Explore the vast range of titles available.

The combination of obesity and hypertension is associated with high morbidity and mortality; however, the mechanism underlying obesity-induced hypertension remains unclear. In this study, we detected the possible effects of TRPV1, a previously identified antihypertensive calcium (Ca 2+ ) channel in adipose tissue, on the occurrence of obesity and hypertension in mice lacking UCP1, a spontaneously genetically manipulated obesity model, by generating TRPV1 and UCP1 double knockout mice. In these mice, obesity and hypertension appeared earlier and were more severe than in mice with the knockout of UCP1 or TRPV1 alone. The knockout of TRPV1 in UCP1 knockout mice further reduced functional brown adipose tissue (BAT) generation; decreased resting oxygen consumption, heat production, and locomotor activities; and was accompanied by severe mitochondrial respiratory dysfunction in BAT. Mechanistically, TRPV1, UCP1, and LETM1 acted as a complex to maintain an appropriate mitochondrial Ca 2+ level, and TRPV1 knockout caused a compensatory increase in mitochondrial Ca 2+ uptake via LETM1 activation. However, the compensatory response was blocked in UCP1 −/− mice, resulting in dramatically reduced mitochondrial Ca 2+ uptake and higher production of ATP and oxidative stress. This study provides in vivo evidence for the critical role of BAT mitochondrial Ca 2+ homeostasis in obesity-associated hypertension and indicates that the TRPV1/UCP1/LETM1 complex may be an alternative intervention target.

Primary aldosteronism (PA) is the most common form of endocrine hypertension. The available animal models of PA rely on gene manipulation, thus fail to duplicate the general pathological process of PA in humans. Meriones unguiculatus (MU) has been reported to possess a large size of adrenal gland and an elevated ability to save water. In this study, we aimed to confirm whether MU can serve as an ideal animal model of PA. Sprague Dawley rats of the same body weight (SD1) or age (SD2) as MU were used as control groups. Blood pressure and serum aldosterone, renin and electrolyte levels were measured, and the oral salt loading test was used as confirmatory test to compare the inhibition level of the renin angiotensin aldosterone system (RAAS) among the three groups. The expression and distribution of CYP11B2 (aldosterone synthase) were evaluated in the adrenal gland of each group. MU exhibited typical clinical manifestations of PA, including hypertension, hyperaldosteronism, low renin levels and strong sodium retention and potassium excretion abilities. Compared with control groups, the inhibitory effect of a high-sodium diet on the RAAS was milder in MU, accompanied by significant cardiac dysfunction. The protein expression level and distribution area of CYP11B2 were significantly increased in the adrenal gland of MU. The current study reveals that MU could serve as an ideal spontaneous PA model. The increased expression and distribution of CYP11B2 stimulate the excessive aldosterone production in a renin-independent manner, leading to a significant increase in blood pressure in MU.

Background Altered adipokine secretion in dysfunctional adipose tissue facilitates the development of atherosclerotic diseases including lower extremity peripheral artery disease (PAD). Asprosin is a recently identified adipokine and displays potent regulatory role in metabolism, but the relationship between asprosin and lower extremity PAD remains uninvestigated. Methods 33 type 2 diabetes mellitus (T2DM) patients (DM), 51 T2DM patients with PAD (DM + PAD) and 30 healthy normal control (NC) volunteers were recruited and the blood samples were collected for detecting the circulatory asprosin level and metabolomic screening. RNA sequencing was performed using the aorta tissues from the type 2 diabetic db/db mice and human umbilical vein endothelial cells (HUVECs) were treated with asprosin to determine its impact on the endothelial-to-mesenchymal transition (EndMT). Results The circulating levels of asprosin in DM + PAD group were significantly higher than that of NC group and the DM group. Circulating asprosin level was remarkably negatively correlated with ankle-brachial index (ABI), even after adjusting for age, sex, body mass index (BMI) and other traditional risk factors of PAD. Logistic regression analysis revealed that asprosin is an independent risk factor for PAD and receiver-operator characteristic (ROC) curve determined a good sensitivity (74.5%) and specificity (74.6%) of asprosin to distinguish PAD. Data from metabolomics displayed a typical characteristics of de novo amino acid synthesis in collagen protein production by myofibroblasts in patients with PAD and activation of TGF-β signaling pathway appeared in the aortic tissue of db/db mice. Asprosin directly induces EndMT in HUVECs in a TGF-β-dependent manner as TGF-β signaling pathway inhibitor SB431542 erased the promotional effect of asprosin on EndMT. Conclusions Elevated circulatory asprosin level is an independent risk factor of lower extremity PAD and might serve as a diagnostic marker. Mechanistically, asprosin directly induces EndMT that participates in vascular injury via activation of TGF-β signaling pathway. Trial registration This trial was registered at clinicaltrials.gov as NCT05068895

Impaired aerobic exercise capacity and skeletal muscle dysfunction are associated with cardiometabolic diseases. Acute administration of capsaicin enhances exercise endurance in rodents, but the long-term effect of dietary capsaicin is unknown. The capsaicin receptor, the transient receptor potential vaniUoid 1 （TRPV1） cation channel has been detected in skeletal muscle, the role of which remains unclear. Here we report the function of TRPV1 in cultured C2C12 myocytes and the effect of TRPV1 activation by dietary capsaicin on energy metabolism and exercise endurance of skeletal muscles in mice. In vitro, capsaicin increased cytosolic free calcium and peroxisome proliferator-acti- vated receptor-γcoactivator-1α （PGC-1α） expression in C2C12 myotubes through activating TRPV1. In vivo, PGC-1α in skeletal muscle was upregulated by capsaicin-induced TRPV1 activation or genetic overexpression of TRPV1 in mice. TRPV1 activation increased the expression of genes involved in fatty acid oxidation and mitochondrial respiration, promoted mitochondrial biogenesis, increased oxidative fbers, enhanced exercise endurance and prevented high-fat diet-induced metabolic disorders. Importantly, these effects of capsaicin were absent in TRPVl-deficient mice. We conclude that TRPV1 activation by dietary capsaicin improves energy metabolism and exercise endurance by upregulating PGC-1α in skeletal muscles. The present results indicate a novel therapeutic strategy for managing metabolic diseases and improving exercise endurance.

Background Roux-en-Y gastric bypass (RYGB) surgery is an effective metabolic surgery against diabetes and obesity. Clinical evidence indicates that patients with severe obesity have a poor curative effect in losing weight if they suffer from leptin or its receptor deficiency, but the underlying mechanism remains elusive. Here, we investigated the effect of leptin receptor deficiency on metabolic dysfunction in db/db mice treated by RYGB surgery. Methods The db/db mice and their heterozygote control db/m mice were subjected to RYGB or sham surgery. Body weight, blood glucose, food intake and glucose tolerance were evaluated. Micro-PET/CT and histological analysis were performed to examine the glucose uptake of tissues and the fat changes in mice. The key factors in glucose and fatty acid metabolism were detected by western blot analysis. Results Compared with the sham group, the db/db mice in the RYGB group showed more significant weight regain after surgical recovery and improvement in hyperinsulinemia and glucose tolerance. However, the total body fat and multiple organ lipid deposition of RYGB-treated db/db mice was increased. The underlying mechanism studies suggested that the activation of AMPK regulated GLUT4 to increase glucose uptake, but AMPK could not promote fatty acid oxidation through the JAK2/STAT3 pathway under leptin receptor deficiency in db/db mice. Conclusion We conclude that leptin receptor deficiency impedes the AMPK activation-mediated fat catabolism but does not affect AMPK-related glucose utilization after metabolic surgery in db/db mice. This result helps select surgical indications for patients with obesity and diabetes.

The recent discovery of superconductivity with a transition temperature ( T c ) at 18 K in K x picene has extended the possibility of high- T c superconductors in organic materials. Previous experience based on similar hydrocarbons, like alkali-metal doped phenanthrene, suggested that even higher transition temperatures might be achieved in alkali-metals or alkali-earth-metals doped such polycyclic-aromatic-hydrocarbons (PAHs), a large family of molecules composed of fused benzene rings. Here we report the discovery of high- T c superconductivity at 33 K in K-doped 1,2:8,9-dibenzopentacene (C 30 H 18 ). To our best knowledge, it is higher than any T c reported previously for an organic superconductor under ambient pressure. This finding provides an indication that superconductivity at much higher temperature may be possible in such PAHs system and is worthy of further exploration.

Primary aldosteronism (PA) is the most common form of endocrine hypertension. The available animal models of PA rely on gene manipulation, thus fail to duplicate the general pathological process of PA in humans. Meriones unguiculatus (MU) has been reported to possess a large size of adrenal gland and an elevated ability to save water. In this study, we aimed to confirm whether MU can serve as an ideal animal model of PA. Sprague Dawley rats of the same body weight (SD1) or age (SD2) as MU were used as control groups. Blood pressure and serum aldosterone, renin and electrolyte levels were measured, and the oral salt loading test was used as confirmatory test to compare the inhibition level of the renin angiotensin aldosterone system (RAAS) among the three groups. The expression and distribution of CYP11B2 (aldosterone synthase) were evaluated in the adrenal gland of each group. MU exhibited typical clinical manifestations of PA, including hypertension, hyperaldosteronism, low renin levels and strong sodium retention and potassium excretion abilities. Compared with control groups, the inhibitory effect of a high-sodium diet on the RAAS was milder in MU, accompanied by significant cardiac dysfunction. The protein expression level and distribution area of CYP11B2 were significantly increased in the adrenal gland of MU. The current study reveals that MU could serve as an ideal spontaneous PA model. The increased expression and distribution of CYP11B2 stimulate the excessive aldosterone production in a renin-independent manner, leading to a significant increase in blood pressure in MU.

Primary aldosteronism (PA) is the most common form of endocrine hypertension. The available animal models of PA rely on gene manipulation, thus fail to duplicate the general pathological process of PA in humans. Meriones unguiculatus (MU) has been reported to possess a large size of adrenal gland and an elevated ability to save water. In this study, we aimed to confirm whether MU can serve as an ideal animal model of PA. Sprague Dawley rats of the same body weight (SD1) or age (SD2) as MU were used as control groups. Blood pressure and serum aldosterone, renin and electrolyte levels were measured, and the oral salt loading test was used as confirmatory test to compare the inhibition level of the renin angiotensin aldosterone system (RAAS) among the three groups. The expression and distribution of CYP11B2 (aldosterone synthase) were evaluated in the adrenal gland of each group. MU exhibited typical clinical manifestations of PA, including hypertension, hyperaldosteronism, low renin levels and strong sodium retention and potassium excretion abilities. Compared with control groups, the inhibitory effect of a high-sodium diet on the RAAS was milder in MU, accompanied by significant cardiac dysfunction. The protein expression level and distribution area of CYP11B2 were significantly increased in the adrenal gland of MU. The current study reveals that MU could serve as an ideal spontaneous PA model. The increased expression and distribution of CYP11B2 stimulate the excessive aldosterone production in a renin-independent manner, leading to a significant increase in blood pressure in MU.

Transient receptor potential channel 5 (TRPC5) is predominantly distributed in the brain, especially in the central amygdala (CeA), which is closely associated with pain and addiction. Although mounting evidence indicates that the CeA is related to energy homeostasis, the possible regulatory effect of TRPC5 in the CeA on metabolism remains unclear. Here, we reported that the expression of TRPC5 in the CeA of mice was increased under a high-fat diet (HFD). Specifically, the deleted TRPC5 protein in the CeA of mice using adeno-associated virus resisted HFD-induced weight gain, accompanied by increased food intake. Furthermore, the energy expenditure of CeA-specific TRPC5 deletion mice (TRPC5 KO) was elevated due to augmented white adipose tissue (WAT) browning and brown adipose tissue (BAT) activity. Mechanistically, deficiency of TRPC5 in the CeA boosted nonshivering thermogenesis under cold stimulation by stimulating sympathetic nerves, as the β3-adrenoceptor (Adrb3) antagonist SR59230A blocked the effect of TRPC5 KO on this process. In summary, TRPC5 deletion in the CeA alleviated the metabolic deterioration of mice fed a HFD, and these phenotypic improvements were correlated with the increased sympathetic distribution and activity of adipose tissue.

Endothelial dysfunction and vascular rarefaction are supposed to be secondary to metabolic diseases, while recent evidence has revealed the primary roles of endothelium in initiating and accelerating metabolic disorders. Here, the effects and underlying mechanisms of endothelial SIRT3 in modulating the whitening of BAT during obesity progression were explored. Therefore, mice with global or BAT regional endothelium-specific Sirt3 knockout were constructed and fed with high-fat diet (HFD). The results showed that both global and BAT regional endothelium-specific Sirt3 knockout accelerated diet-induced weight gain, accompanied by glucose intolerance, insulin resistance, and BAT whitening. In vitro results revealed that the inhibition or knockdown of endothelial Sirt3 impeded palmitic acid-induced angiogenesis deficiency, while the overexpression of Sirt3 exhibited the opposite effects. Furtherly, endothelial Sirt3 overexpression ameliorated palmitic acid-induced adipocyte dysfunction and proinflammatory macrophages polarization in a paracrine way. Mechanistically, endothelial SIRT3 deficiency increased the acetylation of fatty acid synthase (FASN), which disturbed the fatty acid metabolism and thus, leading to angiogenesis insufficiency. Moreover, loss of SIRT3 promoted adipocytes dysfunction and proinflammatory macrophage polarization via CASP1-mediated pyroptosis. Endothelial SIRT3 loss contributed to diet-induced BAT whitening and obesity progression and thus, could be a therapeutic target in treating obesity and associated metabolic diseases.