American journal of physiology. Endocrinology and metabolism最新文献

Cystic fibrosis (CF) is a genetic disease that primarily affects the pancreas and lungs. CF dyslipidemia is characterized by decreased circulating lipids and increased ectopic lipid deposition in liver, pancreas, and lungs. Pancreatic exocrine insufficiency precedes the onset of CF-related diabetes (CFRD). We hypothesized that different mechanisms contribute to CFRD development and progression, including features of type 1 and type 2 diabetes mellitus (T1DM and T2DM). Thus, we compared their plasma inflammatory, metabolic/hormonal, and lipidomic profiles, using Luminex assays and untargeted mass spectrometry analyses. Then, we compared the lipidomic profiles of lung biopsies and plasma extracellular vesicles (EVs) of CFRD and patients with other lung diseases (LDs). Inflammatory cytokines (IL6 and IL1β) and chemokines (IL8 and MCP-1) were increased in the plasma of CFRD as compared with T1DM, whereas only cytokines increased when comparing with T2DM. Low insulin and C-peptide characterized CFRD and T1DM. Phosphatidylcholine, phosphatidylethanolamine, and storage lipids were reduced, and free fatty acids (FAs) were increased in CFRD plasma compared with T1DM and T2DM. When comparing CFRD with LD, systemic inflammation was increased to a similar extent. Increased levels of sphingolipids, glycerolipids, and acylcarnitines were found in lung biopsies of CFRD as compared with LD. Increased triacylglycerols in lung biopsies positively correlated with lung inflammatory infiltrates (CD68-positive cells) of patients with CFRD. In conclusion, CFRD is characterized by altered lipid metabolism, insulin deficiency, and insulin resistance, partially overlapping with both T1DM and T2DM. CFRD also involves ectopic lung lipids accumulation correlating with increased in situ inflammation.NEW & NOTEWORTHY CFRD is characterized by altered lipid metabolism, insulin deficiency, and insulin resistance, which are distinctive features that partially overlap with both T1DM and T2DM. Systemic inflammation with elevated free FA and reduced plasma lipids is also present in CFRD. Lipids are increased in lung biopsies, whose lipidomic profiles are similar to those of blood-derived EVs. CFRD develops ectopic lipid accumulation in the lungs, correlating with heightened local inflammation and reduced plasma lipid transport.

Heart disease, including diabetic cardiomyopathy, is a leading cause of mortality in patients with type 2 diabetes (T2D). Defects in heart function are accompanied by marked changes in cardiac metabolism, including dysregulation of lipid and glucose metabolism, mitochondrial dysfunction, and oxidative stress. In addition to these metabolic defects, the heart is an important endocrine organ. However, although T2D has been shown to impact the secretome of liver, skeletal muscle, and adipose tissue (among others), little is known about the secretome of the heart and the influence of T2D on cardiac protein secretion. Using precision-cut heart slices from mice with insulin resistance (20-wk of high-fat feeding) and T2D (db/db mice) compared with their respective controls, we performed mass spectrometry proteomics analysis of cardiac protein secretion and proteins contained within extracellular vesicles (EVs). We reveal striking remodeling of cardiac protein secretion in T2D but not diet-induced insulin resistance. Specifically, we show a marked increase in the secretion of inner mitochondrial membrane (IMM) proteins in T2D, which was accompanied by a disproportional accumulation of outer mitochondrial membrane proteins within the heart. This was associated with increased mitochondrial oxidative stress, selective oxidative damage to IMM proteins, and reduced markers of LC3-mediated mitophagy in the db/db heart, highlighting secretion of mitochondrial components as a potential alternative pathway for mitochondrial quality control. Altogether, this study provides an in-depth proteomics analysis showing remodeling of cardiac protein secretion in T2D and provides insights into a possible link between mitochondrial oxidative stress and the release of mitochondrial components.NEW & NOTEWORTHY Diabetic cardiomyopathy is a leading cause of death in patients with type 2 diabetes (T2D). Here, we show striking remodeling of cardiac protein secretion in mice with T2D, particularly an increase in the release of inner mitochondrial membrane proteins, which was associated with increased oxidative stress within the diabetic heart.

Mitochondria are key regulators of metabolism and ATP supply in skeletal muscle, while circadian rhythms influence many physiological processes. However, whether mitochondrial function is intrinsically regulated in a circadian manner in mouse skeletal muscle is inadequately understood. Accordingly, we measured postabsorptive transcript abundance of markers of mitochondrial autophagy, dynamics, and metabolism [extensor digitorum longus (EDL), soleus, gastrocnemius], protein abundance of electron transport chain complexes (EDL and soleus), enzymatic activity of succinate dehydrogenase (tibialis anterior and plantaris), and maximal mitochondrial respiration (tibialis anterior) in different skeletal muscles from female C57BL/6NJ mice at four zeitgeber times: 1, 7, 13, and 19. Our findings demonstrate that markers of mitochondrial function and oxidative metabolism do not display intrinsic time-of-day regulation at the gene, protein, enzymatic, or functional level. The core-clock genes Bmal1 and Dbp exhibited intrinsic circadian rhythmicity in skeletal muscle (i.e., EDL, soleus, gastrocnemius) and circadian amplitude varied by muscle type. These findings demonstrate that female mouse skeletal muscle does not display circadian regulation of markers of mitochondrial function or oxidative metabolism over 24 h.NEW & NOTEWORTHY The prominent hypothesis in the field of skeletal muscle chronobiology is that markers of skeletal muscle mitochondrial function are intrinsically time-of-day regulated. However, this has not yet been directly tested. Thus, we measured several markers of mitochondrial function in five muscles from female mice, and maximal uncoupled respiration, at four timepoints across a 24-h day. Our findings indicate that markers of mitochondrial function are not intrinsically regulated by time-of-day in female mouse muscle.

Because higher adiposity is associated with cardiometabolic disease, we assessed the relationship between body composition (body fat percentage; BF%) and postprandial metabolic flexibility [change in respiratory exchange ratio (RER) from fasting]. Young adults [n = 27, n = 15 females, body mass index (BMI) = 27.1 ± 4.5; BF% = 30.4 ± 8.7; mean ± SD] without overt pathology completed a 100 g oral glucose tolerance test (OGTT). Indirect calorimetry before (fasting) and following (30, 60, 90, and 120 min) consumption was used to calculate respiratory exchange ratio (RER) and oxidation of carbohydrates (CHOX) and fats (FOX). Serum and plasma were collected at corresponding time points and analyzed for glucose, insulin, and nonesterified fatty acids (NEFAs). Two-way repeated measures ANOVA was used to compare data between normal weight and overweight/obesity by BMI. The effect of BF% on postprandial metabolic flexibility was tested via linear mixed models while adjusting for potential confounders. During the OGTT, blood glucose, serum insulin, plasma lactate, RER, and CHOX all significantly increased, whereas plasma NEFAs and whole body FOX decreased (all P < 0.05). BF% modified the relationship between postprandial RER and time (P = 0.019); individuals with higher BF% increase their RER faster and to a greater extent (i.e., greater metabolic flexibility) than those with lower BF%. Body fat percentage is associated with greater postprandial metabolic flexibility during an OGTT in young adults. Despite increased adiposity, metabolic flexibility may be preserved, representing a compensatory adaptation to decreased glucose storage in the postprandial period.NEW & NOTEWORTHY Previous studies have suggested that obesity blunts postprandial metabolic flexibility. By directly analyzing the effect of body composition on postprandial metabolic flexibility, we show that healthy young adults with higher body fat percentages have increased postprandial metabolic flexibility in response to concurrent hyperglycemia. This suggests a preserved, metabolically flexible phenotype in young adults with higher body fat percentages.

Patients with rheumatoid arthritis (RA) are at increased risk of insulin resistance and cardiovascular disease, and exercise is a key nonpharmacological therapy. We examined whether interleukin-6 (IL-6) inhibition, a common biological treatment for RA, impairs the acute metabolic benefits of exercise, given IL-6's proposed role as a mediator of exercise-induced glucose metabolism. This was a single-center, nonrandomized study involving 20 postmenopausal women with RA [10 on IL-6 inhibitor (IL-6i), 10 on TNF-α inhibitor (TNF-αi)]. Participants underwent a hyperinsulinemic-euglycemic clamp (HEC) and fluorine-18 fluorodeoxyglucose positron emission tomography and magnetic resonance imaging ([¹⁸F]FDG PET/MRI) to assess whole body and skeletal muscle glucose uptake. Muscle biopsies were performed before and 240 min after a 30-min moderate-to-vigorous intensity aerobic exercise session to analyze molecular responses, including RNA sequencing (RNA-Seq) and protein expression. Participants had a mean age of 57.8 ± 5.1 yr and a mean body mass index (BMI) of 28.2 ± 4.9 kg/m². Disease duration averaged 18.0 ± 7.5 yr, and both groups had comparable clinical characteristics. Acute exercise did not elicit significant between-group differences in insulin sensitivity (M value: 4.51 ± 1.34 vs. 4.28 ± 0.87; P value > 0.05) or skeletal muscle glucose uptake, indicating that IL-6 inhibition does not impair the metabolic responses to acute exercise. Comparing post to preexercise, IL-6i participants exhibited increased glucose transporter type 4 (GLUT4) expression (P value = 0.01) and distinct cytokine profiles, including elevated IL-8 (P value = 0.04) and IL-10 (P value = 0.02) levels. RNA-Seq analysis showed comparable pathway enrichment between groups, with upregulation of TNF-α and IL-6-Janus kinase-signal transducer and activator of transcription 3 (JAK-STAT3) signaling. IL-6 inhibition does not blunt the acute metabolic benefits of exercise in RA, supporting its safety as a nonpharmacological intervention. Trial registration: Clinicaltrials.gov (NCT04927546).NEW & NOTEWORTHY A single session of aerobic exercise has a similar effect on insulin sensitivity and muscle glucose uptake in women with RA treated with either IL-6i or TNF-αi. The study supports exercise as a safe and complementary strategy for patients with RA on IL-6i or TNF-αi therapy, reinforcing its inclusion in clinical care and the need for further research on long-term outcomes.

We previously identified Jumonji domain-containing 8 (JMJD8) as a regulator of lipid droplet (LD) hypertrophy in adipocytes through modulation of AMPK-dependent perilipin-2 (PLIN2) phosphorylation. Given PLIN2's established role in hepatic steatosis, we investigated whether JMJD8 also regulates lipid accumulation in the liver. Here, we report that JMJD8 expression is significantly elevated in the livers of mice fed either a high-fat diet (HFD) or the metabolic-associated fatty liver disease (MAFLD)-inducing Gubra Amylin NASH (GAN) diet. To define the metabolic role of JMJD8 in the liver, we generated liver-specific Jmjd8 knockout (Jmjd8^LKO) mice. Hepatic deletion of Jmjd8 reduced triglyceride (TG) accumulation under both dietary conditions, without affecting overall body weight or adiposity. Lipidomic analyses revealed a redistribution of lipid classes in Jmjd8 knockout livers on HFD, with decreased storage lipids and increased membrane phospholipids. Jmjd8^LKO mice also displayed improved insulin sensitivity and glucose tolerance under HFD but not the GAN diet. Mechanistically, although JMJD8 interacts with PLIN2, its prosteatotic effect appears to be independent of PLIN2. These findings indicate that JMJD8 promotes hepatic steatosis and metabolic dysregulation under HFD by altering lipid class distribution, highlighting its potential as a therapeutic target in obesity-associated metabolic disease.NEW & NOTEWORTHY This study identifies Jumonji domain-containing 8 (JMJD8) as a previously unrecognized driver of hepatic steatosis and metabolic dysfunction in diet-induced fatty liver disease. Liver-specific deletion of Jmjd8 protects against triglyceride accumulation and insulin resistance, redirecting hepatic lipid composition from energy storage toward membrane remodeling. These findings establish JMJD8 as a key intracellular regulator of lipid homeostasis and glucose metabolism and highlight its potential as a therapeutic target for metabolic-associated fatty liver disease.

Maternal exercise is a widely recommended and safe intervention associated with the improvement of maternal gestational and infant metabolic health. Although various modes of exercise are deemed safe during pregnancy, the effects of supervised maternal aerobic, resistance, and combination (aerobic + resistance) exercise remain understudied. Specifically, it remains unknown how different modes of maternal exercise affect the placenta, an organ central to maternal-fetal communication and successful pregnancy outcomes. This study aimed to characterize the placental proteomic changes in response to controlled and supervised maternal exercise during gestation. Results demonstrate that the placental proteomic landscape changes in a maternal exercise mode-specific way. In addition, proteomics revealed that ∼20% of the identified placental proteins were associated with maternal exercise volume during gestation. These results highlight the differential effect maternal exercise modes have on the placental proteome and further implicate the placenta in mediating the effects of maternal exercise on maternal and infant health. ClinicalTrials.gov Identifier: NCT03838146 and NCT04805502.NEW & NOTEWORTHY This article highlights the broad and significant changes that occur in the placental proteome in response to different types of maternal exercise. Our findings further reveal that the overall volume of maternal exercise was associated with alterations in nearly 25% of the identified placental proteins, suggesting that both the type and amount of maternal physical activity may play important roles in shaping placental function and possibly contributing to fetal development.

After finding that minimal amounts of adrenocorticotropic hormone (ACTH_1-24) prevented osteonecrosis in rabbits, we studied bone formation at nanomolar ACTH_1-24, in vivo in rabbits and in vitro in human osteoblasts. ACTH_1-24 in rabbits at 0.6 μg/kg/day had no measurable effect on cortisol. Groups of five rabbits given 0.6 μg/kg/day of ACTH_1-24 enhanced trabecular bone in the rabbit femoral head relative to saline-treated controls (controls), increased bone volume/total volume (BV/TV) by micro-computed tomography, P < 0.03. Xylenol orange and calcein labeling in vivo showed increased trabecular bone formation with 0.6 μg/kg/day of ACTH_1-24, P = 0.0089 vs. controls. In contrast, the cortex of the femoral shaft was unaffected, BV/TV, P > 0.95 ACTH_1-24 vs. controls. Bone marrow mRNA by PCR showed no change in osteoclast markers and confirmed increased osteoblast markers, P < 0.05. In vitro, ACTH_1-24 elevated expression of collagen 1, alkaline phosphatase (ALP), osteocalcin (bone gamma carboxyglutamate protein), and RunX2 in human osteoblasts differentiated on polyethylene terephthalate (PET) membranes. Optimal response was at 10^-9 to 10^-12 M. Vascular endothelial growth factor (VEGF) receptors fms-related receptor tyrosine kinase 1 and FLK-1, and ACTH_1-24 receptors MC2R were upregulated at 10^-12 M ACTH_1-24. Pathway analysis included increased bone morphogenetic protein 2, Smad1, Wnt-1, β-catenin, and transforming growth factor, beta 1 pathways. Because bone-forming osteoblasts are metabolically highly active, we studied mRNA expression of mitochondrial complex 1 (NDUFA5, NDUFS2, NDUFB1, and NDUFB6) members with key roles in energy production. This increased at 10^-12 M ACTH_1-24. An ELISA for mitochondrial complex 1 activity showed maximum activity at 10^-9 M and high activity at 10^-12 M ACTH_1-24. Thus, long-term very low-dose ACTH_1-24 increases bone formation in vivo and in vitro.NEW & NOTEWORTHY This is the first study to assess directly the effects of very low concentrations of ACTH_1-24, picomolar to micromolar, on regulation of bone growth. It shows effects on bone mass in the femoral heads and by labeling bone formation in rabbits in vitro, and effect on key proteins related to bone growth mechanisms in cell preparations of human bone-forming cells in vitro.

Adiponectin and leptin are key adipokines that play crucial roles in metabolic regulation and in fetal and neonatal growth. In adults, lower adiponectin/leptin ratio (AdipoQ/Lep) has been suggested as a potential biomarker for metabolic risk. This study aimed to investigate whether the AdipoQ/Lep ratio in fetal blood correlates with the maternal and neonatal phenotypes and whether it holds predictive value for the cardiometabolic risk of the offspring in early life. Umbilical cord blood (UCB) samples were collected at birth, and the concentrations of adiponectin and leptin levels were measured using ELISA kits. Infants were evaluated echocardiographically at 5 ± 2 mo old (range: 1-12 mo), and these parameters were correlated with the AdipoQ/Lep levels. Results show that fetal AdipoQ/Lep ratio was lower in infants born to mothers with prepregnancy obesity. Both prepregnancy weight and maternal weight at the end of the gestation correlated with the AdipoQ/Lep ratio in UCB, whereas gestational weight gain showed no such association. In addition, birth weight, birth length, and body mass index (BMI)-for-age Z-score were negatively correlated with the AdipoQ/Lep ratio. Notably, lower levels of this adipokine-based biomarker were associated with reduced Z-score of left ventricular end-diastolic diameter. However, multiple linear regression analysis showed that maternal obesity and somatometry at birth influence infants' cardiac function and structure, independent of UCB AdipoQ/Lep ratio, adiponectin, or leptin alone. To our knowledge, this is the first investigation to explore the relationship between fetal AdipoQ/Lep levels, maternal-neonatal weight, and early cardiac alterations, highlighting the biomarker's potential predictive value for early-life cardiometabolic risk.NEW & NOTEWORTHY This study is the first to explore the association between fetal adiponectin/leptin (AdipoQ/Lep) ratio and maternal and neonatal anthropometrics and early alterations in cardiac structure. Although maternal and neonatal weight metrics impact infant heart development, this occurs independently of the AdipoQ/Lep. However, lower levels of AdipoQ/Lep ratio were associated with reduced Z-score of left ventricular end-diastolic diameter, offering insights into fetal programming mechanisms linked to maternal metabolic status during pregnancy.