle protein synthesis in cultured muscle cells. These results highlight the trade-offs between muscle hypertrophy and metabolic health in mice and underscore the importance of balanced training regimens to optimize overall metabolic health and muscle function. Our results provide further insight into how concurrent strength and endurance training can be optimized for health and performance benefits.<b>NEW & NOTEWORTHY</b> This study provides novel insights into the mechanisms underlying the interference effect that occurs in concurrent training, highlighting the potential systemic benefits of combining resistance and endurance exercises. Despite a reduction in muscle hypertrophy, concurrent training enhances metabolic adaptations and systemic health markers and offers a comprehensive approach to improving both muscle and metabolic fitness.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"328 5","pages":"E695-E710"},"PeriodicalIF":4.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961061","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":"GLP-1 receptor agonist exendin-4 suppresses food intake by inhibiting hindbrain orexigenic NPY neurons.","authors":"Jiayi Shen, Mengtian Wang, Guodong Pang, Yan Zhang, Jian Zhang, Yuyan Shi, Ji Liu, Cheng Zhan","doi":"10.1152/ajpendo.00528.2024","DOIUrl":"10.1152/ajpendo.00528.2024","url":null,"abstract":"<p><p>Peripherally delivered glucagon-like peptide-1 (GLP-1)-based drugs suppress eating through their action in the brain. However, the specific neuronal mechanisms, especially their impacts on the orexigenic circuit, remain largely elusive. Neuropeptide Y (NPY) neurons in the nucleus tractus solitarius (NTS) are newly identified as orexigenic neurons with a potent eating-stimulating effect, but their responses to GLP-1 drugs are unknown. Through ex vivo electrophysiological recordings, we study the impacts of GLP-1 receptor (GLP-1R) agonist exendin-4 on NTS^NPY neurons. We discovered that the GLP-1R agonist exendin-4 inhibits NTS^NPY neuronal activity via GABA_b receptors by augmenting presynaptic GABA release. We also explored the contribution of NTS^NPY neurons to exendin-4-mediated eating suppression. Interestingly, chemogenetic activation of NTS^NPY neurons effectively counteracted exendin-4-induced anorexigenic effect. Moreover, chemogenetic inhibition of NTS^NPY neurons mimicked the eating-suppressing effect of exendin-4. Collectively, our findings highlight a population of orexigenic NTS^NPY neurons that may be targeted by a GLP-1R agonist to suppress food intake, suggesting that this neuronal population has translational importance as a potential therapeutic target for obesity treatment.<b>NEW & NOTEWORTHY</b> This study discovers that the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 indirectly inhibits the majority of orexigenic hindbrain NPY neurons via GABA_b receptors by augmenting presynaptic GABA release. Chemogenetic activation of these NPY neurons effectively counteracts exendin-4 (Exn-4)-induced anorexigenic effect, whereas chemogenetic inhibition of them mimics the eating-suppressing effect of exendin-4. This study uncovers a mechanism by which Exn-4 inhibits orexigenic hindbrain NPY neurons, thereby providing new insights into how GLP-1 drugs suppress food intake.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E661-E674"},"PeriodicalIF":4.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699378","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":"Increased cGMP improves microvascular exercise training adaptations in diet-induced obesity.","authors":"Nathan C Winn, David A Cappel, Ethan D Pollack, Louise Lantier, Jillian K Riveros, Deanna P Bracy, Joshua A Beckman, David H Wasserman","doi":"10.1152/ajpendo.00368.2024","DOIUrl":"10.1152/ajpendo.00368.2024","url":null,"abstract":"<p><p>With the development of atherosclerosis, impaired microvascular function can result in diminished capacity for ambulation and is a risk factor for type 2 diabetes. Dynamic changes in vascular tone are determined, in large part, by the endothelial nitric oxide synthase (eNOS)/nitric oxide (NO)/cGMP axis. We used pharmacological gain of function of the eNOS/NO/cGMP axis in diet-induced obese (DIO) mice and reduced function in lean mice to test the hypothesis that functionality of this vascular control mechanism parallels the benefits of an exercise training regimen. DIO mice have 50% lower exercise capacity (<i>P</i> < 0.0001) than lean mice and were used for pharmacological gain of function. The phosphodiesterase-5a (PDE-5a) inhibitor, sildenafil, increases cGMP and was administered to DIO mice daily. In sedentary mice, neither acute nor chronic sildenafil improves exercise capacity. In contrast, chronic sildenafil synergizes with exercise training to improve performance during an incremental exercise test. Improved exercise performance was accompanied by a 40% increase in basal skeletal muscle capillary flow velocity and <i>∼</i>20% increase in plasma-perfused capillary density measured via intravital microscopy. Loss of function was tested in lean mice hemizygous for endothelial cell (EC) specific eNOS creating an EC-eNOS knockdown (KD). EC-eNOS KD decreases capillary density and exercise tolerance in sedentary mice; however, it did not prevent exercise-training-induced improvements in endurance capacity. These data show that <i>1</i>) increasing cGMP with sildenafil enhances microcirculatory function and exercise work tolerance that results from training; <i>2</i>) eNOS KD does not prevent the microcirculatory or improvements in exercise tolerance with training. PDE-5a inhibitors combined with physical exercise are a potential mechanism for improving ambulation in patients with circulatory limitations.<b>NEW & NOTEWORTHY</b> This study used pharmacological gain-of-function and genetic loss-of-function approaches to test the hypothesis that the eNOS/NO/cGMP axis is central to exercise training adaptations in microcirculatory function and exercise capacity. Chronic but not acute treatment with the PDE5 inhibitor, sildenafil, synergizes with exercise training to improve performance with incremental exercise in obese mice; whereas endothelium-specific knockdown in eNOS does not blunt the microcirculatory adaptations and improvements in exercise tolerance with training.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"328 5","pages":"E711-E722"},"PeriodicalIF":4.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961022","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":"The choice of diet is determinative for the manifestation of UCP1-dependent diet-induced thermogenesis.","authors":"Raman Ahluwalia, Ineke H N Luijten, Celso P B Sousa-Filho, G Ruda F Braz, Natasa Petrovic, Irina G Shabalina, Barbara Cannon, Jan Nedergaard","doi":"10.1152/ajpendo.00038.2025","DOIUrl":"10.1152/ajpendo.00038.2025","url":null,"abstract":"<p><p>The existence of the phenomenon of diet-induced thermogenesis-and its possible mediation by UCP1 in brown adipose tissue-has long been, and is presently, an important metabolic controversy. Particularly, several recent studies have failed to observe the hallmark of the phenomenon: augmentation of diet-induced obesity (i.e., fat mass) in UCP1-ablated mice, thus further casting doubt on the possible importance of this thermogenesis, for example in human metabolic control. However, scrutiny of the experimental details revealed important procedural differences between experiments that did not show or did show this augmentation of diet-induced obesity. Particularly, there were notable differences between the commercial diets used (Research Diets or Ssniff). We, therefore, tested to what degree these differences would suffice to explain the absence of a UCP1 effect. Wild-type mice fed Research Diets high-fat diet became obese, but UCP1-ablated mice became even more obese, as expected if UCP1-dependent diet-induced thermogenesis exists. Mice fed the Ssniff high-fat diet became less obese than those on the Research Diets food-and, importantly, no effect of UCP1 ablation was seen. The result with the Research Diets diet was fully due to differences in total fat mass and not explainable by differences in food intake. The two diets are different in carbohydrate (sucrose) and lipid (lard vs. palm oil) composition and in texture and taste. Probably some of these factors explain the difference, but the important conclusion is that when an appropriate diet was offered, the body weight manifestation of the phenomenon of UCP1-dependent diet-induced thermogenesis was a reproducible phenomenon, the existence of which may have significance also for human metabolic control.<b>NEW & NOTEWORTHY</b> A main reason for the present interest in brown adipose tissue in humans is the possibility that this tissue mediates diet-induced thermogenesis, i.e., the ability to combust some of the foods eaten, thus lessening the burden of obesity. However, several recent papers have queried the existence of diet-induced thermogenesis. We demonstrate that these negative observations are explainable by the types of diet offered, and diet-induced thermogenesis thus remains a potentially important contributor to metabolic equilibrium.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E653-E660"},"PeriodicalIF":4.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646955","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":"Central lipid sensing pathways contribute to the control of puberty and its alterations in conditions of obesity.","authors":"Elvira Rodríguez-Vázquez, Álvaro Aranda-Torrecillas, María López-Sancho, Manuel Jiménez-Puyer, Silvia Daza-Dueñas, Alexia Barroso, Verónica Sobrino, Francisco Gaytan, Elia Obis, Juan M Castellano, Manuel Tena-Sempere","doi":"10.1152/ajpendo.00493.2024","DOIUrl":"10.1152/ajpendo.00493.2024","url":null,"abstract":"<p><p>Childhood obesity, especially in girls, often correlates with advanced puberty and long-term comorbidities. Among the central circuits controlling energy homeostasis, hypothalamic lipid sensing pathways, involving free fatty-acid receptors (FFARs), peroxisome proliferator-activated receptors (PPARs), and the bile-acid (BA) receptor, Takeda G protein-coupled receptor 5 (TGR5), have been recognized as major players, with putative pathogenic roles in obesity and its complications. However, their contribution to pubertal regulation and obesity-induced pubertal alterations remains largely unexplored. We describe herein changes in the hypothalamic profiles of specific lipid species, including certain fatty-acyls, BA derivatives, and several glycerolphospholipids, during the juvenile-pubertal transition and conditions of overweight linked to precocious puberty in female rats. Hypothalamic expression of the FFAR, <i>Gpr84</i>, as well as <i>Ppar-γ</i> and <i>Tgr5</i> gradually increased during the infantile-prepubertal transition, whereas early overfeeding increased hypothalamic mRNA levels of the FFARs, <i>Gpr43</i>, and <i>Gpr84</i>. Expression of <i>Gpr84</i>, <i>Ppar-α</i>, and <i>Tgr5</i> was documented in FACS-isolated Kiss1 neurons from juvenile and pubertal female mice. Central pharmacological gain- and loss-of-function manipulations of GPR84-, PPAR-, or TGR5-signaling in prepubertal lean and early overfed female rats resulted in specific changes in pubertal timing. In lean rats, central blockade of PPAR-γ/α delayed puberty onset, whereas in early overfed rats, central stimulation of TGR5 signaling partially prevented obesity-induced advanced puberty; effects that were also marginally observed after GPR84 inhibition. Our results disclose the role of brain lipid-sensing pathways in the control of puberty, with a variable contribution of central FFAR-, PPAR-, and TGR5-signaling depending on the maturational and nutritional status.<b>NEW & NOTEWORTHY</b> Puberty is highly sensitive to body energy status, and child obesity is often linked to perturbed puberty. However, whether this comes from excessive energy stores or specific nutrient signals altered in obesity remains largely unexplored. Using suitable preclinical models of early obesity and accelerated puberty, we disclose herein conclusive evidence for altered hypothalamic lipid profiles and the roles of specific lipid-sensing pathways in pubertal control, with a variable contribution depending on the maturational and nutritional status.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E675-E694"},"PeriodicalIF":4.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762684","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":"Roles of circadian clocks in macrophage metabolism: implications in inflammation and metabolism of lipids, glucose, and amino acids.","authors":"Mohammad Irfan Dar, Yusuf Hussain, Xiaoyue Pan","doi":"10.1152/ajpendo.00009.2025","DOIUrl":"10.1152/ajpendo.00009.2025","url":null,"abstract":"<p><p>Macrophages are essential immune cells that play crucial roles in inflammation and tissue homeostasis and are important regulators of metabolic processes, such as the metabolism of glucose, lipids, and amino acids. The regulation of macrophage metabolism by circadian clock genes has been emphasized in many studies. Changes in metabolic profiles occurring after the perturbation of macrophage circadian cycles may underlie the etiology of several diseases. Specifically, chronic inflammatory disorders, such as atherosclerosis, diabetes, cardiovascular diseases, and liver dysfunction, are associated with poor macrophage metabolism. Developing treatment approaches that target metabolic and immunological ailments requires an understanding of the complex relationships among clock genes, disease etiology, and macrophage metabolism. This review explores the molecular mechanisms through which clock genes regulate lipid, amino acid, and glucose metabolism in macrophages and discusses their potential roles in the development and progression of metabolic disorders. The findings underscore the importance of maintaining circadian homeostasis in macrophage function as a promising avenue for therapeutic intervention in diseases involving metabolic dysregulation, given its key roles in inflammation and tissue homeostasis. Moreover, reviewing the therapeutic implications of circadian rhythm in macrophages can help minimize the side effects of treatment. Novel strategies may be beneficial in treating immune-related diseases caused by shifted and blunted circadian rhythms via light exposure, jet lag, seasonal changes, and shift work or disruption to the internal clock (such as stress or disease).</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E723-E741"},"PeriodicalIF":4.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794537","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":"Discovery of a novel regulator, 3β-sulfate-5-cholestenoic acid, of lipid metabolism and inflammation.","authors":"Yaping Wang, Arun J Sanyal, Phillip Hylemon, Shunlin Ren","doi":"10.1152/ajpendo.00426.2024","DOIUrl":"10.1152/ajpendo.00426.2024","url":null,"abstract":"<p><p>Mitochondrial oxysterols, cholestenoic acid (CA), 25-hydroxycholesterol (25HC), and 27-hydroxycholesterol (27HC), are potent regulators involved in many important biological events. This study aimed to investigate the metabolic pathways of these oxysterols and their roles between hepatocytes and macrophages. LC-MS/MS analysis showed a novel regulatory molecule, 3β-sulfate-5-cholestenoic acid (3SCA), following the addition of CA in media culturing hepatocytes. Further study showed that 3SCA could also be derived from 27HC. In comparison, 25HC was converted to 25HC3S, which mostly remained in the cells and nuclei. The functional study showed that 3SCA significantly downregulated the expression of genes involved in lipid metabolism in hepatocytes and suppressed gene expression of proinflammatory cytokines induced by lipopolysaccharide in human macrophages. Based on the results, we conclude that 3SCA acts as a secretory regulator for the regulation of lipid metabolism and inflammatory responses in hepatocytes and macrophages. These findings shed light on understanding the unique metabolic pathways of these oxysterols and their possible roles in liver tissues.<b>NEW & NOTEWORTHY</b> This study identifies a novel oxysterol metabolite, 3β-sulfate-5-cholestenoic acid (3SCA), secreted by hepatocytes, which regulates lipid metabolism and inflammatory responses in hepatocytes and macrophages. These findings reveal previously unknown metabolic pathways of mitochondrial oxysterols and their roles in the progression and recovery of metabolic dysfunction-associated steatotic liver disease (MASLD), offering novel insights into potential therapeutic targets.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E543-E554"},"PeriodicalIF":4.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565780","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":"Effect of in utero metformin exposure in gestational diabetes mellitus on infant mesenchymal stem cell metabolism.","authors":"Ericka M Biagioni, John C Rowe, Sripallavi Yendamuri, Breanna L Wisseman, Donghai Zheng, Guofang Zhang, Deborah M Muoio, James E DeVente, Kelsey H Fisher-Wellman, P Darrell Neufer, Linda E May, Nicholas T Broskey","doi":"10.1152/ajpendo.00428.2024","DOIUrl":"10.1152/ajpendo.00428.2024","url":null,"abstract":"<p><p>Offspring exposed to metformin treatment for gestational diabetes mellitus (GDM) experience altered growth patterns that increase the risk for developing cardiometabolic diseases later in life. The adaptive cellular mechanisms underlying these patterns remain unclear. Therefore, the objective of this study was to determine whether chronic in utero metformin exposure associated with GDM treatment elicits infant cellular metabolic adaptations. In a cross-sectional design, 22 pregnant women diagnosed with GDM and treated exclusively with metformin (Met; <i>n</i> = 12) or diet (A1DM; <i>n</i> = 10) were compared. Umbilical cord-derived mesenchymal stem cells (MSCs) were used as a model to study infant metabolism in vitro. OXPHOS and citrate synthase content were assessed by Western blot and intracellular lipid content was measured by Oil Red-O staining. Substrate oxidation and insulin action were measured with ¹⁴C radiolabeled glucose and oleate at baseline and following a 24-h lipid challenge. Mitochondrial respiration was assessed by high-resolution respirometry. Although no differences in infant birth measures were observed between groups, MSC outcomes revealed lower oleate oxidation rates (<i>P</i> = 0.03) and lower mitochondrial capacity (<i>P</i> = 0.009) among Met-MSCs. These findings suggest differences in energy metabolism may be present at birth among offspring exposed to metformin in utero. Lower oleate oxidation and mitochondrial capacity in infant MSC may contribute to altered growth patterns that have been reported among offspring of metformin-treated pregnant women with GDM.<b>NEW & NOTEWORTHY</b> Mesenchymal stem cells (MSCs) of infants born to women with gestational diabetes mellitus (GDM) treated by metformin display lower rates of oleate oxidation despite no limitations in lipid availability compared with GDM treated by diet. Mitochondrial capacity was also lower among infant MSCs from metformin-treated GDM.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E567-E578"},"PeriodicalIF":4.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613025","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":"The effect of a leptin phenotype on weight change and energy expenditure responses to acute and prolonged energetic stressors.","authors":"Kaja Falkenhain, Tomás Cabeza De Baca, Emma J Stinson, Eric Ravussin, Paolo Piaggi, Jonathan Krakoff, Leanne M Redman","doi":"10.1152/ajpendo.00067.2025","DOIUrl":"10.1152/ajpendo.00067.2025","url":null,"abstract":"<p><p>Leptin is a hormone produced by adipocytes that plays a crucial role in regulating energy homeostasis and body mass. Despite its close correlation with body fat, up to ∼40% of variation in plasma leptin concentration remains unexplained, allowing for the classification of a distinct \"leptin phenotype.\" This leptin phenotype-characterized by either relatively high or relatively low leptin concentration relative to an individual's level of body fat-presents an intriguing opportunity to test whether relatively higher (compared with lower) leptin concentrations differentially affect energy expenditure, metabolic adaptation, and susceptibility to weight change in response to energy balance perturbations. To test this hypothesis, we characterized the energy expenditure and weight change response between the two leptin phenotypes (relatively high vs. low) using three distinct experimental contexts: a cross-sectional analysis (<i>n</i> = 104), acute (24-h) perturbations with fasting and overfeeding (<i>n</i> = 77), and chronic perturbations with 24-mo caloric restriction (<i>n</i> = 144) or 8-wk overfeeding (<i>n</i> = 28). Leptin phenotype did not explain variations in energy expenditure responses either in cross-sectional analyses or in response to acute or prolonged energetic stressors. Moreover, leptin phenotype was not a determinant of weight change in response to energy restriction or surplus, or subsequent weight recovery. These results suggest that classifying individuals based on a leptin phenotype does not allow to detect differential susceptibility to energy expenditure adaptations or weight change.<b>NEW & NOTEWORTHY</b> Leptin is linked to body fat, but unexplained variation remains. This study challenges the idea that distinct leptin phenotypes-characterized by relatively high or low leptin concentration for a given level of body fat-affects energy expenditure or weight change in response to acute or prolonged energy stressors. We found no association between leptin phenotypes and energy expenditure or weight change either cross-sectionally or in response to acute or prolonged over- or underfeeding.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E579-E587"},"PeriodicalIF":4.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646957","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}