American journal of physiology. Endocrinology and metabolism最新文献

{"title":"Generation of Ucp1-ires-Cre knock-in mice to enhance specificity and efficiency of gene targeting in brown adipose tissue.","authors":"Jen-Ying Hsu, Wen-Hsin Lu, Yu-Ya Chang, Po-Chen Chiang, Pei-Chih King, Yu-Hsuan Hsu, Yi-Shuian Huang","doi":"10.1152/ajpendo.00533.2025","DOIUrl":"10.1152/ajpendo.00533.2025","url":null,"abstract":"<p><p>Brown adipose tissue (BAT) secretes cytokines that influence the function of other tissues. Given the widespread distribution of brown fat depots, we generated BAT-lacking (ΔBAT) mouse models by specifically eliminating brown adipocytes using the Cre-loxP system combined with a floxed-stop diphtheria toxin A (DTA) cassette. Uncoupling protein 1 (UCP1) is essential for BAT thermogenesis and exhibits a highly restricted expression pattern, so it was chosen to direct BAT-specific Cre recombinase expression. We used CRISPR-Cas9 to insert an ires-Cre sequence downstream of the UCP1 stop codon, developing the novel knock-in line, <i>Ucp1-Cre</i>^YH. <i>Ucp1-Cre</i>^YH and transgenic line <i>TgUcp1-Cre</i>^Evdr mouse (<i>Ucp1</i>-<i>Cre</i>^Evdr) were crossed with Ai14-tdTomato and floxed-CPEB2 mice to assess Cre specificity and efficiency. ΔBAT mice were then generated by crossing each Cre line with floxed-stop DTA mice, followed by assessments of locomotor activity, body weight, and glucose tolerance. Although both Cre lines showed cold-enhanced expression, <i>Ucp1</i>-<i>Cre</i>^Evdr exhibited considerably lower Cre levels in BAT compared with <i>Ucp1</i>-<i>Cre</i>^YH mice, leading to inefficient ablation of some floxed alleles, such as <i>Cpeb2</i>. Moreover, <i>Ucp1</i>-<i>Cre</i>^Evdr mice displayed nonspecific Cre expression, whereas neither line showed evidence of substantial autonomous Cre activity in BAT-resident macrophages. Consequently, ΔBAT^Evdr mice experienced off-target neuronal ablation, resulting in hyperactive locomotion and reduced body weight. Although ΔBAT^YH mice showed normal locomotor activity and body weight, they had a modest weight gain and altered glucose homeostasis only after high-fat-diet feeding. In conclusion, novel <i>Ucp1</i>-Cre knock-in mouse showed specificity and efficiency for gene manipulation in brown adipocytes, highlighting its application in generating BAT-specific knockout and BAT-depleted mouse models.<b>NEW & NOTEWORTHY</b> A novel Ucp1-CreYH knock-in mouse exhibits improved efficiency and specificity of Cre recombinase activity in brown adipose tissue (BAT) compared with the widely used Ucp1-CreEvdr line, which showed nonspecific Cre activity in many organs. A BAT-deprived mouse model, generated with this Cre line, showed normal locomotion and body weight, but altered body weight and glucose homeostasis after high-fat feeding, validating its use for BAT-specific gene manipulation.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E675-E683"},"PeriodicalIF":3.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502724","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":"How long should washout be to reliably measure hepatic de novo lipogenesis using deuterated water? Exploratory analysis from a randomized crossover trial.","authors":"Steven Carter, Louise Bradshaw, Bruno Spellanzon, Elspeth Johnson, Francoise Koumanov, Kaitlyn M J H Dennis, Coco A Taylor Start, Alfonso Moreno-Cabañas, Emma E Vincent, Jennifer L Maher, James A Betts, Dylan Thompson, Leanne Hodson, Javier T Gonzalez","doi":"10.1152/ajpendo.00074.2026","DOIUrl":"10.1152/ajpendo.00074.2026","url":null,"abstract":"<p><p>Deuterated water (²H₂O) can be used to measure de novo lipogenesis (DNL) with minimal participant burden, but implications of tracer washout on repeated measures in humans are unclear. This study is an exploratory analysis of data from a crossover trial to determine the impact of duration between repeated ²H₂O dosing for sequential assessments of DNL, alongside day-to-day variability in DNL. A total of 22 nonobese adults (11 men and 11 women) completed three laboratory visits in a randomized, crossover design (35 ± 13-day washout). Participants consumed 3 g·kg^-1 body water of ²H₂O the evening before laboratory visits. Blood was sampled before ²H₂O ingestion, and the following morning in a fasted state. Deuterium (²H) enrichment of plasma water and very-low-density lipoprotein-triacylglycerol (VLDL-TG)-palmitate were used to determine DNL. Although predosing plasma water ²H enrichments (mole percent) increased across visits from 0.017 ± 0.003% to 0.022 ± 0.008% and 0.027 ± 0.014%, respectively (<i>P</i> < 0.05), postdose enrichments did not display a systematic bias, and nor did ²H enrichments of VLDL-TG-palmitate or measures of DNL [largest mean difference = -1.2%; 95% confidence interval (95% CI) = -12.7% to 9.1%, <i>P</i> = 0.45]. The day-to-day standard deviation and coefficient of variation of fractional hepatic DNL was 2.39% (95% CI = 1.35%-3.42%) and 27% (95% CI = 19%-35%), respectively. Repeated ²H₂O dosing does not systematically bias measures of fasting hepatic DNL when using a washout duration of ∼4 wk. We also found no evidence that DNL is biased by washout durations of 3 wk. Therefore, ²H₂O can be used to reliably assess human hepatic DNL in repeated measures designs with at least 3 wk between sequential measures.<b>NEW & NOTEWORTHY</b> Repeated deuterated water dosing in humans does not systematically bias measures of fasting hepatic DNL when using a washout duration of ∼4 wk. Fasting fractional hepatic DNL can be reliably assessed using deuterated water over sequential visits with as little as 3 wk washout between measures. At the group level, the within-participant variability in fasting hepatic DNL was relatively small and permits efficient detection of minimal clinically important differences in hepatic DNL with crossover studies.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E707-E714"},"PeriodicalIF":3.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147615504","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":"Publisher's note.","authors":"","doi":"10.1152/ajpendo.00123.2026_NOT","DOIUrl":"https://doi.org/10.1152/ajpendo.00123.2026_NOT","url":null,"abstract":"","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"330 5","pages":"E758"},"PeriodicalIF":3.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832273","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 acute and recurrent clamp-induced hypoglycemia on resting metabolic rate in healthy adults.","authors":"Daniel Malmsiø, Johan Dejgaard Onslev, Jørgen F P Wojtaszewski, Ulrik Pedersen-Bjergaard, Kim Zillo Rokamp","doi":"10.1152/ajpendo.00292.2025","DOIUrl":"10.1152/ajpendo.00292.2025","url":null,"abstract":"<p><p>Hypoglycemia is a common and serious side effect to insulin treatment, which has been studied extensively. However, resting metabolic rate during hypoglycemia, and its potential adaptations to recurrent hypoglycemia, has not been characterized. Therefore, we assessed resting metabolic rate before, during, and after recurrent clamped hypoglycemia in healthy males, conjecturing, by evolutionary reasoning, that energy would be conserved during and after recurrent hypoglycemia. We recruited 31 subjects, who underwent a 4-day experiment: <i>days 1</i> and <i>4</i> with adrenaline infusion and <i>days 2</i> and <i>3</i> with recurrent clamped hypoglycemia (2.8 mmol/L). Indirect calorimetric measurements of O₂ consumption, CO₂ production, respiratory exchange rate (RER), energy expenditure (EE), and glucose oxidation (GO) were made with a ventilated hood system. We found that subjects undergoing acute hypoglycemia increased O₂, CO₂, RER, EE, and GO (e.g., first hypoglycemia: mean difference of 10.7 mL/min, 18.2 mL/min, 0.03, 89.6 kcal/day, and 0.05 g/min in O₂, CO₂, and EE, respectively; all <i>P</i> values < 0.05) compared with euglycemia. Furthermore, the baseline values of O₂, CO₂, RER, EE, and GO increased after recurrent hypoglycemia (<i>day 4</i> vs. <i>day 1</i>): O₂: 9.22 mL/min (<i>P</i> value = 0.036); CO₂: 40.30 mL/min (<i>P</i> value < 0.0001); RER: 0.12 (<i>P</i> value < 0.0001); EE: 117.0 kcal/day (<i>P</i> value = 0.001); GO: 0.105 g/min (<i>P</i> value < 0.00001). Resting metabolic rate and glucose oxidation increased acutely in response to insulin-induced hypoglycemia. More notably, a similar increase in resting metabolic rate was observed following recurrent hypoglycemia, suggesting a sustained stress response the day following the last hypoglycemic episode.<b>NEW & NOTEWORTHY</b> Acute hypoglycemia increases resting metabolic rate. Acute hypoglycemia increases glucose oxidation. Recurrent hypoglycemia increases resting metabolic rate, as indicated by elevated baseline measurements after repeated exposures. Recurrent hypoglycemia increases glucose oxidation, as indicated by elevated baseline measurements after repeated exposures.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E572-E585"},"PeriodicalIF":3.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147442259","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 interaction between glucose levels and body mass index on the regulation of the circulating sphingolipidome in humans.","authors":"Camillo Morano, Lucia Centofanti, Michele Dei Cas, Riccardo Zanzi, Giuseppe De Pinto, Monica Bignotto, Paola Zermiani, Elena Bianco, Federica Samartin, Sara Penati, Ilaria Pes, Ilaria Goggi, Pamela Senesi, Graziano Serrao, Loredana Bucciarelli, Francesca Bravi, Antonio Russo, Marco Trinchera, Pier Maria Battezzati, Monica Ferraroni, Franco Folli, Rita Paroni","doi":"10.1152/ajpendo.00049.2026","DOIUrl":"10.1152/ajpendo.00049.2026","url":null,"abstract":"<p><p>Circulating sphingolipids have been associated with diabetes risk and chronic complications. This study characterized the sphingolipidome in a subset of the CA.ME.LI.A. cohort to identify lipid signatures related to sex, body mass index (BMI), and fasting glucose levels. Three hundred sixty-seven subjects (217 men) were stratified into six groups based on BMI (normal weight or overweight/obese) and fasting glucose levels (normal, impaired, or diabetes). Circulating sphingolipids were measured by LC-MS/MS. The effects of BMI, glucose levels, and their interaction on the sphingolipidome were analyzed using a two-way ANOVA model. Women showed higher circulating sphingolipid levels than men, except for ganglioside GM3. Glucose levels produced relevant changes on hexosyl- and lactosylceramides, which were significantly reduced in subjects with diabetes, independently of BMI. Some ceramide and sphingomyelin species also varied only according to glucose levels. Dihydroceramide 18:0 and 24:1 were higher in overweight/obese subjects, whereas sphingomyelin 18:1 and GM3 24:0 were higher in normal-weight individuals. Gangliosides GM3 were higher in normal body weight with normal glucose levels and impaired fasting glucose as compared with overweight obese individuals of the same categories. Sphingomyelin 18:1, GM3 24:1, sphingosine, and dihydrosphingosine-1-phosphate levels were significantly regulated by both BMI and glucose. In overweight/obese individuals, sphingosine-1-phosphate and dihydrosphingosine-1P levels were reduced in impaired fasting glucose and diabetes. The circulating sphingolipidome differs in men and women, being modulated by BMI and glucose levels. These data support the concept that sphingolipids could be novel biomarkers for obesity, diabetes, and associated complications.<b>NEW & NOTEWORTHY</b> Sphingolipid glycosylation is an enzymatic process that does not follow the pattern of nonenzymatic hemoglobin glycosylation. Unexpectedly, hexosyl- and lactosylceramides decreased in impaired fasting glucose and diabetes, with and without obesity. On the other hand, dihydroceramides increased in overweight/obesity with prediabetes/diabetes. The circulating sphingolipidome is differentially regulated in humans according to sex, glucose, and BMI.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E589-E605"},"PeriodicalIF":3.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502644","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":"Is high insulin protective or detrimental? Mathematical modeling reveals the base of the iceberg.","authors":"Boya Yang, Joon Ha, Arthur S Sherman","doi":"10.1152/ajpendo.00414.2025","DOIUrl":"10.1152/ajpendo.00414.2025","url":null,"abstract":"<p><p>Type 2 diabetes (T2D) progression involves complex interactions over time, yet longitudinal human data remain limited. Mathematical modeling enables reconstruction of individualized disease trajectories and mechanistic insights from sparse clinical observations. We developed a series of obesity-diabetes progression models, incorporating proposed mechanisms of glucose-insulin regulation and identified the best-performing framework using individualized longitudinal data from Southwest Native Americans. This population, with high rates of hyperinsulinemia and T2D progression, offers a good opportunity to investigate whether hyperinsulinemia is a primary factor in T2D. The model captured heterogeneous trajectories of glucose, insulin, insulin sensitivity, and beta-cell function, under the assumption that hyperinsulinemia reflects compensation for insulin resistance rather than a primary defect. We extended the model to study a subset of the population carrying an <i>ABCC8</i> loss-of-function variant linked to primary rather than compensatory hyperinsulinemia. The simulations reproduced the observed earlier diabetes onset in heterozygous carriers by incorporating chronic calcium stress, which accelerates beta-cell failure when combined with insulin resistance. In contrast, homozygous carriers exhibited severe early-onset diabetes even without insulin resistance. These findings suggest that high insulin secretion alone does not initiate diabetes unless it is extreme but may exacerbate progression in the presence of metabolic stress caused by insulin resistance. Importantly, the model predicts that Ca²⁺-reducing therapies in all the genotypes can mitigate beta-cell dysfunction if applied sufficiently early and at appropriate intensity. This study addresses controversial questions in diabetes pathogenesis and provides a platform for personalized disease stratification and therapeutic development.<b>NEW & NOTEWORTHY</b> This study presents the first obesity-diabetes model validated against four-dimensional, individualized longitudinal data, capturing heterogeneous disease trajectories and quantifying key mechanisms of progression. Uniquely, it investigates the transition from primary hyperinsulinemia to beta-cell failure in <i>ABCC8</i> loss-of-function carriers and highlights the potential of early, appropriately dosed Ca²⁺-reducing therapies to delay disease progression, providing new genotype- and stage-specific insights.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E627-E640"},"PeriodicalIF":3.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13155763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147375858","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":"A low-cost trait: sebum secretion in mammalian energy budgets.","authors":"Marlon R Schneider","doi":"10.1152/ajpendo.00091.2026","DOIUrl":"10.1152/ajpendo.00091.2026","url":null,"abstract":"","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E586-E588"},"PeriodicalIF":3.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147430171","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":"Mechanisms of norepinephrine-induced Ca²⁺ responses in perivascular adipose tissue.","authors":"Julia R Jamka, Emma D Flood, William F Jackson, Brian D Gulbransen","doi":"10.1152/ajpendo.00364.2025","DOIUrl":"10.1152/ajpendo.00364.2025","url":null,"abstract":"<p><p>Structural changes in microcirculation are often considered the first signs of vascular damage due to hypertension. A key tissue type emerging as a regulator of vascular tone is perivascular adipose tissue (PVAT). PVAT is a complex collection of adipocytes, immune cells, nerves, collagen fibers, and capillaries that surround most blood vessels. Norepinephrine (NE) is an important catecholamine that has emerged as a key driver of PVAT anticontractile factors. The release of anticontractile factors such as nitric oxide (NO) and adiponectin counteract smooth muscle contraction and limit vasoconstriction. NE stimulates adrenergic receptors such as β3, β2, and α1a, leading to the activation of Gs and Gq signal transduction cascades. Despite the importance of NE in promoting PVAT vasoactive functions, the cellular signal transduction mechanisms that underlie this effect remain unknown. Here, we used Ca²⁺ and NO imaging, selective drugs, and immunofluorescence to investigate mechanisms of NE-induced Ca²⁺ responses in PVAT. Our findings demonstrate that NE-induced Ca²⁺ signaling in PVAT is mediated by α1a, β2, and β3 adrenergic receptors, with depot-specific differences. Ca²⁺ responses in mesenteric PVAT, aortic PVAT, and white adipose tissue originate largely from internal stores. Selective agonism used in Ca²⁺ and NO imaging supports the role of adrenergic receptors as major mediators of NE-induced responses with depot-specific differences. Immunofluorescence confirmed that all three receptor subtypes are present on the adipocyte membrane and the vasculature. Together, these results highlight the complexity of adrenergic signaling in PVAT.<b>NEW & NOTEWORTHY</b> Norepinephrine (NE)-induced Ca²⁺ signaling in PVAT is mediated by adrenergic receptors with depot-specific roles. All three receptor subtypes contribute in mPVAT and aPVAT, whereas α1a predominates in white adipose tissue. Internal Ca²⁺ stores are the primary Ca²⁺ source for NE-induced signaling across depots. Ca²⁺ imaging with selective agonists supports α1a's role, and NO imaging highlights depot diversity. Immunofluorescence data confirm receptor expression on adipocytes and vasculature, indicating complex signaling pathways in adipose tissues studied here across depots.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E641-E658"},"PeriodicalIF":3.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147571876","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":"Acute metabolic effects of cannabinoid receptor modulators during sequential hyperglycemic, euglycemic-hyperinsulinemic clamps in healthy individuals.","authors":"Chee W Chia, Eric Y Tang, Roy G Cutler, Susan S You, Qinghua Chen, Adeline Y M Choo, Denise L Melvin, Christopher E Ramsden, Dimitrios Kapogiannis, Josephine M Egan","doi":"10.1152/ajpendo.00391.2025","DOIUrl":"10.1152/ajpendo.00391.2025","url":null,"abstract":"<p><p>The endocannabinoid (eCB) system is involved in a vast array of physiological processes including regulating metabolism through insulin secretion and action. In this physiological study of 21 healthy men, we investigated the acute effects of a nonspecific cannabinoid receptor agonist nabilone (NAB 2 mg) and a specific cannabinoid receptor 1 (CB₁R) antagonist CP-945,598 at two concentrations (low dose CP, LDCP 15 mg and high dose CP, HDCP 45 mg) on insulin secretion, insulin action, and glucose disposal-all compared with placebo (PL). One of the following compounds-NAB, LDCP, HDCP, or PL-was administered in a randomized and blinded fashion during each of the four visits, where in-between visit was spaced at least 6 wk apart. We used the sequential hyperglycemic, euglycemic-hyperinsulinemic clamp procedure carried out after >10 h of fasting to assess glucose-induced insulin secretion and insulin sensitivity, and we measured glucose utilization and production by means of the deuterated glucose disposal test. In addition, we measured serum levels of endocannabinoids and various <i>N</i>-acylethanolamines over the course of the sequential clamps. Our major findings were as follows: <i>1</i>) insulin secretion was not impacted by NAB or CP during the hyperglycemic clamp compared with PL; <i>2</i>) insulin sensitivity was significantly increased by NAB but decreased by HDCP, both compared with PL, during the euglycemic-hyperinsulinemic clamp; <i>3</i>) under the conditions of the experiments outlined, non-esterified fatty acids, and many circulating <i>N</i>-acylethanolamines levels, including the endocannabinoid anandamide (AEA), were reduced in a saturable insulin-dependent manner during the clamps.<b>NEW & NOTEWORTHY</b> Under controlled environment of the clamps in healthy, non-obese men, cannabinoid receptor agonist enhanced whereas cannabinoid receptor 1 antagonist diminished insulin sensitivity in a dose-dependent manner. During the clamps, elevated plasma insulin levels had a suppressive effect on circulating non-esterified fatty acids (NEFAs), anandamides (AEAs), and several <i>N</i>-acylethanolamines. Insulin, however, had no impact on circulating 2-arachidonoylglycerol (2-AG) levels. Neither the cannabinoid receptor agonist nor the cannabinoid receptor-1 antagonist had an effect on insulin secretion.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E659-E674"},"PeriodicalIF":3.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147497184","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":"Correction of Hypoxemia and Hypoglycemia Restores Muscle Mitochondrial Respiration and Remodels Mitochondrial Proteome in Growth-Restricted Sheep Fetuses.","authors":"Weicheng Zhao, Daniel B Chrisenberry, Mariangel Varela, Rosa I Luna-Ramirez, Miranda J Anderson, Paul R Langlais, Laura D Brown, Sean W Limesand","doi":"10.1152/ajpendo.00073.2026","DOIUrl":"https://doi.org/10.1152/ajpendo.00073.2026","url":null,"abstract":"<p><p>Placental insufficiency causes fetal hypoxemia and hypoglycemia and is a major driver of fetal growth restriction (FGR). In FGR skeletal muscle, mitochondrial respiration is reduced, partially due to altered mitochondrial protein abundance. We have shown that maternal oxygen and fetal glucose supplementation alleviates fetal hypoxemia and hypoglycemia and improves skeletal muscle satellite cell proliferation. However, its effects on muscle mitochondrial respiratory function and proteomic profiles remain unknown. Here, we tested whether correcting fetal hypoxemia and hypoglycemia restores mitochondrial oxidative phosphorylation and normalizes mitochondrial proteomic profiles in FGR sheep skeletal muscle. Placental insufficiency and FGR were induced by maternal hyperthermia during gestation. Near-term fetuses were chronically catheterized and received 7-10 days of maternal tracheal oxygen insufflation and fetal intravenous (IV) glucose infusion (FOG) or maternal air insufflation and fetal IV saline infusion (FAS). Both were compared to normally-grown control fetuses without supplementation (CON). Principal component analysis of the mitochondrial proteome indicated that FOG clustered closer to CON than to FAS. Abundances of 48 of 80 proteins that were differentially expressed in FAS vs CON returned to CON levels with FOG supplementation. Mitochondria isolated from CON and FOG muscle had similar glutamate/malate-driven state 3 (ADP stimulated) respiration, and both rates were greater than FAS mitochondria. Mitochondrial complex I activity was lower in FAS compared to CON, and FOG showed an intermediate level that was not different from either group. Together, these findings indicate that prenatal oxygen and glucose supplementation rescued mitochondrial respiratory dysfunction and partially normalized mitochondrial proteome in FGR skeletal muscle.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759885","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}