American journal of physiology. Endocrinology and metabolism最新文献

{"title":"Counterregulatory responses of healthy cats to insulin- induced-hypoglycemia.","authors":"Jocelyn Mott, Christopher Adin, Chiquitha Crews, Marc Evan Salute, Antonio Maria Tardo, Lauren Porter, Alisa Berg, Chen Gilor","doi":"10.1152/ajpendo.00269.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00269.2024","url":null,"abstract":"<p><p>In health, insulin-induced-hypoglycemia (IIH) activates counterregulatory hormones responses and parasympathetic (PS) and sympathoadrenal systems which leads to increased glucagon secretion. In diabetes mellitus, these responses are impaired, resulting in greater severity and delayed recovery from hypoglycemia. These counterregulatory responses in health and disease have been documented in humans, rodents, and dogs, but not yet in cats. The aim of this study was to describe and quantify glucagon, PS and cortisol responses in healthy purpose bred cats at increasing levels of IIH. Glucagon, cortisol, and pancreatic polypeptide (PP) were measured at euglycemia and during stepped hyperinsulinemic-hypoglycemic clamps at two levels of glycemia: moderate hypoglycemia (blood glucose [BG] ~60 mg/dL) and severe hypoglycemia (BG ~45 mg/dL). At moderate hypoglycemia, a cortisol response occurred. At moderate hypoglycemia there was no change in PP and glucagon from baseline. With severe hypoglycemia, both glucagon and PP concentrations decreased from baseline and were not supportive of glucagon and parasympathetic activation in response to IIH. While cortisol increases during IIH, the counterregulatory response to IIH in healthy cats differs from other species, in that glucagon and PS responses were not detected. Moreover, in face of constant inhibition by IIH, glucagon secretion seems dependent on glucose, decreasing when glucose infusion rates were decreased. Understanding counterregulatory responses to hypoglycemia in healthy cats is the first step to exploring how diabetes might impair these responses in cats, as seen in other species.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514394","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":"L-type calcium channel blockade worsens glucose tolerance and β-cell function in C57BL6/J mice exposed to intermittent hypoxia.","authors":"Stanley M Chen Cardenas, Tess A Baker, Larissa A Shimoda, Ernesto Bernal-Mizrachi, Naresh M Punjabi","doi":"10.1152/ajpendo.00423.2023","DOIUrl":"10.1152/ajpendo.00423.2023","url":null,"abstract":"<p><p>Intermittent hypoxemia (IH), a pathophysiologic consequence of obstructive sleep apnea (OSA), adversely affects insulin sensitivity, insulin secretion, and glucose tolerance. Nifedipine, an L-type calcium channel blocker frequently used for the treatment of hypertension, can also impair insulin sensitivity and secretion. However, the cumulative and interactive repercussions of IH and nifedipine on glucose homeostasis have not been previously investigated. Adult male C57BL6/J mice were exposed to either nifedipine or vehicle concurrently with IH or intermittent air (IA) over 5 days. IH exposure entailed cycling fractional-inspired oxygen levels between 0.21 and 0.055 at a rate of 60 events/h. Nifedipine (20 mg/kg/day) or vehicle was administered via subcutaneous osmotic pumps resulting in four groups of mice: IA-vehicle (control), IA-nifedipine, IH-vehicle, and IH-nifedipine. Compared with IA (control), IH increased fasting glucose (mean Δ: 33.0 mg/dL; <i>P</i> < 0.001) and insulin (mean Δ: 0.53 ng/mL; <i>P</i> < 0.001) with nifedipine having no independent effect. Furthermore, glucose tolerance was worse with nifedipine alone, and IH further exacerbated the impairment in glucose disposal (<i>P</i> = 0.013 for interaction). Nifedipine also decreased glucose-stimulated insulin secretion and the insulinogenic index, with addition of IH attenuating those measures further. There were no discernible alterations in insulin biosynthesis/processing, insulin content, or islet morphology. These findings underscore the detrimental impact of IH on insulin sensitivity and glucose tolerance while highlighting that nifedipine exacerbates these disturbances through impaired β-cell function. Consequently, cautious use of L-type calcium channel blockers is warranted in patients with OSA, particularly in those at risk for type 2 diabetes.<b>NEW & NOTEWORTHY</b> The results of this study demonstrate the interaction between intermittent hypoxemia (IH) and nifedipine in a murine model. IH raises fasting glucose and insulin levels, with nifedipine exacerbating these disturbances. Glucose tolerance worsens when nifedipine is administered alone, and IH magnifies the impairment in glucose disposal. These findings raise the possibility of potential deleterious effects of L-type calcium channel blockers in patients with obstructive sleep apnea (OSA).</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"328 2","pages":"E161-E172"},"PeriodicalIF":4.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021717","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":"Carbohydrate supplementation maintains physical performance during short-term energy deficit despite reductions in exogenous glucose oxidation.","authors":"Lee M Margolis, Jillian T Allen, Nancy E Murphy, Christopher T Carrigan, Emily E Howard, David E Barney, Devin J Drummer, Julia Michalak, Arny A Ferrando, Stefan M Pasiakos, Jess A Gwin","doi":"10.1152/ajpendo.00418.2024","DOIUrl":"10.1152/ajpendo.00418.2024","url":null,"abstract":"<p><p>Exogenous glucose oxidation is reduced 55% during aerobic exercise after 3 days of complete starvation. Whether energy deficits more commonly experienced by athletes and military personnel similarly affect exogenous glucose oxidation and what impact this has on physical performance remains undetermined. This randomized, longitudinal parallel study aimed to assess the effects of varying magnitudes of energy deficit (DEF) on exogenous glucose oxidation and physical performance compared with energy balance (BAL). Participants consumed a 4-day BAL diet, followed by a 6-day 20% (<i>n</i> = 10), 40% (<i>n</i> = 10), or 60% (<i>n</i> = 10) DEF diet. At the end of each energy phase, participants performed 90-min of steady-state cycle ergometry (56 ± 3% V̇o_2peak) while consuming a glucose drink (80 g), followed by a time to exhaustion (TTE) performance test. Substrate oxidation (g/min) was determined by indirect calorimetry and ¹³C-glucose. Muscle glycogen (mmol/kg dry wt) and transcript accumulation were assessed in rested fasted muscle collected before exercise in each phase. Muscle glycogen was lower (<i>P</i> = 0.002) during DEF (365 ± 179) than BAL (456 ± 125), regardless of group. Transcriptional regulation of glucose uptake (<i>GLUT4</i> and <i>IRS2</i>) and glycogenolysis (<i>HKII</i> and <i>PKM</i>) were lower (<i>P</i> < 0.05) during DEF than BAL, independent of group. Regardless of group, exogenous glucose oxidation was 10% lower (<i>P</i> < 0.001) during DEF (0.38 ± 0.08) than BAL (0.42 ± 0.08). There was no evidence of a difference in TTE between BAL and DEF or between groups. In conclusion, despite modest reduction in exogenous glucose oxidative capacity during energy deficit, physical performance was similar compared with balance.<b>NEW & NOTEWORTHY</b> Short-term (6-day) energy deficit reduced exogenous glucose oxidation during exercise. Though less exogenous glucose was used for fuel, young healthy individuals appear to have a metabolic resilience to short-term periods of low energy availability, with no observed differences in the ability to take up and oxidize exogenous glucose between minimal (20%), moderate (40%), and severe (60%) energy deficits. Similar metabolic responses to carbohydrate supplementation independent of deficit severity likely contributed to sustainment of physical performance.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E242-E253"},"PeriodicalIF":4.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998516","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":"Metabolomic and transcriptomic remodeling of bone marrow myeloid cells in response to maternal obesity.","authors":"Yem J Alharithi, Elysse A Phillips, Tim D Wilson, Sneha P Couvillion, Carrie D Nicora, Priscila Darakjian, Shauna Rakshe, Suzanne S Fei, Brittany R Counts, Thomas O Metz, Robert P Searles, Sushil Kumar, Alina Maloyan","doi":"10.1152/ajpendo.00333.2024","DOIUrl":"10.1152/ajpendo.00333.2024","url":null,"abstract":"<p><p>Maternal obesity puts the offspring at high risk of developing obesity and cardiometabolic diseases in adulthood. Here, we utilized a mouse model of maternal high-fat diet (HFD)-induced obesity that recapitulates metabolic perturbations seen in humans. We show increased adiposity in the offspring of HFD-fed mothers (Off-HFD) when compared with the offspring of regular diet-fed mothers (Off-RD). We have previously reported significant immune perturbations in the bone marrow of newly weaned Off-HFD. Here, we hypothesized that lipid metabolism is altered in the bone marrow of Off-HFD versus Off-RD. To test this hypothesis, we investigated the lipidomic profile of bone marrow cells collected from 3-week-old Off-RD and Off-HFD. Diacylglycerols (DAGs), triacylglycerols (TAGs), sphingolipids, and phospholipids were remarkably different between the groups, independent of fetal sex. Levels of cholesteryl esters were significantly decreased in Off-HFD, suggesting reduced delivery of cholesterol. These were accompanied by age-dependent progression of mitochondrial dysfunction in bone marrow cells. We subsequently isolated CD11b+ myeloid cells from 3-wk-old mice and conducted metabolomic, lipidomic, and transcriptomic analyses. The lipidomic profiles of myeloid cells were similar to those of bone marrow cells and included increases in DAGs and decreased TAGs. Transcriptomics revealed altered expression of genes related to immune pathways, including macrophage alternative activation, B-cell receptors, and transforming growth factor-β signaling. All told, this study revealed lipidomic, metabolomic, and gene expression abnormalities in bone marrow cells broadly, and in bone marrow myeloid cells particularly, in the newly weaned offspring of mothers with obesity, which might at least partially explain the progression of metabolic and cardiovascular diseases in their adulthood.<b>NEW & NOTEWORTHY</b> Our data revealed significant immunometabolic perturbations in the bone marrow and myeloid cells in the newly weaned offspring born to mothers with obesity. Adaptation to an adverse maternal intrauterine environment affects bone marrow metabolism at a very young age and might affect responses to immune challenges that appear later in life, for example, infections or cancer.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E254-E271"},"PeriodicalIF":4.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942696","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":"Neuroimmunometabolism: how metabolism orchestrates immune response in healthy and diseased brain.","authors":"Anil Kumar Rana, Babita Bhatt, Chitralekha Gusain, Surya Narayan Biswal, Debashree Das, Mohit Kumar","doi":"10.1152/ajpendo.00331.2024","DOIUrl":"10.1152/ajpendo.00331.2024","url":null,"abstract":"<p><p>Neuroimmunometabolism describes how neuroimmune cells, such as microglia, adapt their intracellular metabolic pathways to alter their immune functions in the central nervous system (CNS). Emerging evidence indicates that neurons also orchestrate the microglia-mediated immune response through neuro-immune cross talk, perhaps through metabolic signaling. However, little is known about how the brain's metabolic microenvironment and microglial intracellular metabolism orchestrate the neuroimmune response in healthy and diseased brains. This review addresses the balance of immunometabolic substrates in healthy and diseased brains, their metabolism by brain-resident microglia, and the potential impact of metabolic dysregulation of these substrates on the neuroimmune response and pathophysiology of psychiatric disorders. This review also suggests metabolic reprogramming of microglia as a preventive strategy for the management of neuroinflammation-related brain disorders, including psychiatric diseases.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E217-E229"},"PeriodicalIF":4.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942698","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":"Induction of erythropoietin by dietary medium-chain triacylglycerol in humans.","authors":"Josephine M Kanta, Annemarie Lundsgaard, Amanda Schaufuss, Maximilian Kleinert, Bente Kiens, Andreas M Fritzen","doi":"10.1152/ajpendo.00415.2024","DOIUrl":"10.1152/ajpendo.00415.2024","url":null,"abstract":"<p><p>Erythropoietin (EPO) is pivotal in regulating red blood cell (erythrocyte) concentrations and is primarily synthesized in the kidney. Recent research has unveiled a possible link between elevated circulating concentrations of ketone bodies (KB) and circulating EPO concentrations; however, it is not known whether nutritionally induced endogenous ketogenesis can be a stimulus to induce EPO in humans. Therefore, this study aimed to assess whether acute and chronic intake of medium-chain fatty acid-containing triacylglycerol (MCT), which rapidly enhances endogenous circulating KB, would elevate circulating EPO concentrations in humans, as indicated by prior work with exogenous KB administration. The study followed a crossover design involving 16 young men undergoing two 8-day MCT or energy-matched long-chain fatty acid-containing triacylglycerol (LCT) interventions in a randomized order. Five-hour test days were performed before and after each intervention, in which circulating KB and EPO concentrations as well as hematological parameters were assessed. Acute intake of MCT yielded a 222% sustained 5-h elevation in KB concentrations compared with LCT-with notable peak values of 0.7 ± 0.1 mmol·L^-1 (312% above basal values). Remarkably, within just 8 days of daily MCT intake an impressive 38% increase in basal, fasting plasma EPO concentrations (7.19 ± 1.14 to 9.91 ± 1.25 mIU·mL^-1) was demonstrated. In conclusion, this study unveils a novel physiological stimulus of circulating EPO concentrations in humans, potentially offering a new dietary approach to counter anemia in cardiovascular diseases.<b>NEW & NOTEWORTHY</b> This study is the first to assess the effects of nutritionally induced ketogenesis by acute and subchronic intake of medium-chain fatty acids on plasma erythropoietin concentrations. Medium-chain fatty acid intake increases postprandial ketone body concentrations and within only 8 days of daily intake substantially enhances basal plasma erythropoietin concentrations in young men. We therefore reveal a dietary stimulus of endogenous circulating erythropoietin concentrations in humans, with the potential to counter anemia in cardiovascular diseases.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E210-E216"},"PeriodicalIF":4.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942656","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":"Roux-en-Y gastric bypass alleviates kidney inflammation and improves kidney function in <i>db/db</i> mice by activating TLCA/TGR5 pathway.","authors":"Hongmei Lang, Jie Xiang, Xiaorong Chen, Dan Tong, Lijuan Wang, Aidi Mou, Daoyan Liu, Peng Gao, Zongshi Lu, Zhiming Zhu","doi":"10.1152/ajpendo.00248.2024","DOIUrl":"10.1152/ajpendo.00248.2024","url":null,"abstract":"<p><p>Diabetic kidney disease (DKD) is a severe diabetic microvascular complication featured by chronic low-grade inflammation. Roux-en-Y gastric bypass (RYGB) surgery has gained importance as a safe and effective surgery to treat DKD. Bile acids significantly change after RYGB, which brings a series of metabolic benefits, but the relationship with the improvement of DKD is unclear. Therefore, this study performed RYGB surgery on <i>db/db</i> mice to observe the beneficial effects of the surgery on the kidneys and performed bile acid-targeted metabolomics analysis to explore bile acid changes. We found that RYGB significantly reduced albuminuria in <i>db/db</i> mice, improved renal function, reversed renal structural lesions, and attenuated podocyte injury and inflammation. Notably, bile acid metabolomic analysis revealed taurolithocholic acid (TLCA) as the most significantly altered bile acid after RYGB. Furthermore, in vitro and in vivo validation experiments revealed that TLCA supplementation improved renal function and reduced renal inflammatory damage in <i>db/db</i> mice. In addition, TLCA inhibited high glucose-induced inflammatory damage in MPC-5 cells, and its mechanism of action may be related to activating Takeda G protein-coupled receptor 5 (TGR5), inhibiting NF-κB phosphorylation, and thus inhibiting inflammatory response. In conclusion, RYGB may play a protective role in the kidneys of diabetic mice by activating the TLCA/TGR5 pathway.<b>NEW & NOTEWORTHY</b> This study determined that the renal protective effect of Roux-en-Y gastric bypass (RYGB) in <i>db/db</i> mice was associated with elevated serum TLCA. Notably, TLCA supplementation improved renal function and alleviated podocyte inflammatory injury in <i>db/db</i> mice, which was associated with the TGR5/NF-κB pathway.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E148-E160"},"PeriodicalIF":4.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833380","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":"Celebrating 30 years of the discovery of leptin: a revolutionary shift in understanding obesity and metabolism.","authors":"Estefania P Azevedo","doi":"10.1152/ajpendo.00520.2024","DOIUrl":"10.1152/ajpendo.00520.2024","url":null,"abstract":"","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E272-E273"},"PeriodicalIF":4.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998517","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":"Macrophage immunometabolism: emerging targets for regrowth in aging muscle.","authors":"Zachary J Fennel, Ryan M O'Connell, Micah J Drummond","doi":"10.1152/ajpendo.00403.2024","DOIUrl":"10.1152/ajpendo.00403.2024","url":null,"abstract":"<p><p>The recovery from muscle atrophy is impaired with aging as characterized by improper muscle remodeling and sustained functional deficits. Age-related deficits in muscle regrowth are tightly linked with the loss of early pro-inflammatory macrophage responses and subsequent cellular dysregulation within the skeletal muscle niche. Macrophage inflammatory phenotype is regulated at the metabolic level, highlighting immunometabolism as an emerging strategy to enhance macrophage responses and restore functional muscle regrowth. Accordingly, metabolic targets with an emphasis on glycolytic, hypoxia, and redox-related pathways stand out for their role in promoting macrophage inflammation and enhancing muscle regrowth in aging. Here we highlight promising immuno-metabolic targets that could be leveraged to restore optimal pro-inflammatory macrophage function in aging and enhance muscle regrowth following muscular atrophy.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"328 2","pages":"E186-E197"},"PeriodicalIF":4.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063098","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":"Constitutive loss of kynurenine-3-monooxygenase changes circulating kynurenine metabolites without affecting systemic energy metabolism.","authors":"Kyle D Dumont, Paulo R Jannig, Margareta Porsmyr-Palmertz, Jorge L Ruas","doi":"10.1152/ajpendo.00386.2024","DOIUrl":"10.1152/ajpendo.00386.2024","url":null,"abstract":"<p><p>Kynurenic acid (KYNA) and quinolinic acid (QUIN) are metabolites of the kynurenine pathway of tryptophan degradation with opposing biological activities in the central nervous system. In the periphery, KYNA is known to positively affect metabolic health, whereas the effects of QUIN remain less explored. Interestingly, metabolic stressors, including exercise and obesity, differentially change the balance between circulating KYNA and QUIN. Here, we hypothesized that chronically elevated levels of circulating KYNA and reduced levels of QUIN would manifest as differences in whole body energy metabolism. To test this, we used a mouse model lacking the enzyme kynurenine 3-monooxygenase (KMO), thus shunting kynurenine away from QUIN synthesis and toward KYNA production. KMO-deficient and wild-type littermate male and female mice were evaluated under chow and high-fat diets. Comprehensive kynurenine pathway metabolite profiling in plasma showed that the loss of KMO elicits robust changes in circulating levels of kynurenine metabolites. This included a 45-fold increase in kynurenine, a 26-fold increase in KYNA, and a 99% decrease in QUIN levels, depending on the diet. However, despite these changes, loss of KMO did not significantly impact whole body energy metabolism or change the transcriptomic profile of subcutaneous adipose tissue on either diet. With KMO inhibitors being considered therapeutic candidates for various disorders, this work shows that chronic systemic KMO inhibition does not have widespread metabolic effects. Our data also indicate that the beneficial effects of KYNA on metabolism may depend on its acute, intermittent elevation in circulation, akin to transient exercise-induced signals that mediate improved metabolic health.<b>NEW & NOTEWORTHY</b> The kynurenine pathway of tryptophan degradation is influenced by metabolic stressors: exercise raises circulating KYNA levels, while obesity is linked to increased QUIN. We investigated whether a mouse model lacking KMO-leading to increased circulating KYNA and decreased QUIN-would exhibit changes in energy metabolism. We found that energy metabolism was largely unaffected despite robust changes in circulating kynurenine metabolites, suggesting that systemic KMO inhibition may not have widespread metabolic effects.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E274-E285"},"PeriodicalIF":4.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977229","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}