Changes in thyroid hormones predict weight regain in patients with obesity who undergo metabolic surgery.

AIM: To investigate the relationship between thyroid function and weight regain in patients with obesity after metabolic surgery. METHODS: This retrospective study enrolled 162 patients who underwent metabolic surgery. Correlations between decreases in thyroid hormone levels and changes in weight, waist circumference (WC) and the Chinese visceral adiposity index (CVAI) were assessed. Binary logistic regression and receiver operating characteristic (ROC) curves were used to identify predictors and clinically useful cut-off values, respectively. RESULTS: The levels of thyroid-stimulating hormone (TSH) and free triiodothyronine (FT3) decreased markedly at 1 year after surgery, as did weight, body mass index (BMI), triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, WC and CVAI. Decreases in TSH and FT3 after metabolic surgery were associated with changes in weight, BMI and CVAI. Binary logistic regression and ROC curve analyses confirmed that decreases in TSH can predict good weight loss after metabolic surgery to some extent. Finally, binary logistic regression and ROC curve analyses confirmed that changes in TSH can predict weight regain after metabolic surgery. CONCLUSIONS: Changes in TSH and FT3 after metabolic surgery were correlated with changes in weight and CVAI. Changes in thyroid hormones can predict weight regain in patients with obesity who underwent metabolic surgery.

Mitochondrial dysfunction caused by SIRT3 inhibition drives proinflammatory macrophage polarization in obesity.

OBJECTIVE: Metabolic reprogramming is a main feature of proinflammatory macrophage polarization, a process that leads to inflammation in dysfunctional adipose tissue. Therefore, the study aim was to explore whether sirtuin 3 (SIRT3), a mitochondrial deacetylase, participates in this pathophysiological process. METHODS: Macrophage-specific Sirt3 knockout (Sirt3-MKO) mice and wild-type littermates were treated with a high-fat diet. Body weight, glucose tolerance, and inflammation were evaluated. Bone marrow-derived macrophages and RAW264.7 cells were treated with palmitic acid to explore the mechanism of SIRT3 on inflammation. RESULTS: The expression of SIRT3 was significantly repressed in both bone marrow-derived macrophages and adipose tissue macrophages in mice fed with a high-fat diet. Sirt3-MKO mice exhibited accelerated body weight and severe inflammation, accompanied with reduced energy expenditure and worsened glucose metabolism. In vitro experiments showed that SIRT3 inhibition or knockdown exacerbated palmitic acid-induced proinflammatory macrophage polarization, whereas SIRT3 restoration displayed opposite effects. Mechanistically, SIRT3 deficiency resulted in hyperacetylation of succinate dehydrogenase that led to succinate accumulation, which suppressed the transcription of Kruppel-like factor 4 via increasing histone methylation on its promoter, thus evoking proinflammatory macrophages. CONCLUSIONS: This study emphasizes an important preventive role of SIRT3 in macrophage polarization and implies that SIRT3 is a promising therapeutic target for obesity.

Cx43 acts as a mitochondrial calcium regulator that promotes obesity by inducing the polarization of macrophages in adipose tissue.

Metabolic reprogramming of macrophages initiates the polarization of pro-inflammatory macrophages that exacerbates adipocyte dysfunction and obesity. The imbalance of mitochondrial Ca2+ homeostasis impairs mitochondrial function and promotes inflammation. Connexin 43 (Cx43), a ubiquitous gap junction protein, has been demonstrated to regulate intracellular Ca2+ homeostasis. Here we explored whether macrophage Cx43 affects the obesity process by regulating the polarization of macrophage. HFD treatment induced obesity and exacerbated macrophages infiltration with upregulation of macrophages Cx43. Macrophage-specific knockout of Cx43 reduced HFD-induced obesity by alleviating inflammation in adipose tissue, with less pro-inflammatory M1 macrophage infiltration. Consistently, inhibition or knockdown of Cx43 improved palmitic acid (PA) induced mitochondrial dysfunction, as indicated by improved oxidative phosphorylation (OXPHOS), reduced formation of mitochondria-associated membranes (MAM) and mitochondrial Ca2+ overload. Mechanistically, Cx43 interacted with the mitochondrial Ca2+ uniporter (MCU) and knockdown of Cx43 alleviated PA-induced succinate dehydrogenase (SDH) oxidation by lowering MCU-mediated mitochondrial Ca2+ uptake, which then, promoting the polarization of pro-inflammatory M1 macrophages. Thus, this study identified Cx43 as a mitochondrial Ca2+ regulator that aggravates obesity via promoting macrophages polarized to M1 pro-inflammatory phenotype and suggests that Cx43 might be a promising therapeutic target antagonizing obesity.

Catheter-based adrenal ablation: an alternative therapy for patients with aldosterone-producing adenoma.

Unilateral adrenalectomy is the standard treatment for patients with aldosterone-producing adenoma (APA), but it lacks an option for patients with APA who refuse or are not suitable for surgery. In this study, we studied whether catheter-based adrenal ablation for APA is comparable to adrenalectomy. A total of 2185 hypertensive patients were screened, and 112 patients with APA were recruited and counselled on the treatment options. Fifty-two patients opted for catheter-based adrenal ablation, and 60 opted for adrenalectomy. Clinical and biochemical outcomes were assessed at 6 months after treatment. Factors associated with hypertension remission and the advantages and limitations of this approach were evaluated. According to the primary aldosteronism surgical outcome (PASO) criteria, complete and partial clinical success was achieved in 21 (40.4%) and 23 (44.2%) patients in the ablation group vs. 33 (55.0%) and 23 (38.3%) patients in the adrenalectomy group, respectively. Complete and partial biochemical success was achieved in 30 (57.7%) and 17 (32.7%) patients in the ablation group vs. 51 (85.0%) and 5 (8.3%) patients in the adrenalectomy group, respectively. The complete clinical success rate was not (P > 0.05), but the complete biochemical success rate was significantly different between the two groups (P < 0.01). Factors associated with adrenal ablation-mediated hypertension remission were hypertension duration and serum potassium level at baseline. Compared with surgery, adrenal ablation requires a shorter operating time and time to resume physical activity. Catheter-based adrenal ablation may be an alternative and feasible option for APA patients unwilling to receive surgical treatment.

TRPC5 deletion in the central amygdala antagonizes high-fat diet-induced obesity by increasing sympathetic innervation.

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 ß3-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.

Salt-Induced Hepatic Inflammatory Memory Contributes to Cardiovascular Damage Through Epigenetic Modulation of SIRT3.

BACKGROUND: High salt intake is the leading dietary risk factor for cardiovascular diseases. Although clinical evidence suggests that high salt intake is associated with nonalcoholic fatty liver disease, which is an independent risk factor for cardiovascular diseases, it remains elusive whether salt-induced hepatic damage leads to the development of cardiovascular diseases. METHODS: Mice were fed with normal or high-salt diet for 8 weeks to determine the effect of salt loading on liver histological changes and blood pressure, and salt withdrawal and metformin treatment were also conducted on some high-salt diet-fed mice. Adeno-associated virus 8, global knockout, or tissue-specific knockout mice were used to manipulate the expression of some target genes in vivo, including SIRT3 (sirtuin 3), NRF2 (NF-E2-related factor 2), and AMPK (AMP-activated protein kinase). RESULTS: Mice fed with a high-salt diet displayed obvious hepatic steatosis and inflammation, accompanied with hypertension and cardiac dysfunction. All these pathological changes persisted after salt withdrawal, displaying a memory phenomenon. Gene expression analysis and phenotypes of SIRT3 knockout mice revealed that reduced expression of SIRT3 was a chief culprit responsible for the persistent inflammation in the liver, and recovering SIRT3 expression in the liver effectively inhibits the sustained hepatic inflammation and cardiovascular damage. Mechanistical studies reveal that high salt increases acetylated histone 3 lysine 27 (H3K27ac) on SIRT3 promoter in hepatocytes, thus inhibiting the binding of NRF2, and results in the sustained inhibition of SIRT3 expression. Treatment with metformin activated AMPK, which inhibited salt-induced hepatic inflammatory memory and cardiovascular damage by lowering the H3K27ac level on SIRT3 promoter, and increased NRF2 binding ability to activate SIRT3 expression. CONCLUSIONS: This study demonstrates that SIRT3 inhibition caused by histone modification is the key factor for the persistent hepatic steatosis and inflammation that contributes to cardiovascular damage under high salt loading. Avoidance of excessive salt intake and active intervention of epigenetic modification may help to stave off the persistent inflammatory status that underlies high-salt-induced cardiovascular damage in clinical practice.

Determination of adrenal hypersecretion in primary Aldosteronism without aldosterone-production adenomas.

BACKGROUND: Primary aldosteronism (PA) is highly prevalent in hypertensive population. Adrenal vein sampling (AVS) is the only procedure to assess adrenal aldosterone hypersecretion in PA. PA patients without aldosterone-producing adenomas (APA) frequently have unilateral aldosterone hypersecretion (UAH). These patients could bear inappropriate adrenalectomy without AVS. This study aims to identify which clinical characteristics should be recommended to perform AVS in these PA patients. METHODS: This study was performed from January 2018 to July 2019 at a center for hypertension and metabolic diseases. Adrenal computed tomography (CT) scan, biochemical evaluation, and AVS were performed. RESULTS: Total 141 patients were included in this study. Aldosterone to renin ratio (ARR) after confirmatory test is highly associated with adrenal laterality. The specificity of ARR > 10 (ng/dL)/(mU/L) after confirmatory test is 100%. After confirmatory test, patients with ARR > 10 (ng/dL)/(mU/L) had higher plasma aldosterone concentration and incidences of ischemic heart diseases and renal damage(p < 0.05). CONCLUSIONS: After confirmatory tests, ARR > 10 (ng/dL)/(mU/L) indicates adrenal laterality, with increasingly cardiorenal damage in PA patients without APA. Thus, AVS should be recommended in these patients before surgery. TRIAL REGISTRATION: NCT03398785 , Date of Registration: December 24, 2017.

Achieving blood pressure targets and antihypertensive effects through metabolic surgery in type 2 diabetes patients with hypertension.

AIMS: The effect of metabolic surgery compared with that of conventional therapy on target blood pressure (BP)and defined daily dose (DDD) of antihypertensive drugs in type 2 diabetes (T2DM) patients with hypertension remains unclear. This study aimed to investigate the differences in target BP and DDD between metabolic surgery and conventional treatment in T2DM patients with hypertension. MATERIALS AND METHODS: This was a prospective study of 535 diabetes patients who underwent metabolic surgery (n = 112) and medical treatment (n = 423). Changes in the target BP from baseline to every follow-up were analysed. RESULTS: Metabolic surgery decreased both office systolic and diastolic BP (DBP) and also significantly reduced ambulatory systolic BP (SBP; 132 ± 2 vs. 119 ± 1 mmHg, p < 0.0001), but not DBP (78 ± 1 vs. 76 ± 1 mmHg, p = 0.177). Patients maintained their SBP at <120 mmHg after 2 years (50% vs. 1.9%, p < 0.0001). Moreover, the rate of achieving the target SBP of 130 and 140 mmHg was also significantly higher in the surgery group, and this started from the initial 6 months after commencing treatment to the end of follow-up. The dosage (DDD: 1.44 ± 0.65 vs. 0.32 ± 0.05, p < 0.001) of antihypertensive medication was significantly decreased after metabolic surgery. Furthermore, metabolic surgery, but not medical treatment, markedly improved the risks of atherosclerotic cardiovascular disease. CONCLUSIONS: Metabolic surgery can effectively achieve the BP target and reduce the usage of antihypertensive medications as well as improve multiple metabolic dysfunction in T2DM patients with hypertension. This study provides an alternative approach to antagonize the metabolic related hypertension.

Adrenal Artery Ablation for the Treatment of Hypercortisolism Based on Adrenal Venous Sampling: A Potential Therapeutic Strategy.

AIM: Hypercortisolism is characterized by metabolic disorders and high mortality rates. Adrenalectomy and medical therapies are considered major treatment options. However, some patients, especially young patients, are strongly against undergoing surgery in case of secondary hypocortisolism or relapses that require replacement supplements or pharmacological interventions. In such cases, alternative therapies are needed to treat hypercortisolism. METHODS: We report a 27-year-old Chinese female with adrenal cortisol-producing adenoma. The patient's circadian rhythm and concentrations of cortisol were abnormal, accompanying with an increased 24-hour urinary cortisol level. Computed tomography (CT) revealed a nodular soft-tissue mass in the right adrenal gland. RESULTS: Cortisol hypersecretion from the right adrenal gland was verified by adrenal venous sampling (AVS). Adrenal artery ablation was performed. After ablation, long-term follow-up showed that the patient's symptoms subsided and abnormal laboratory test results returned to normal without pharmacological treatment. CONCLUSION: AVS might be a promising method to aid the diagnosis of cortisol-producing adenoma. Adrenal artery ablation is minimally invasive and may be useful for the treatment of adrenal adenoma or nodular diseases, especially in patients who cannot undergo surgery.

Reducing NADPH Synthesis Counteracts Diabetic Nephropathy through Restoration of AMPK Activity in Type 1 Diabetic Rats.

Diabetic nephropathy (DN) is a major complication of diabetes mellitus and a primary cause of end-stage renal failure. Clinical studies indicate that metabolic surgery improves DN; however, the mechanism remains unclear. Here, we report that Roux-en-Y Gastric Bypass (RYGB) surgery significantly blocked and reversed DN without affecting the insulin signaling pathway. This protective role of RYGB surgery is almost blocked by either inhibition or knockout of 5'AMP-activated protein kinase (AMPK) in podocytes. Furthermore, mRNA microarray data reveal that RYGB surgery obviously reduced the gene expression involved in nicotinamide adenine dinucleotide phosphate (NAPDH) synthesis. The expression of a key NADPH synthase, hexose-6-phosphate dehydrogenase (H6PD), was inhibited by the low plasma corticosterone level after surgery. In addition, blocking NAPDH synthesis by knocking down H6PD mimicked the beneficial role of RYGB surgery through activation of AMPK in podocytes. Therefore, this study demonstrates that reducing NADPH production is critical for renal AMPK activation in response to RYGB surgery.

Adrenal artery ablation for primary aldosteronism without apparent aldosteronoma: An efficacy and safety, proof-of-principle trial.

Primary aldosteronism (PA) is associated with resistant hypertension and cardiovascular events. There are some limitations of current medical and surgical therapies for PA. To determine the efficacy and safety of catheter-based adrenal artery ablation for treatment of PA patients who refused both surgery and medical therapy, we performed this prospective cohort study. Thirty-six PA patients without apparent aldosteronoma were treated by adrenal artery ablation. Primary outcome was postoperative blood pressure and defined daily dose (DDD) of antihypertensive medications after adrenal ablation. Secondary outcome was biochemical success. We assessed outcomes based on Primary Aldosteronism Surgical Outcome (PASO) criteria. Adrenal CT scan, biochemical evaluation, adrenal artery ablation and adrenal venous sampling (AVS) were underwent. After adrenal ablation, complete clinical success (normotension without antihypertensive medication) was achieved in 9/36 (25.0%) patients and partial clinical success (reduction in blood pressure or less antihypertensive medication) in 13/36 (36.1%) patients. Complete biochemical success (correction of hypokalemia and normalization of aldosterone-to-renin ratio) was achieved in 16/36 (44.4%) patients. Office-based and ambulatory blood pressures were reduced by 17/7 and 11/2 mmHg at 6 months after ablation, respectively. The plasma cortisol level in the ablation group decreased slightly, but no patient developed hypoadrenocorticism. Catheter-based adrenal ablation appears to produce substantial and sustained blood pressure reduction and biochemical improvement, with only minor adverse events in PA patients without apparent aldosteronoma. This therapy could be an important supplement for current PA treatments.

Detrimental Effect of C-Reactive Protein on the Cardiometabolic Cells and Its Rectifying by Metabolic Surgery in Obese Diabetic Patients.

BACKGROUND: High-sensitivity C-reactive protein (hs-CRP) has been regarded as a biomarker of low-degree inflammation in illness; however, whether CRP exerts its pathogenic effect on the cardiometabolic system remains unknown. Aside from the beneficial effects of metabolic surgery on cardiometabolic system, its impact on inflammation still worth examining. Thus, this study aims to investigate the effect of CRP on adipose and vascular cells, and their responses to metabolic surgery in obese diabetic patients. PATIENTS AND METHODS: The expression of CRP and RAS- and ERK-related factors in the adipocytes and VSMCs were measured. Obese patients with type 2 diabetes who underwent metabolic surgery were followed up for 2 years thereafter. Laboratory tests, which included serum hs-CRP levels and visceral fat thickness (VFT), were obtained before and after surgery. RESULTS: CRP administration significantly and dose-dependently increased the intracellular-free calcium concentration ([Ca2+]i) in cultured adipocytes and in the VSMCs. CRP administration significantly increased ACE, Ang II, AT1R and p-ERK expressions, but reduced ACE2 expression in both the adipocytes and VSMCs. Clinical study showed that VFT was closely associated with serum hs-CRP. Furthermore, VFT and serum hs-CRP were found to be highly associated with blood pressure. Finally, metabolic surgery remarkably decreased blood pressure, visceral fat and serum hs-CRP levels. CONCLUSION: CRP has a detrimental effect on cardiometabolic cells, aside from functioning merely as a biomarker. Serum hs-CRP levels are highly associated with hypertension and visceral obesity, which can be antagonized by metabolic surgery in obese diabetic patients.

Caloric Restriction Exacerbates Angiotensin II-Induced Abdominal Aortic Aneurysm in the Absence of p53.

p53-dependent vascular smooth muscle cell senescence is a key pathological process of abdominal aortic aneurysm (AAA). Caloric restriction (CR) is a nonpharmacological intervention that prevents AAA formation. However, whether p53 is indispensable to the protective role of CR remains unknown. In this study, we investigated the necessity of p53 in the beneficial role of CR in AAA formation and the underlying mechanisms. We subjected p53+/+ and p53-/- mice to 12 weeks of CR and then examined the incidence of Ang II (angiotensin II)-induced AAA formation. We found that both CR and p53 knockout reduced Ang II-induced AAA formation; however, CR markedly increased the incidence of AAA formation and exacerbated aortic elastin degradation in p53-/- mice, accompanied by increased vascular senescence, reactive oxygen species generation, and reduced energy production. Analysis of mitochondrial respiratory activity revealed that dysfunctional complex IV accounts for the abnormal mitochondrial respiration in p53-/- vascular smooth muscle cells treated by CR serum. Mechanistically, ablation of p53 almost totally blocked the protective role of CR by inhibiting SCO2 (cytochrome C oxidase assembly protein 2)-dependent mitochondrial complex IV activity. Overexpression of SCO2 restored the beneficial effect of CR on antagonizing Ang II-induced expression of AAA-related molecules and reactive oxygen species generation in p53-/- vascular smooth muscle cells. Together, our findings demonstrate that the existence of p53 in vascular smooth muscle cells is critical to the protective role of CR in Ang II-induced AAA formation by maintaining an appropriate mitochondrial function.

Non-insulin determinant pathways maintain glucose homeostasis upon metabolic surgery.

Insulin is critical for glucose homeostasis, and insulin deficiency or resistance leads to the development of diabetes. Recent evidence suggests that diabetes can be remitted independent of insulin. However, the underlying mechanism remains largely elusive. In this study, we utilized metabolic surgery as a tool to identify the non-insulin determinant mechanism. Here, we report that the most common metabolic surgery, Roux-en-Y gastric bypass (RYGB), reduced insulin production but persistently maintained euglycemia in healthy Sprague-Dawley (SD) rats and C57 mice. This reduction in insulin production was associated with RYGB-mediated inhibition of pancreatic preproinsulin and polypyrimidine tract-binding protein 1. In addition, RYGB also weakened insulin sensitivity that was evaluated by hyperinsulinemic-euglycemic clamp test and downregulated signaling pathways in insulin-sensitive tissues. The mechanistic evidence suggests that RYGB predominately shifted the metabolic profile from glucose utilization to fatty acid oxidation, enhanced the energy expenditure and activated multiple metabolic pathways through reducing gut energy uptake. Importantly, the unique effect of RYGB was extended to rats with islet disruption and patients with type 2 diabetes. These results demonstrate that compulsory rearrangement of the gastrointestinal tract can initiate non-insulin determinant pathways to maintain glucose homeostasis. Based on the principle of RYGB action, the development of a noninvasive intervention of the gastrointestinal tract is a promising therapeutic route to combat disorders characterized by energy metabolism dysregulation.

Statin therapy improved long-term prognosis in patients with major non-cardiac vascular surgeries: a systematic review and meta-analysis.

OBJECTIVE: To investigate whether statin intervention will improve the long-term prognosis of patients undergoing major non-cardiac vascular surgeries. METHODS: Major database searches for clinical trials enrolling patients undergoing major non-cardiac vascular surgeries, including lower limb revascularization, carotid artery surgeries, arteriovenous fistula, and aortic surgeries, were performed. Subgroup analyses, stratified by surgical types or study types, were employed to obtain statistical results regarding survival, patency rates, amputation, and cardiovascular and stroke events. Odds ratio (ORs) and 95% confidence intervals (CIs) were calculated by Review Manager 5.3. Sensitivity analysis, publication bias and meta-regression were conducted by Stata 14.0. RESULTS: In total, 34 observational studies, 8 prospective cohort studies and 4 randomized controlled clinical trials (RCTs) were enrolled in the present analysis. It was demonstrated that statin usage improved all-cause mortality in lower limb, carotid, aortic and mixed types of vascular surgery subgroups compared with those in which statins were not used. Additionally, the employment of statins efficiently enhanced the primary and secondary patency rates and significantly decreased the amputation rates in the lower limb revascularization subgroup. Furthermore, for other complications, statin intervention decreased cardiovascular events in mixed types of vascular surgeries and stroke incidence in the carotid surgery subgroup. No significant publication bias was observed. The meta-regression results showed that the morbidity of cardiovascular disease or the use of aspirin might affect the overall estimates in several subgroups. CONCLUSIONS: This meta-analysis demonstrated that statin therapy was associated with improved survival rates and patency rates and with reduced cardiovascular or stroke morbidities in patients who underwent non-cardiac vascular surgeries.

Ameliorating Endothelial Mitochondrial Dysfunction Restores Coronary Function via Transient Receptor Potential Vanilloid 1-Mediated Protein Kinase A/Uncoupling Protein 2 Pathway.

Coronary heart disease arising from atherosclerosis is a leading cause of cardiogenic death worldwide. Mitochondria are the principal source of reactive oxygen species (ROS), and defective oxidative phosphorylation by the mitochondrial respiratory chain contributes to ROS generation. Uncoupling protein 2 (UCP2), an adaptive antioxidant defense factor, protects against mitochondrial ROS-induced endothelial dysfunction in atherosclerosis. The activation of transient receptor potential vanilloid 1 (TRPV1) attenuates vascular dysfunction. Therefore, whether TRPV1 activation antagonizes coronary lesions by alleviating endothelial mitochondrial dysfunction and enhancing the activity of the protein kinase A/UCP2 pathway warrants examination. ApoE(-/-), ApoE(-/-)/TRPV1(-/-), and ApoE(-/-)/UCP2(-/-) mice were fed standard chow, a high-fat diet (HFD), or the HFD plus 0.01% capsaicin. HFD intake profoundly impaired coronary vasodilatation and myocardial perfusion and shortened the survival duration of ApoE(-/-) mice. TRPV1 or UCP2 deficiency exacerbated HFD-induced coronary dysfunction and was associated with increased ROS generation and reduced nitric oxide production in the endothelium. The activation of TRPV1 by capsaicin upregulated UCP2 expression via protein kinase A phosphorylation, thereby alleviating endothelial mitochondrial dysfunction and inhibiting mitochondrial ROS generation. In vivo, dietary capsaicin supplementation enhanced coronary relaxation and prolonged the survival duration of HFD-fed ApoE(-/-) mice. These effects were not observed in ApoE(-/-) mice lacking the TRPV1 or UCP2 gene. The upregulation of protein kinase A /UCP2 via TRPV1 activation ameliorates coronary dysfunction and prolongs the lifespan of atherosclerotic mice by ameliorating endothelial mitochondrial dysfunction. Dietary capsaicin supplementation may represent a promising intervention for the primary prevention of coronary heart disease.

Gastrointestinal intervention ameliorates high blood pressure through antagonizing overdrive of the sympathetic nerve in hypertensive patients and rats.

BACKGROUND: We investigated the hypothesis that the favorable effects of gastrointestinal (GI) intervention on hypertension (HTN) and cardiovascular (CV) disturbances are mediated by antagonizing overdrive of the sympathetic nervous system (SNS). METHODS AND RESULTS: Hypertensive patients with metabolic disturbances underwent laparoscopic Roux-en-Y gastric bypass surgery, and spontaneously hypertensive rats (SHRs) underwent RYGB or sham surgery. Blood pressure (BP), heart rate (HR), endothelium-dependent flow-mediated dilation, and anthropometric as well as laboratory parameters were measured at baseline and during follow-up. Changes of BP and HR in response to cold stress, renal sympathetic nervous activity (RSNA), vasoconstriction induced by electrical field stimulation, microinjection of nucleus of the solitary tract (NTS), and CV function and structure were examined in SHRs with or without surgery. Compared with baseline, BP and HR were significantly reduced in both hypertensive patients with type 2 diabetes and rats. Impaired endothelial-dependent vasodilatation and metabolic disturbances in hypertensive patients were also ameliorated after surgery. CV disturbances were reversed by surgery in SHRs. Under acute cold exposure, the variations in BP and HR were smaller in surgically treated SHRs, compared to sham SHRs. RSNA and vasoconstriction induced by perivascular nerve stimulation as well as NTS-mediated changes of BP were decreased in surgically treated SHRs, compared to sham SHR. Weight loss did not affect BP and RSNA in sham SHRs. CONCLUSIONS: GI intervention ameliorates HTN in both hypertensive patients and rats by inhibiting overdrive of the SNS. Therefore, targeting gastrointestine could be a novel strategy to treat HTN with metabolic disturbances.

Transient receptor potential vanilloid 1 activation enhances gut glucagon-like peptide-1 secretion and improves glucose homeostasis.

Type 2 diabetes mellitus (T2DM) is rapidly prevailing as a serious global health problem. Current treatments for T2DM may cause side effects, thus highlighting the need for newer and safer therapies. We tested the hypothesis that dietary capsaicin regulates glucose homeostasis through the activation of transient receptor potential vanilloid 1 (TRPV1)-mediated glucagon-like peptide-1 (GLP-1) secretion in the intestinal cells and tissues. Wild-type (WT) and TRPV1 knockout (TRPV1(-/-)) mice were fed dietary capsaicin for 24 weeks. TRPV1 was localized in secretin tumor cell-1 (STC-1) cells and ileum. Capsaicin stimulated GLP-1 secretion from STC-1 cells in a calcium-dependent manner through TRPV1 activation. Acute capsaicin administration by gastric gavage increased GLP-1 and insulin secretion in vivo in WT but not in TRPV1(-/-) mice. Furthermore, chronic dietary capsaicin not only improved glucose tolerance and increased insulin levels but also lowered daily blood glucose profiles and increased plasma GLP-1 levels in WT mice. However, this effect was absent in TRPV1(-/-) mice. In db/db mice, TRPV1 activation by dietary capsaicin ameliorated abnormal glucose homeostasis and increased GLP-1 levels in the plasma and ileum. The present findings suggest that TRPV1 activation-stimulated GLP-1 secretion could be a promising approach for the intervention of diabetes.

Increased migration of monocytes in essential hypertension is associated with increased transient receptor potential channel canonical type 3 channels.

Increased transient receptor potential canonical type 3 (TRPC3) channels have been observed in patients with essential hypertension. In the present study we tested the hypothesis that increased monocyte migration is associated with increased TRPC3 expression. Monocyte migration assay was performed in a microchemotaxis chamber using chemoattractants formylated peptide Met-Leu-Phe (fMLP) and tumor necrosis factor-α (TNF-α). Proteins were identified by immunoblotting and quantitative in-cell Western assay. The effects of TRP channel-inhibitor 2-aminoethoxydiphenylborane (2-APB) and small interfering RNA knockdown of TRPC3 were investigated. We observed an increased fMLP-induced migration of monocytes from hypertensive patients compared with normotensive control subjects (246 ± 14% vs 151 ± 10%). The TNF-α-induced migration of monocytes in patients with essential hypertension was also significantly increased compared to normotensive control subjects (221 ± 20% vs 138 ± 18%). In the presence of 2-APB or after siRNA knockdown of TRPC3 the fMLP-induced monocyte migration was significantly blocked. The fMLP-induced changes of cytosolic calcium were significantly increased in monocytes from hypertensive patients compared to normotensive control subjects. The fMLP-induced monocyte migration was significantly reduced in the presence of inhibitors of tyrosine kinase and phosphoinositide 3-kinase. We conclude that increased monocyte migration in patients with essential hypertension is associated with increased TRPC3 channels.

TRPV1 activation prevents nonalcoholic fatty liver through UCP2 upregulation in mice.

Nonalcoholic fatty liver is characterized by the fatty deformation and lipid deposition of hepatic parenchymal cells that are associated with cardiometabolic diseases. In this study, we report the effect of capsaicin on its receptor, transient receptor potential vanilloid 1 (TRPV1) cation channel, in preventing fatty liver formation. Functional TRPV1 has been detected in hepatocytes and liver tissues. TRPV1 activation by capsaicin reduced lipid accumulation and triglyceride level in the liver from wild-type (WT) mice. However, these effects were absent in the liver from TRPV1(-/-) mice. Chronic dietary capsaicin increased the hepatic uncoupling protein 2 (UCP2) expression in WT but not in TRPV1(-/-) mice (P < 0.01). We conclude that TRPV1 long-time activation might prevent high-fat diet-induced fatty liver in mice through upregulation of hepatic UCP2. Dietary capsaicin may represent a promising intervention in populations at high risk for fatty liver.