Yinxing Ni

Activation of the cold-sensing TRPM8 channel triggers UCP1-dependent thermogenesis and prevents obesity

Brown adipose tissue (BAT) is an energy-expending organ that produces heat. Expansion or activation of BAT prevents obesity and diabetes. Chronic cold exposure enhances thermogenesis in BAT through uncoupling protein 1 (UCP1) activation triggered via a β-adrenergic pathway. Here, we report that the cold-sensing transient receptor potential melastatin 8 (TRPM8) is functionally present in mouse BAT. Challenging brown adipocytes with menthol, a TRPM8 agonist, up-regulates UCP1 expression and requires protein kinase A activation. Upon mimicking long-term cold exposure with chronic dietary menthol application, menthol significantly increased the core temperatures and locomotor activity in wild-type mice; these effects were absent in both TRPM8(-/-) and UCP1(-/-) mice. Dietary obesity and glucose abnormalities were also prevented by menthol treatment. Our results reveal a previously unrecognized role for TRPM8, suggesting that stimulation of this channel mediates BAT thermogenesis, which could constitute a promising way to treat obesity.

Blood pressure-lowering effects of GLP-1 receptor agonists exenatide and liraglutide: a meta-analysis of clinical trials

Aside from lowering blood glucose, glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) attract much attention because of their cardioprotective effects. The aim of this study was to assess the blood pressure‐lowering effects of the GLP‐1 RAs exenatide and liraglutide compared with other common drugs used to treat type 2 diabetes (T2DM) based on randomized controlled trials (RCTs) including data describing complete blood pressure (BP) changes from baseline.

Association of angiotensin-converting enzyme 2 gene A/G polymorphism and elevated blood pressure in Chinese patients with metabolic syndrome.

To establish whether angiotensin-converting enzyme 2 (ACE2) gene A/G single nucleotide polymorphism is associated with hypertension in Chinese patients with metabolic syndrome. The study was conducted in 353 patients with metabolic syndrome. The alleles of the ACE2 A/G polymorphism, which is located on the X chromosome, were detected using polymerase chain reaction and subsequent cleavage by Alu I restriction endonuclease. G allele frequencies in patients with metabolic syndrome were 36.6% in female subjects and 43.4% in male subjects, respectively. Female patients with metabolic syndrome who carry the GG genotype had a significantly higher diastolic blood pressure compared with other genotypes. Multivariate logistic regression showed that female gender (P = 0.019) and carrying only the G allele (odds ratio 2.83 [95% CI 1.36 to 5.91]; P = 0.005) were significantly associated with increased diastolic blood pressure. It is concluded that the ACE2 A/G polymorphism is associated with hypertension in patients with metabolic syndrome.

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.

Activation of Transient Receptor Potential Vanilloid 1 by Dietary Capsaicin Delays the Onset of Stroke in Stroke-Prone Spontaneously Hypertensive Rats

Background and Purpose— Previous studies show that endothelial nitric oxide synthase (eNOS) plays a prominent role in maintaining cerebral blood flow and preventing stroke. Capsaicin in hot pepper can increase the phosphorylation of eNOS in endothelial cells. We test the hypothesis that chronic dietary capsaicin can prevent stroke through activation of cerebrovascular transient receptor potential vanilloid 1 (TRPV1) channels in stroke-prone spontaneously hypertensive rats (SHRsp). Methods— SHRsp were fed dietary capsaicin, and their onset of stroke was examined. TRPV1 knockout and transgenic mice were used for determining the function of TRPV1 channels. Expression of eNOS and cerebrovascular reactivity were examined. Results— Immunofluorescence showed TRPV1 channels and eNOS coexpression in cerebral arterioles. Administration of capsaicin significantly increased phosphorylated eNOS in carotid arteries from wild-type mice but not in TRPV1 knockout mice. Inhibition of eNOS using NG-nitro-L-arginine methyl ester, removal of endothelium, or mutant TRPV1 significantly reduced capsaicin-induced endothelium-dependent relaxation of basilar arteries in mice. Chronic dietary capsaicin also remarkably increased eNOS expression in carotid arteries from SHRsp. Compared with Wistar-Kyoto rats, SHRsp had impaired endothelium-dependent relaxation of basilar arteries. Administration of capsaicin or L-arginine significantly improved the endothelium-dependent relaxation of basilar arteries in SHRsp. SHRsp had hypertrophy of cerebral arterioles, which was reversed by dietary capsaicin. Importantly, long-term administration of capsaicin significantly delayed the onset of stroke and increased the survival time in SHRsp. Conclusions— Activation of TRPV1 channels by dietary capsaicin mediated increases in phosphorylation of eNOS and could represent a novel target for dietary intervention of stroke.

Activation of TRPV1 channel by dietary capsaicin improves visceral fat remodeling through connexin43-mediated Ca2+ Influx

BackgroundThe prevalence of obesity has dramatically increased worldwide and has attracted rising attention, but the mechanism is still unclear. Previous studies revealed that transient receptor potential vanilloid 1 (TRPV1) channels take part in weight loss by enhancing intracellular Ca2+ levels. However, the potential mechanism of the effect of dietary capsaicin on obesity is not completely understood. Ca2+ transfer induced by connexin43 (Cx43) molecules between coupled cells takes part in adipocyte differentiation. Whether TRPV1-evoked alterations in Cx43-mediated adipocyte-to-adipocyte communication play a role in obesity is unknown.Materials and methodsWe investigated whether Cx43 participated in TRPV1-mediated adipocyte lipolysis in cultured 3T3-L1 preadipocytes and visceral adipose tissues from humans and wild-type (WT) and TRPV1-deficient (TRPV1-/-) mice.ResultsTRPV1 and Cx43 co-expressed in mesenteric adipose tissue. TRPV1 activation by capsaicin increased the influx of Ca2+ in 3T3-L1 preadipocytes and promoted cell lipolysis, as shown by Oil-red O staining. These effects were deficient when capsazepine, a TRPV1 antagonist, and 18 alpha-glycyrrhetinic acid (18α-GA), a gap-junction inhibitor, were administered. Long-term chronic dietary capsaicin reduced the weights of perirenal, mesenteric and testicular adipose tissues in WT mice fed a high-fat diet. Capsaicin increased the expression levels of p-CaM, Cx43, CaMKII, PPARδ and HSL in mesenteric adipose tissues from WT mice fed a high-fat diet, db/db mice, as well as obese humans, but these effects of capsaicin were absent in TRPV1-/- mice. Long-term chronic dietary capsaicin decreased the body weights and serum lipids of WT mice, but not TRPV1-/- mice, fed a high-fat diet.ConclusionThis study demonstrated that capsaicin activation of TRPV1-evoked increased Ca2+ influx in Cx43-mediated adipocyte-to-adipocyte communication promotes lipolysis in both vitro and vivo. TRPV1 activation by dietary capsaicin improves visceral fat remodeling through the up-regulation of Cx43.

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.

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.

Metformin-based treatment for obesity-related hypertension: a randomized, double-blind, placebo-controlled trial.

Objectives: Obesity and hypertension are associated with an adverse metabolic profile and systemic low-grade inflammation. Metformin reduces weight and inflammation in patients with diabetes, but it is unclear whether it has beneficial effects in patients without diabetes. The objective was to explore whether metformin-based treatment could benefit obesity-related hypertension without diabetes. Methods: A randomized, double-blind, placebo-controlled factorial trial was conducted in 360 obese hypertensive patients without diabetes in Chongqing, China. After a 1–2-week run-in period, patients were randomly assigned to metformin (500 mg once per day) or placebo, as well as to an antihypertensive medication. Change in blood pressure, obesity measurements and metabolic profile were assessed at 24 weeks. Results: The 180 participants randomized to metformin and 180 randomized to placebo were similar at baseline. At 24 weeks, metformin compared with placebo did not have significant effects on blood pressure, blood glucose, high-density or low-density lipoprotein cholesterol, but it did reduce total serum cholesterol (0.27mmol/l, P = 0.038). Metformin also significantly reduced weight (−0.7 kg, P = 0.006), BMI (−0.2 kg/m2, P = 0.024), waist circumference (−0.9 cm, P = 0.008), and both subcutaneous (−6.1 cm2, P = 0.043) and visceral adiposity (−5.4 cm2, P = 0.028) as measured by computed tomography, and lowered serum high-sensitivity C-reactive protein levels (−0.6 mg/dl, P < 0.001). There was no significant difference in adverse events (P = 0.785). Conclusions: Metformin has no effect on blood pressure and blood glucose levels, but it does reduce total cholesterol, abdominal obesity and C-reactive protein levels in obese hypertensive patients without diabetes.

Sex difference in cardiometabolic risk profile and adiponectin expression in subjects with visceral fat obesity.

This study investigates the sex difference of cardiometabolic risk profiles in subjects with visceral fat obesity (VFO) but normal waist circumference (WC). VFO, which is defined as visceral adipose tissue (VAT) area more than 100 cm(2) by computed tomography (CT), and cardiometabolic risk profiles were assessed in 437 subjects with normal WC (197 female subjects and 240 male subjects). The expression of adiponectin and its receptor in abdominal adipose tissue was measured in a subgroup of the subjects. Compared with the male subjects, female subjects had a larger abdominal subcutaneous adipose tissue (SAT) area (158+/-56 vs 116+/-38 cm(2), P<0.01), smaller VAT area (67+/-44 vs 78+/-33 cm(2); P<0.01), and lower prevalence of VFO (12.2 vs 24.2%, P<0.001). This finding was accompanied by upregulated expressions of adiponectin and its receptor in abdominal adipose tissue in female subjects. Without VFO, the risk profiles were not significantly different between male subjects and female subjects. Although risk factors were increased and intensified in both sexes in the presence of VFO, female subjects with VFO were associated with greater cardiometabolic risks than male subjects. A regression analysis indicates the ratio of VAT/SAT for female subjects, whereas VAT and age for male subjects were independently associated with clustering of multiple cardiometabolic risk factors. In conclusion, in subjects with normal WC, the prevalence of VFO is lower and the expression of adiponectin and its receptor is higher in female subjects compared with male subjects. Although VFO was associated with increased risk in both sexes, the risk profile in female subjects with VFO was more pronounced.