Qidi Wang

Brown Adipose Tissue in Humans Is Activated by Elevated Plasma Catecholamines Levels and Is Inversely Related to Central Obesity

Background Recent studies have shown that adult human possess active brown adipose tissue (BAT), which might be important in controlling obesity. It is known that ß-adrenoceptor-UCP1 system regulates BAT in rodent, but its influence in adult humans remains to be shown. The present study is to determine whether BAT activity can be independently stimulated by elevated catecholamines levels in adult human, and whether it is associated with their adiposity. Methodology/Principal Findings We studied 14 patients with pheochromocytoma and 14 normal subjects who had performed both 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and plasma total metanephrine (TMN) measurements during 2007–2010. The BAT detection rate and the mean BAT activity were significantly higher in patients with elevated TMN levels (Group A: 6/8 and 6.7±2.1 SUVmean· g/ml) than patients with normal TMN concentrations (Group B: 0/6 and 0.4±0.04 SUVmean· g/ml) and normal subjects (Group C: 0/14 and 0.4±0.03 SUVmean·g/ml). BAT activities were positively correlated with TMN levels (R = 0.83, p<0.0001) and were inversely related to body mass index (R = −0.47, p = 0.010), visceral fat areas (R = −0.39, p = 0.044), visceral/total fat areas (R = −0.52, p = 0.0043) and waist circumferences (R = −0.43, p = 0.019). Robust regression revealed that TMN (R = 0.81, p<0.0001) and waist circumferences (R = −0.009, p = 0.009) were the two independent predictors of BAT activities. Conclusions/Significance Brown adipose tissue activity in adult human can be activated by elevated plasma TMN levels, such as in the case of patients with pheochromocytoma, and is negatively associated with central adiposity.

Brown Adipose Tissue Activation Is Inversely Related to Central Obesity and Metabolic Parameters in Adult Human

Background Recent studies have shown that adult human possess active brown adipose tissue (BAT), which might be important in affecting obesity. However, the supporting evidence on the relationship between BAT and central obesity and metabolic profile in large population based studies is sparse. Methodology/Principal Findings We studied 4011 (2688 males and 1323 females) tumor-free Chinese adults aged 18-89 for BAT activities, visceral/subcutaneous fat areas (VFA/SFA), waist circumferences (WC) and metabolic parameters. We found that the prevalence of BAT was around 2.7% in our study participants, with a significant sexual difference (5.5% in the females vs. 1.3% in the males; p<0.0001). BAT detection was increased in low temperature and declined in elderly subjects. The BAT positive subjects had lower BMI (P<0.0001), less SFA (P<0.01), VFA (P<0.0001), WC (P<0.0001), lower fasting glucose and triglyceride levels (both P<0.01) and increased HDL cholesterol concentrations (P<0.0001), compared with the BAT negative subjects. Robust logistic regression revealed that after adjustment for covariates (including age, sex, BMI, VFA, SFA and WC), age and BMI in the males (0.92 [95%CI, 0.88-0.96] and 0.84 [95% CI, 0.75-0.96], both P ≤0.008) while age and VFA in the females (0.87 [95%CI, 0.83-0.91] and 0.98 [95%CI, 0.97-0.99], respectively, P<0.05) were independently associated with detectable BAT. Conclusions/Significance Our data suggest that decreased amount of active BAT might be associated with accumulation of visceral fat content and unfavorable metabolic outcomes.

The PI3K/AKT/mTOR Signaling Pathway Is Overactivated in Primary Aldosteronism

Background To date, the available non-invasive remedies for primary aldosteronism are not satisfactory in clinical practice. The phosphoinositide 3-kinase (PI3Ks)/protein kinase B (PKB or AKT)/mammalian target of rapamycin (mTOR) signaling pathway is essential for tumorigenesis and metastasis in many types of human tumors, including renal cancer, adrenal carcinoma and pheochromocytoma. The possibility that this pathway is also necessary for the pathogenesis of primary aldosteronism has not yet been explored. To answer this question, we investigated the activity of the PI3K/AKT/mTOR signaling pathway in normal adrenal glands (NAGs), primary aldosteronism (PA) patients and NCI-H295R cells. Methodology/Principal Findings Between January 2005 and December 2011, we retrospectively reviewed the records of 45 patients with PA. We compared clinical characteristics (age, gender and biochemical data) and the expression of phospho-AKT (p-AKT), phospho-mTOR (p-mTOR), phospho-S6 (p-S6) and vascular endothelial growth factor (VEGF) by immunohistochemical staining and western blotting, analyzing 30 aldosterone-producing adenomas (APAs), 15 idiopathic hyperaldosteronism (IHA) tissues and 12 NAGs following nephrectomy for renal tumors (control group). Compared with the control group, most of the PA patients presented with polydipsia, polyuria, resistant hypertension, profound hypokalemia, hyperaldosteronemia and decreased plasma renin activity. Compared with normal zona glomerulosa, the levels of p-AKT, p-mTOR, p-S6 and VEGF were significantly upregulated in APA and IHA. No significant differences were found between APA and IHA in the expression of these proteins. Additionally, positive correlations existed between the plasma aldosterone levels and the expression of p-AKT and p-mTOR. In vitro studies showed that mTOR inhibitor rapamycin could inhibit cell proliferation in NCI-H295R cells in a dose- and time-dependent manner. Furthermore, this inhibitor also decreased aldosterone secretion. Conclusions Our data suggest that the PI3K/AKT/mTOR signaling pathway, which was overactivated in APA and IHA compared with normal zona glomerulosa, may mediate aldosterone hypersecretion and participate in the development of PA.

Raptor regulates functional maturation of murine beta cells

Diabetes is associated with beta cell mass loss and islet dysfunctions. mTORC1 regulates beta cell survival, proliferation and function in physiological and pathological conditions, such as pregnancy and pancreatectomy. Here we show that deletion of Raptor, which is an essential component of mTORC1, in insulin-expressing cells promotes hypoinsulinemia and glucose intolerance. Raptor-deficient beta cells display reduced glucose responsiveness and exhibit a glucose metabolic profile resembling fetal beta cells. Knockout islets have decreased expression of key factors of functional maturation and upregulation of neonatal markers and beta cell disallowed genes, resulting in loss of functional maturity. Mechanistically, Raptor-deficient beta cells show reduced expression of DNA-methyltransferase 3a and altered patterns of DNA methylation at loci that are involved in the repression of disallowed genes. The present findings highlight a novel role of mTORC1 as a core mechanism governing postnatal beta cell maturation and physiologic beta cell mass during adulthood.

Liraglutide protects pancreatic beta cells during an early intervention in Gato-Kakizaki rats.

Glucagon‐like peptide‐1 (GLP‐1) analogues have emerged as insulin secretagogues and are widely used in type 2 diabetic patients. GLP‐1 analogues also demonstrate a promotion of beta cell proliferation and reduction of apoptosis in rodents. In the present study, we investigated the protection of pancreatic beta cells by early use (at the age of 2 weeks) of GLP‐1 analogue, liraglutide in Gato‐Kakizaki (GK) rats and explored the underlying mechanisms.

The mTORC2/PKC pathway sustains compensatory insulin secretion of pancreatic β cells in response to metabolic stress

BACKGROUND Compensation of the pancreatic β cell functional mass in response to metabolic stress is key to the pathogenesis of Type 2 Diabetes. The mTORC2 pathway governs fuel metabolism and β cell functional mass. It is unknown whether mTORC2 is required for regulating metabolic stress-induced β cell compensation. METHODS We challenged four-week-old β-cell-specific Rictor (a key component of mTORC2)-knockout mice with a high fat diet (HFD) for 4weeks and measured metabolic and pancreatic morphological parameters. We performed ex vivo experiments to analyse β cell insulin secretion and electrophysiology characteristics. Adenoviral-mediated overexpression and lentiviral-ShRNA-mediated knocking down proteins were applied in Min6 cells and cultured primary mouse islets. RESULTS βRicKO mice showed a significant glucose intolerance and a reduced plasma insulin level and an unchanged level β cell mass versus the control mice under HFD. A HFD or palmitate treatment enhanced both glucose-induced insulin secretion (GIIS) and the PMA (phorbol 12-myristate 13-acetate)-induced insulin secretion in the control islets but not in the βRicKO islets. The KO β cells showed similar glucose-induced Ca2+ influx but lower membrane capacitance increments versus the control cells. The enhanced mTORC2/PKC proteins levels in the control HFD group were ablated by Rictor deletion. Replenishing PKCα by overexpression of PKCα-T638D restored the defective GIIS in βRicKO islets. CONCLUSIONS The mTORC2/Rictor pathway modulates β cell compensatory GIIS under nutrient overload mediated by its phosphorylation of PKCα. GENERAL SIGNIFICANCE This study suggests that the mTORC2/PKC pathway in β cells is involved in the pathogenesis of T2D.

Liraglutide protects pancreatic beta cells during an early intervention in Gato-Kakizaki rats (Gato-Kakizaki大鼠使用利拉鲁肽进行早期干预可以保护胰腺β细胞)

Glucagon‐like peptide‐1 (GLP‐1) analogues have emerged as insulin secretagogues and are widely used in type 2 diabetic patients. GLP‐1 analogues also demonstrate a promotion of beta cell proliferation and reduction of apoptosis in rodents. In the present study, we investigated the protection of pancreatic beta cells by early use (at the age of 2 weeks) of GLP‐1 analogue, liraglutide in Gato‐Kakizaki (GK) rats and explored the underlying mechanisms.

Sfrp5 mediates glucose-induced proliferation in rat pancreatic β-cells

The cellular and molecular mechanisms of glucose-stimulated β-cell proliferation are poorly understood. Recently, secreted frizzled-related protein 5 (encoded by Sfrp5; a Wnt signaling inhibitor) has been demonstrated to be involved in β-cell proliferation in obesity. A previous study demonstrated that glucose enhanced Wnt signaling to promote cell proliferation. We hypothesized that inhibition of SFRP5 contributes to glucose-stimulated β-cell proliferation. In this study, we found that the Sfrp5 level was significantly reduced in high glucose-treated INS-1 cells, primary rat β-cells, and islets isolated from glucose-infused rats. Overexpression of SFRP5 diminished glucose-stimulated proliferation in both INS-1 cells and primary β-cells, with a concomitant inhibition of the Wnt signaling pathway and decreased cyclin D2 expression. In addition, we showed that glucose-induced Sfrp5 suppression was modulated by the PI3K/AKT pathway. Therefore, we conclude that glucose inhibits Sfrp5 expression via the PI3K/AKT pathway and hence promotes rat pancreatic β-cell proliferation.

BMI Modulates the Effect of Thyroid Hormone on Lipid Profile in Euthyroid Adults

The impacts of thyroid hormones (TH) on lipid profile in euthyroid adults have gained much attention. It is currently unknown whether BMI influences such interaction. In the present study, we investigate the role of BMI in modulating the association between TH and lipid parameters in 1372 euthyroid healthy adults. Our results show that thyroid parameters are differentially associated with lipid profile. FT3 is positively correlated with total cholesterol (β = 0.176 ± 0.046, P < 0.001) and LDL cholesterol levels (β = 0.161 ± 0.040, P < 0.001). FT4 is negatively correlated with TG (β = −0.087 ± 0.029, P < 0.01) while positively correlated with HDL cholesterol levels (β = 0.013 ± 0.005, P < 0.01). TSH is positively associated with TG (β = 0.145 ± 0.056, P < 0.05) and total cholesterol levels (β = 0.094 ± 0.030, P < 0.01). Importantly, BMI modulates the effect of TH on lipid profile: the interaction of FT4 and BMI and the interaction of FT3 and BMI reach statistical significance in predicting TG and HDL cholesterol levels, respectively. Stratified according to BMI levels, most associations between TH and lipid profile are significant only in normal-weight group. In conclusion, in euthyroid adults, high normal FT3, TSH levels, and low normal FT4 levels are associated with unfavorable lipid profile. BMI mediates the effect of thyroid function on lipid profile in euthyroid adults.

Beta cell dedifferentiation in T2D patients with adequate glucose control and non-diabetic chronic pancreatitis.

Context Type 2 diabetes (T2D) and pancreatogenic diabetes are both associated with loss of functional β-cell mass. Previous studies have proposed β-cell dedifferentiation as a mechanism of islet β-cell failure, but its significance in humans is still controversial. Objective To determine whether β-cell dedifferentiation occurs in human T2D with adequate glucose control and in nondiabetic chronic pancreatitis (NDCP), we examined pancreatic islets from nine nondiabetic controls, 10 patients with diabetes with well-controlled fasting glycemia, and four individuals with NDCP. Design We calculated the percentage of hormone-negative endocrine cells and multihormone endocrine cells and scored the pathological characteristics; that is, inflammatory cell infiltration, fibrosis, atrophy, and steatosis, in each case. Results We found a nearly threefold increase in dedifferentiated cells in T2D with adequate glucose control compared with nondiabetic controls (10.0% vs 3.6%, T2D vs nondiabetic controls, P < 0.0001). The dedifferentiation rate was positively correlated with the duration of diabetes. Moreover, we detected a considerable proportion of dedifferentiated cells in NDCP (10.4%), which correlated well with the grade of inflammatory cell infiltration, fibrosis, and atrophy. Conclusions The data support the view that pancreatic β-cells are dedifferentiated in patients with T2D with adequate glucose control. Furthermore, the existence of abundant dedifferentiated cells in NDCP suggests that inflammation-induced β-cell dedifferentiation can be a cause of pancreatogenic diabetes during disease progress.