Hongying Ye

Growth Hormone Induces Hepatic Production of Fibroblast Growth Factor 21 through a Mechanism Dependent on Lipolysis in Adipocytes

Background: Both growth hormone (GH) and FGF21 are fasting-inducible hormones involved in modulation of lipolysis. Results: GH injection caused a rapid elevation of circulating FGF21 in mice, and such an effect was blocked by the lipolysis inhibitor niacin. FGF21 knock-out mice exhibited greater potency in GH-induced lipolysis. Conclusion: GH and FGF21 form a negative feedback loop to fine-tune lipolysis in adipocytes. Significance: This study provides a novel insight on hormonal control of lipolysis. Fibroblast growth factor (FGF) 21 and growth hormone (GH) are metabolic hormones that play important roles in regulating glucose and lipid metabolism. Both hormones are induced in response to fasting and exert their actions on adipocytes to regulate lipolysis. However, the molecular interaction between these two hormones remains unclear. Here we demonstrate the existence of a feedback loop between GH and FGF21 on the regulation of lipolysis in adipocytes. A single bolus injection of GH into C57 mice acutely increases both mRNA and protein expression of FGF21 in the liver, thereby leading to a marked elevation of serum FGF21 concentrations. Such a stimulatory effect of GH on hepatic FGF21 production is abrogated by pretreatment of mice with the lipolysis inhibitor niacin. Direct incubation of either liver explants or human HepG2 hepatocytes with GH has no effect on FGF21 expression. On the other hand, FGF21 production in HepG2 cells is significantly induced by incubation with the conditioned medium harvested from GH-treated adipose tissue explants, which contains high concentrations of free fatty acids (FFA). Further analysis shows that FFA released by GH-induced lipolysis stimulates hepatic FGF21 expression by activation of the transcription factor PPARα. In FGF21-null mice, both the magnitude and duration of GH-induced lipolysis are significantly higher than those in their wild type littermates. Taken together, these findings suggest that GH-induced hepatic FGF21 production is mediated by FFA released from adipose tissues, and elevated FGF21 in turn acts as a negative feedback signal to terminate GH-stimulated lipolysis in adipocytes.

Adipose Tissue-specific Inhibition of Hypoxia-inducible Factor 1α Induces Obesity and Glucose Intolerance by Impeding Energy Expenditure in Mice

Hypoxia in adipose tissue has been postulated as a possible contributor to obesity-related chronic inflammation, insulin resistance, and metabolic dysfunction. HIF1α (hypoxia-inducible factor 1α), a master signal mediator of hypoxia response, is elevated in obese adipose tissue. However, the role of HIF1α in obesity-related pathologies remains to be determined. Here we show that transgenic mice with adipose tissue-selective expression of a dominant negative version of HIF1α developed more severe obesity and were more susceptible to high fat diet-induced glucose intolerance and insulin resistance compared with their wild type littermates. Obesity in the transgenic mice was attributed to impaired energy expenditure and reduced thermogenesis. Histological examination of interscapular brown adipose tissue (BAT) in the transgenic mice demonstrated a markedly increased size of lipid droplets and decreased mitochondrial density in adipocytes, a phenotype similar to that in white adipose tissue. These changes in BAT of the transgenic mice were accompanied by decreased mitochondrial biogenesis and reduced expression of key thermogenic genes. In the transgenic mice, angiogenesis in BAT was decreased but was little affected in white adipose tissue. These findings support an indispensable role of HIF1α in maintaining the thermogenic functions of BAT, possibly through promoting angiogenesis and mitochondrial biogenesis in this tissue.

The Critical Role of Astragalus Polysaccharides for the Improvement of PPRAα-Mediated Lipotoxicity in Diabetic Cardiomyopathy

Background Obesity-related diabetes mellitus leads to increased myocardial uptake and oxidation of fatty acids, resulting in a form of cardiac dysfunction referred to as lipotoxic cardiomyopathy. We have shown previously that Astragalus polysaccharides (APS) administration was sufficient to improve the systemic metabolic disorder and cardiac dysfunction in diabetic models. Methodology/Principal Findings To investigate the precise role of APS therapy in the pathogenesis of myocardial lipotoxity in diabetes, db/db diabetic mice and myosin heavy chain (MHC)- peroxisome proliferator-activated receptor (PPAR) α mice were characterized and administrated with or without APS with C57 wide- type mice as normal control. APS treatment strikingly improved the myocyte triacylglyceride accumulation and cardiac dysfunction in both db/db mice and MHC-PPARα mice, with the normalization of energy metabolic derangements in both db/db diabetic hearts and MHC-PPARα hearts. Consistently, the activation of PPARα target genes involved in myocardial fatty acid uptake and oxidation in both db/db diabetic hearts and MHC-PPARα hearts was reciprocally repressed by APS administration, while PPARα-mediated suppression of genes involved in glucose utilization of both diabetic hearts and MHC-PPARα hearts was reversed by treatment with APS. Conclusions We conclude that APS therapy could prevent the development of diabetic cardiomyopathy through a mechanism mainly dependent on the cardiac PPARα-mediated regulatory pathways.

Resistin Production from Adipose Tissue Is Decreased in db/db Obese Mice, and Is Reversed by Rosiglitazone

Objective This study was designed to (1) investigate the expression profiles of resistin in db/db mice and its dynamic association with metabolic parameters; and (2) evaluate the effects of Rosiglitazone on production of resistin. Methods Db/db mice and their lean litter mates were used for this study. Epididymal fat tissue was excised from mice of different age (from 5 to 12 weeks) for ex vivo incubation. Resistin,along with adiponectin,in serum and conditioned culture medium of epididymal fat pads were measured with immunoassays. The gene expression of resistin was determined by real-time PCR. Rosiglitazone or the vehicle (PBS) was administered into db/db mice by daily intra-gastric gavage. Differentiated 3T3-L1 adipocytes were used for in vitro evaluation. Results The secretion of resistin from the fat pads in db/db mice was significantly lower than that in lean mice (P<0.01). The mRNA expression of the resistin gene in fat tissue of db/db mice at the age of 5 weeks was decreased by 60.5% compared to lean controls (p<0.05). Serum levels of resistin were comparable between the obese and lean groups, perhaps due to the increased total fat mass in db/db mice. Correlation analysis showed that serum resistin levels were positively correlated to resistin secretion from fat pads(r = 0.844,P = 0.000), while negatively associated with the body weight (r = −0.515, P = 0.000) and fasting glucose level (r = −0.357, P = 0.002). Notably, treatment with rosiglitazone increased the serum resistin levels by 66.4%(P<0.05)in db/db mice. In 3T3-L1 adipocytes, Rosiglitazone (10 uM) markedly enhanced the secretion of resistin by 120% (P<0.01) and its gene expression by 78.1% (P<0.05). Conclusion Both resistin gene expression and its secretion from the epididymal adipose tissue were decreased in db/db obese mice, while the insulin-sensitizing drug rosiglitazone increased resistin production. Our results do not support the role of resistin as an etiological link between obesity and diabetes.

Sudoscan is an effective screening method for asymptomatic diabetic neuropathy in Chinese type 2 diabetes mellitus patients.

The aim of the present study was to use the sudomotor function test, Sudoscan, as a screening method for the evaluation of asymptomatic diabetic distal symmetric polyneuropathy in Chinese type 2 diabetes patients. As a result, more attention could be paid to those asymptomatic patients who could be easily neglected and underdiagnosed in everyday clinic.

Incidence of Pituitary Apoplexy and Its Risk Factors in Chinese People: A Database Study of Patients with Pituitary Adenoma

Background There are few studies of the incidence and clinical characteristics of pituitary apoplexy (PA) in pituitary adenoma patients, and the findings have been inconsistent. Objective The aim of the study was to retrospectively assess the incidence, clinical presentation, surgical management and postoperative complications of PA in pituitary adenoma patients. Methods A database was specifically designed to collect clinical, therapeutic, prognostic and histological information about pituitary adenoma patients. Using multivariate logistic regression, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to identify associated factors. Results A total of 2021 pituitary adenoma patients were recruited. 97 (4.8%) patients had PA. The incidence of PA was 10.11% in patients with pituitary macroadenoma, and 0.36% in patients with microadenoma. Variables for the logistic regression model independently associated with PA were sex (male vs. female, OR = 2.54, 95% CI: 1.59~4.07), tumor type (negative staining vs. positive staining, OR = 2.04, 95% CI: 1.29~3.23), and tumor size (macroadenoma vs. microadenoma, OR = 26.46, 95% CI = 9.66~72.46). Headache, visual deterioration, and vomiting were the most common symptoms in patients with pituitary adenoma. Patients with and without PA had similar frequency of visual deterioration, head trauma, acromegalic appearance, galactorrhoea, cold intolerance and Cushingoid appearance, but headache, vomiting, ptosis, diplopia, fever and blindness were significantly more common in patients with PA. Pearson Chi-Square tests revealed a significant difference in surgical approach between patients with and without PA (95.88% vs. 85.57%, P = 0.01). Conclusion Our findings suggest that PA is not a rare event. Male sex, non-functioning tumor, and macroadenoma are associated with an increased risk of PA. Compared with pituitary adenoma patients without PA, patients with PA have more severe symptoms.

The Diagnostic Value of Neuropathy Symptom and Change Score, Neuropathy Impairment Score and Michigan Neuropathy Screening Instrument for Diabetic Peripheral Neuropathy

Aims: This study aims to evaluate the diagnostic capabilities of neuropathy symptom and change (NSC) score, neuropathy impairment score (NIS) and Michigan neuropathy screening instrument (MNSI) in diagnosing diabetic peripheral neuropathy (DPN). Methods: A total of 131 patients with type II diabetes received NSC, NIS and MNSI scoring systems. Electromyography/nerve conduction velocity (EMG/NCV) test was taken as gold standard. Correlations between EMG/NCV test and the 3 scorings, and their sensitivity, specificity, positive and negative predictive values, accuracy and kappa (κ) value were analyzed. Results: The prevalence of DPN was 43.5% according to EMG/NCV findings. EMG/NCV test was significantly positive correlated with all the 3 scorings, highest with NIS scoring (r = 0.653, p < 0.001). Compared with EMG/NCV test, NSC score was most sensitive (85.96%) but least specific (77.03%); NIS score had lower sensitivity (59.65%) but best specificity (98.65%) and accuracy (81.68%). Both had high concordance with EMG/NCV test (κ = 0.61). Sensitivity, specificity and accuracy of MNSI were highest (70.18, 98.65 and 80.15%) at the cutoff values of >1.0, >2.5 and >1.5, respectively (κ = 0.58). Conclusions: Both NSC and NIS were accurate and reliable diagnostic methods for DPN. The combined application of NSC and NIS was recommended in DPN diagnosis.

Astragalus polysaccharides repress myocardial lipotoxicity in a PPARalpha-dependent manner in vitro and in vivo in mice.

BACKGROUND The role of peroxisome proliferator-activated receptor alpha (PPARα) in the development of myocardial lipotoxicity is widely observed in diabetic disorders. Thus, we investigated if treatment of Astragalus polysaccharides modulates lipotoxic cardiomyopathy both in vivo and in vitro through PPARα mechanisms. METHODOLOGY/PRINCIPAL FINDINGS The effects of Astragalus polysaccharides (APS) on PPARα target gene expression and protein levels were tested in vitro and in vivo, including in mice with PPARα cardiac-restricted overexpression [myosin heavy chain (MHC)-PPARα] and in H9c2 embryonic rat cardiomyocytes with or without PPARα agonist. Echocardiographic studies, analyses of myocardial triglyceride and cardiac fuel utilization analyses were also performed in MHC-PPARα mice. Treatment with APS prevented myocardial triglyceride accumulation and cardiac dysfunction in the MHC-PPARα mice, with the normalization of energy metabolic derangements in hearts including reduced free fatty acids utilization and increased glucose uptake. Consistently, both in the MHC-PPARα hearts and H9c2 cardiomyocytes with PPARα agonist, the activation of PPARα gene regulatory pathway involved in FFA-oxidation was down-regulated by APS treatment, while the suppression of PPARα target genes involved in glucose uptake and oxidation was normalized by APS administration. CONCLUSIONS Therapy with APS could prevent the development of lipotoxic cardiomyopathy through a mechanism mainly dependent on the cardiac PPARα-mediated regulatory pathways.

SUDOSCAN, an effective tool for screening chronic kidney disease in patients with type 2 diabetes

SUDOSCAN is a non-invasive method of measuring peripheral small fiber and autonomic nerve activity by detection of abnormal sweat gland function through electrochemical skin conductance. It has been reported to be an effective screening tool in early detection of microvascular type 2 diabetes mellitus (T2DM) complications including diabetic neuropathy and nephropathy in recent studies. However, previous studies used estimated glomerular filtration rate (eGFR) as the golden standard, which has a 90% chance of being within 30% of the measured GFR at best. No relevant study has been performed in the Chinese population concerning SUDOSCAN in the screening of diabetic nephropathy (DN) in comparison with GFR. In this cross-sectional study, SUDOSCAN was performed in 176 Chinese patients with T2DM between September 2014 and September 2015. It was found that the SUDOSCAN test had a sensitivity of 57.8% and a specificity of 100% to detect chronic kidney disease at a cut-off SUDOSCAN-DN score of 59.5. The area under receiver operating characteristic curve for DN was 0.85 [95% confidence interval (CI), 0.76–0.93] compared with 0.84 for eGFRMDRD (MDRD, modification of diet in renal disease; 95% CI, 0.71–0.98) and 0.77 for eGFREPI (EPI, epidemiology collaboration; 95% CI, 0.68–0.87). Patients with DN score <59.5 had a significantly lower GFR level (P<0.001) and significantly older age (P<0.001), longer duration of T2DM (P<0.001) and higher risk of diabetic complications, including diabetic neuropathy (P<0.001) and peripheral vascular disease (P<0.05). These results suggested that SUDOSCAN may be useful for detecting patients at risk of impaired renal function as part of a screening program in the Chinese population with T2DM.

Identification of recurrent USP48 and BRAF mutations in Cushing’s disease

Cushing’s disease results from corticotroph adenomas of the pituitary that hypersecrete adrenocorticotropin (ACTH), leading to excess glucocorticoid and hypercortisolism. Mutations of the deubiquitinase gene USP8 occur in 35–62% of corticotroph adenomas. However, the major driver mutations in USP8 wild-type tumors remain elusive. Here, we report recurrent mutations in the deubiquitinase gene USP48 (predominantly encoding p.M415I or p.M415V; 21/91 subjects) and BRAF (encoding p.V600E; 15/91 subjects) in corticotroph adenomas with wild-type USP8. Similar to USP8 mutants, both USP48 and BRAF mutants enhance the promoter activity and transcription of the gene encoding proopiomelanocortin (POMC), which is the precursor of ACTH, providing a potential mechanism for ACTH overproduction in corticotroph adenomas. Moreover, primary corticotroph tumor cells harboring BRAF V600E are sensitive to the BRAF inhibitor vemurafenib. Our study thus contributes to the understanding of the molecular mechanism of the pathogenesis of corticotroph adenoma and informs therapeutic targets for this disease.In this study the authors report USP48 and BRAF are frequently mutated in USP8 wild-type corticotroph adenomas, and cause Cushing’s disease mainly through promoting the promoter activity of POMC. Inhibition of BRAF may be a promising therapeutic strategy for the treatment of patients with BRAF-mutated corticotroph adenomas.