Autophagy induces hair follicle stem cell activation and hair follicle regeneration by regulating glycolysis.

BACKGROUND: Hair follicle stem cells (HFSCs) typically remain quiescent and are activated only during the transition from telogen to anagen to ensure that the hair follicle enters a new cycle. The metabolic behavior of stem cells in tissues is regulated by macroautophagy/autophagy, and changes in HFSC metabolism directly affect their activation and maintenance. However, the role of autophagy in the regulation of HFSC metabolism and function remains unclear. METHODS: Back skin samples were obtained from mice at different hair follicle cycle stages, and immunofluorescence staining was used to monitor autophagy in HFSCs. Mouse and human hair follicles were treated with rapamycin (Rapa, an autophagy activator) or 3-methyladenine (3-MA, an autophagy inhibitor). The effects of autophagy on the hair follicle cycle and HFSC were investigated by imaging, cell proliferation staining, and HFSC-specific marker staining. The influence and mechanism of autophagy on HFSC metabolism were explored using RNA sequencing, real-time polymerase chain reaction, immunohistochemical staining, and detection of lactate and glucose concentrations. Finally, the influence of autophagy-induced glycolysis on HFSC and the hair follicle cycle was verified by stem cell characteristics and in vivo functional experiments. RESULTS: Autophagy in HFSC was highest during the transition from telogen to anagen. Inhibiting autophagy with 3-MA led to early entry into catagen and prolonged telogen, whereas Rapa promoted autophagy and hair growth. Autophagy activated HFSC by increasing the expression and activity of HFSC lactate dehydrogenase (Ldha), thereby transforming HFSC metabolism into glycolysis. Inhibition of Ldha expression counteracted the effects of autophagy. CONCLUSIONS: Autophagy activated HFSC by promoting the transition from HFSC metabolism to glycolysis, ultimately initiating the hair follicle cycle and promoting hair growth.

Origins of the short circuit current of a current mismatched multijunction photovoltaic cell considering subcell reverse breakdown.

In the photovoltaic community, short circuit current (Isc) of a current mismatched multijunction photovoltaic (MJPV) cell was usually thought to be limited by the lowest subcell photocurrent (Imin). However, under certain conditions for multijunction solar cells, Isc≠Imin was observed by researchers, while this effect has not been studied in multijunction laser power converters (MJLPCs). In this work, we provide an in-depth analysis of the formation mechanisms for the Isc of the MJPV cell by measuring I-V curves of the GaAs and InGaAs LPCs with different number of subcells and simulating the I-V curves with the reverse breakdown of each subcell considered. It is found that Isc of an N-junction PV cell can be theoretically equal to any current value within a range from a current lower than Imin to the maximum subcell photocurrent, which is up to the number of subcell current steps in the forward biased I-V curve. An MJPV cell with a constant Imin will demonstrate a higher Isc if it has more subcells, smaller subcell reverse breakdown voltage and smaller series resistance. As a result, Isc tends to be limited by the photocurrent of a subcell closer to the middle cell and is less sensitive to the optical wavelength than Imin. This should be another possible reason why the measured EQE of a multijunction LPC exhibits a wider spectrum width than the calculated Imin-based EQE, whereas this was usually attributed to the luminescent coupling effect merely.

Low Threshold Current and Polarization-Stabilized 795 nm Vertical-Cavity Surface-Emitting Lasers.

Low threshold current and polarization-stabilized 795 nm vertical-cavity surface-emitting lasers (VCSELs) are fabricated by integrating a surface grating of high polarization selectivity and high reflectivity. The rigorous coupled-wave analysis method is used to design the surface grating. For the devices with a grating period of 500 nm, a grating depth of ~150 nm, and a diameter of the surface grating region of 5 µm, a threshold current of 0.4 mA and an orthogonal polarization suppression ratio (OPSR) of 19.56 dB are obtained. The emission wavelength of 795 nm of a single transverse mode VCSEL is achieved at a temperature of 85 °C under an injection current of 0.9 mA. In addition, experiments demonstrate that the threshold and output power also depended on the size of the grating region.

The Association of Serum Irisin with Impaired Glucose Before and After Laparoscopic Sleeve Gastrectomy in Obesity.

BACKGROUND: To demonstrate the association of irisin levels with impaired glucose before and after laparoscopic sleeve gastrectomy (LSG) in patients with obesity. METHODS: Thirty-six patients with obesity undergoing LSG were included. We tested the irisin levels before and after LSG and conducted an evaluation of baseline irisin levels with elevated glucose as well as irisin changes with weight loss and its association with glucose control after LSG. RESULTS: Anthropometric measurements, body fat index, and metabolic parameters were significantly improved in 3 months following LSG (all p < 0.05). Baseline irisin levels were significantly higher in obesity with elevated fasting glucose than that with normal glucose (2.98 [2.37, 3.63] vs. 3.72 [3.06, 5.32], p = 0.031). After adjustment for sex, gender, and body mass index (BMI), obesity with higher irisin levels was prone to have impaired fasting glucose (OR = 2.499, 95% CI = 1.047-5.964). According to receiver operating characteristic curve analysis, the diagnostic accuracy and sensitivity of baseline irisin levels on impaired fasting glucose were 75% and 77.8%. Irisin levels decreased from 3.29 (2.67, 4.43) to 2.82 (2.41, 3.25) ng/mL (p = 0.009) after LSG. The decreases of weight, BMI, and FFA were more in irisin changes group (△irisin ≥ 0.5) than in no irisin changes group (△irisin < 0.5). And △irisin was negatively associated with postprandial glucose (PG) at 3 months after LSG (0.5 h-PG, r = - 0.478, p = 0.029; 2 h-PG, r = - 0.406, p = 0.017). CONCLUSIONS: Elevated baseline irisin levels indicated the impaired glucose in obesity. The decrease of irisin with weight loss provided more evidence for the contribution of serum irisin secretion by fat mass in obesity.

Polarization control of 795 nm vertical-cavity surface-emitting lasers by in-phase surface gratings.

795 nm vertical-cavity surface-emitting lasers (VCSELs) with in-phase surface gratings are fabricated and investigated theoretically and experimentally. The polarization characteristics of 795 nm VCSELs with various grating periods and depths are analyzed using the rigorous coupled-wave analysis (RCWA) method; the dependence of polarization stability on the profile of gratings demonstrates that the trapezoid grating ridge slightly enhances the orthogonal polarization suppression ratio (OPSR), but increases the threshold current. The fabricated VCSELs with a sub-wavelength in-phase surface grating of a duty cycle of 0.5 show stabilized output polarization at the cost of increasing the threshold current which is in agreement with the calculations. The grating VCSELs with a period of 200 nm and an oxide aperture of 3.43µm×4.39µm produce a single-mode output with an OPSR of 16.6 dB and a slope efficiency of 0.42 W/A at 85°C.

Association between liver-type fatty acid-binding protein and hyperuricemia before and after laparoscopic sleeve gastrectomy.

Background: Liver-type fatty acid-binding protein (FABP1) contributes to metabolic disorders. However, the relationship between FABP1 and hyperuricemia remains unknown. We aimed to evaluate the correlation between serum FABP1 and hyperuricemia in patients with obesity before and after laparoscopic sleeve gastrectomy (LSG). Methods: We enrolled 105 patients (47 men and 58 women) with obesity who underwent LSG. They were divided into two groups: normal levels of uric acid (UA) (NUA, n = 44) and high levels of UA (HUA, n = 61) with matching sexes. FABP1 levels and other biochemical parameters were measured at baseline and 3, 6, and 12 months after LSG. Results: Serum FABP1 levels were significantly higher in the HUA group than in the NUA group (34.76 ± 22.69 ng/mL vs. 25.21 ± 21.68 ng/mL, P=0.024). FABP1 was positively correlated with UA (r=0.390, P=0.002) in the HUA group. The correlation still existed after adjusting for confounding factors. Preoperative FABP1 levels were risk factors for hyperuricemia at baseline. UA and FABP1 levels decreased at 3, 6, and 12 months postoperatively. FABP1 showed a more significant decrease in the HUA group than in the NUA group at 12 months (27.06 ± 10.98 ng/mL vs. 9.54 ± 6.52 ng/mL, P=0.003). Additionally, the change in FABP1 levels positively correlated with changes in UA levels in the HUA group 12 months postoperatively (r=0.512, P=0.011). Conclusions: FABP1 was positively associated with UA and may be a risk factor for hyperuricemia in obesity. FABP1 levels were higher but decreased more after LSG in obese patients with hyperuricemia than in those without hyperuricemia.

Restoration of appearance for women after aesthetic eyelash transplantation using a novel eyelash resection technique.

BACKGROUND: Hair transplantation based on the follicular unit extraction provides a new opportunity to improve the appearance of patients with congenital sparse eyelashes. However, disparity between transplanted grafts and original eyelashes and the physiological characteristics of upper eyelid skin cause difficulties with this technique and result in low satisfaction. Removal of unsatisfactory eyelashes is indispensable for restoration of appearance and a second transplantation. Unfortunately, existing methods for hair removal have variable success rates, and hairs frequently regrow. OBJECTIVE: This article introduces an effective method to remove unsatisfactory eyelashes in patients with congenital sparse eyelashes who have undergone eyelash transplantation. METHODS: We used a new technique, which involves resection of eyelashes with a composite strip, to remove unsatisfactory eyelashes in patients who underwent eyelash transplantation. The demographic and clinical characteristics of patients were recorded. Outcomes evaluated included patient satisfaction, hair regrowth, and long-term complications. RESULTS: From 2017 to 2021, 10 patients (20 sides) underwent eyelash removal. All patients were highly satisfied with the outcomes. Unsatisfactory eyelashes were thoroughly removed, and none regrew during 1 year of follow-up. No complications were observed. CONCLUSION: Strip composite eyelash excision is a safe and effective method for patients who have undergone unsatisfactory eyelash transplantation.

Vitamin C status and its change in relation to glucose-lipid metabolism in overweight and obesity patients following laparoscopic sleeve gastrectomy.

OBJECTIVES: Aimed to demonstrate the association of VC and metabolism in the obesity or overweight and determine VC changes after laparoscopic sleeve gastrectomy (LSG). METHODS: A total of 253 overweight or people with obesity were recruited, including 61 with LSG. They were divided into group A (VC < 34 ug/ml) and group B (VC ≥ 34 ug/ml). Glucose-lipid metabolic parameters were compared, and VC status before and 6 and 12 months after LSG were measured. RESULTS: (1) Body weight, body mass index (BMI), neck circumference (NC), waist circumference (WC), hip circumference (HC), waist-to-hip ratio, heart rate (HR), diastolic systolic pressure (DBP), 2-hour postprandial glucose (2h-BG), fasting insulin (FINS), 2-hour postprandial insulin (2h-INS), glycosylated hemoglobin (HBG), homeostasis model of insulin resistance (HOMA-IR), total cholesterol (TCH), triglyceride (TG) and free fatty acid (FFA) were higher while high-density lipoprotein (HDL-C) was lower in group A than group B (p < 0.05). (2) VC was negatively correlated with body weight, BMI, NC, WC and HC, HR, SBP, DBP, and 2h-BG, FINS, 2h-INS, HGB, HOMA-IR, TG and FFA, while positively with HDL-C (p < 0.05). (3) Patients with obesity or hypertriglyceridemia or low HDL-C had lower VC than corresponding group. (p < 0.05). (4) Logistic regression analysis showed that VC was the independent risk factor of hypertriglyceridemia, obesity and low HDL-C 5) VC concentrations were slightly increased in 6 months after LSG, and unchanged in 12 months after LSG. CONCLUSION: VC was closely associated with glucose-lipid metabolism, and may play a protective role in metabolic disorders. LSG would not worsen the VC status or deficiency.

Insulin-Like Growth Factor 1 Related to Chronic Low-Grade Inflammation in Patients with Obesity and Early Change of its Levels After Laparoscopic Sleeve Gastrectomy.

BACKGROUND: Insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein (IGFBP) have an influence on metabolism. However, changes in metabolism after sleeve gastrectomy (SG) are not clearly known. This study investigated the change in IGFBP3 levels in obesity after bariatric surgery. METHODS: We evaluated 36 patients with obesity (14 males, aged 31.36 ± 7.06 years and 22 females, aged 32.55 ± 11.40 years) at baseline and 3 months after SG. Changes in their IGF1, IGFBP3, and IGF1/IGFBP3 ratios and glucose-lipid metabolic, inflammation, and oxidative stress parameters were measured. Enzyme-linked immunosorbent assay was used to measure their IGF1 and IGFBP3 levels. RESULTS: (1) IGFBP3 levels were negatively associated with waist circumference (WC) and waist-to-hip ratio (r = - 0.482, P = 0.043; r = - 0.503, P = 0.033); total IGF1 levels were negatively associated with body mass index and WC (r = - 0.569, P = 0.014; r = - 0.470, P = 0.048); and free IGF1 levels were negatively related to tumor necrosis factor (TNF)-α level independent of age (r = - 0.544, P = 0.020). Free IGF1 levels were negatively associated with uric acid, interleukin-6 (IL-6), IL-8, and TNF-α levels (r = - 0.646, P = 0.032; r = - 0.667, P = 0.025; r = - 0.641, P = 0.033; r = - 0.733, P = 0.010) and positively associated with superoxide dismutase activity (r = 0.635, P = 0.036) in females; this relation was not significant in males (all P > 0.05). Total IGF1 was also negatively associated with C-reactive protein (CRP) level in females (r = - 0.671, P = 0.024). (2) IGFBP3 level significantly decreased at 3 months after bariatric surgery in females (P < 0.001) but not in males (P = 0.815). Total IGF1 level significantly decreased after bariatric surgery (P = 0.048); the change was also significant in females (P = 0.014) but not in males (P = 0.626). Free IGF1 level after bariatric surgery was not statistically different between males (P = 0.605) and females (P = 0.628). (3) In females, the change in IGFBP3 level was associated with a change in high-density lipoprotein cholesterol and free fatty acid levels (r = 0.607, P = 0.003; r = 0.546, P = 0.016), and a change in total IGF1 level was associated with a change in CRP level (r = 0.664, P = 0.009). CONCLUSION: IGF1 level was related to chronic low-grade inflammation and oxidative stress in obesity, especially in females. IGFBP3 and IGF1 levels decreased in obesity after SG, especially in females. Changes in IGF/IGFBP3 levels were associated with a change in the inflammatory state after surgery.

Spexin alleviates insulin resistance and inhibits hepatic gluconeogenesis via the FoxO1/PGC-1α pathway in high-fat-diet-induced rats and insulin resistant cells.

Objective: Recent studies demonstrate circulating serum spexin levels are reduced in obesity or type 2 diabetes mellitus (T2DM) patients and may play a role in glucose metabolism. The mechanism underlying is not known. In this study, we explore whether spexin has a role in insulin resistance and hepatic glucose metabolism. Methods: The correlation between serum spexin levels and the homeostasis model assessment of insulin resistance (HOMA-IR) was studied in newly diagnosed T2DM patients. After intraperitoneal injection of exogenous spexin for 8 weeks, the effect of spexin on exogenous glucose infusion rates (GIR), and hepatic glucose production (HGP) were assessed by extended hyperinsulinemic-euglycemic clamp in high-fat-diet (HFD)-induced rats. Glucose concentration with CRISPR/Cas9-mediated disruption of spexin expression in HepG2 cells culture was observed. Expression of transcription factors (Forkhead box O1, FoxO1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PGC-1α) and key enzymes (G-6-Pase and PEPCK) of gluconeogenesis pathway were observed in vitro and in vivo. Results: The serum spexin level was significantly low in newly diagnosed T2DM patients as compared with healthy patients and significantly negatively correlated with the HOMA-IR values. Exogenous spexin treatment resulted in weight loss and decrease of HOMA-IR value in high-fat-diet (HFD)-induced rats. The exogenous glucose infusion rates (GIR) were higher in the HFD + spexin group than that in the HFD group (358 ± 32 vs. 285 ± 24 µmol/kg/min, P < 0.05). Steady-state hepatic glucose production (HGP) was also suppressed by ~50% in the HFD + spexin group as compared with that in the HFD group. Furthermore, spexin inhibited gluconeogenesis in dose-dependent and time-dependent manner in the insulin-resistant cell model. CRISPR/Cas9-mediated knockdown of spexin in HepG2 cells activated gluconeogenesis. Moreover, spexin was shown regulating gluconeogenesis by inhibiting FoxO1/PGC-1α pathway, and key gluconeogenic enzymes, (PEPCK and G-6-Pase) in both HFD-induced rats and insulin-resistant cells. Conclusions: Spexin plays an important role in insulin resistance in HFD-induced rats and insulin-resistant cells. Regulation of the effects of spexin on insulin resistance may hold therapeutic value for metabolic diseases.

Gender difference in the relationship between serum uric acid reduction and improvement in body fat distribution after laparoscopic sleeve gastrectomy in Chinese obese patients: a 6-month follow-up.

BACKGROUND: Hyperuricemia is related to obesity and fat accumulation. This study aimed to observe the effects of laparoscopic sleeve gastrectomy (LSG) on serum uric acid (sUA) level and body fat distribution in obese patients. The relationships between post-LSG improvement in sUA levels and body fat distribution changes, as well as their sex-related differences, were also explored. METHODS: In total, 128 obese patients (48 men; 80 women) who underwent LSG were enrolled. Anthropometric indicators, glucose and lipid metabolic indicators, and sUA levels were measured pre-LSG and 6 months post-LSG. The body compositions were measured via dual-energy X-ray absorptiometry. The patients were divided into normal-sUA (NUA) and high-sUA (HUA) groups based on preoperative sUA levels. RESULTS: Compared with the NUA group, the reduction of sUA levels 6 months post-LSG was more significant in the HUA group. In addition, sUA reduction in the female HUA group was more significant than that of the male HUA group (P < 0.01). Changes in serum uric acid levels (ΔsUA) in the male HUA group was positively correlated with changes in body weight, body mass index, neck circumference, and hip circumference (r = 0.618, 0.653, 0.716, and 0.501, respectively; P < 0.05 in all cases). It was also positively correlated with changes in fat mass in the gynoid region, android region, and legs, (r = 0.675, 0.551, and 0.712, respectively; P < 0.05 in all cases), and negatively correlated with changes in total testosterone (ΔTT) (r = - 0.517; P = 0.040). Furthermore, ΔTT in this group was closely associated with the improved sex-related fat distribution. The ΔsUA in the female HUA group was positively correlated with changes in fasting serum C peptide and ΔLNIR (r = 0.449 and 0.449, respectively; P < 0.05 in both cases). In addition, it was also positively correlated with changes in visceral adipose tissue (VAT) fat mass, VAT fat volume, and VAT fat area (r = 0.749, 0.749, and 0.747, respectively; P < 0.01 in all cases). CONCLUSIONS: sUA levels of obese patients with hyperuricemia improved 6 months after LSG. Reduction of sUA after LSG was correlated with improved body fat distribution, and the relationships also displayed sex-based differences. Uric acid might be an important metabolic regulator associated with fat distribution and sex hormones.

Endoplasmic reticulum stress induced by lipopolysaccharide is involved in the association between inflammation and autophagy in INS­1 cells.

Type 2 diabetes is a chronic inflammatory disease. Autophagy, the dynamic process of lysosomal degradation of damaged organelles and proteins, may protect ß­cells from destruction by inflammation in type 2 diabetes. The present study investigated the role of autophagy, inflammation and endoplasmic reticulum (ER) stress in type 2 diabetes. INS­1 cells were incubated with lipopolysaccharide. The chemical chaperone 4­phenylbutyric acid was used to inhibit ER stress, and 3­methyadenine (3­MA) was used to inhibit autophagy. Apoptosis was detected by flow cytometry and cell proliferation using Cell Counting kit­8 solution. Light chain­3B, interleukin (IL) 1ß, caspase­1 and C/EBP homologous protein production were assessed by western blotting, and rat activating transcription factor 4 and rat binding immunoglobulin heavy chain protein gene expression were determined by real­time reverse transcription­polymerase chain reaction. The results showed that inhibiting autophagy with 3­MA unexpectedly contributed to cell death in ß­cells. This response was associated with an increase in inflammatory cytokines, including IL1ß and caspase­1. Inhibiting ER stress with 4­phenylbutyric acid led to a decrease in cell apoptosis. These results showed that autophagy may have a protective effect by reducing inflammatory cytokines in ß­cells. In addition, the inositol­requiring enzyme 1 pathway mediated the ER stress associated with autophagy and inflammatory cytokines (IL1ß and caspase­1). Therefore, inflammatory cytokines may be critical signalling nodes, which are associated with ER stress­mediated ß­cell death.

Vitexin alleviates lipopolysaccharide­induced islet cell injury by inhibiting HMGB1 release.

Diabetes mellitus (DM) is a chronic metabolic disease, where the predominant pathogenesis is pancreatic ß­cells dysfunction or injury. It has been well established that inflammation leads to a gradual exhaustion of pancreatic ß­cell function with decreased ß­cell mass likely resulting from pancreatic ß­cells apoptosis or death. Vitexin, a major bioactive flavonoid compound in plants has numerous pharmacological properties, including antioxidant, anti­inflammatory and antimyeloperoxidase. Whether vitexin can protect pancreatic ß­cells against lipopolysaccharide (LPS)­induced pro­inflammatory cytokine production and apoptosis has received little attention. The present study investigated the potential effects of vitexin on LPS­induced pancreatic ß­cell injury and apoptosis. It was revealed that apoptosis and damage induced by LPS in islet tissue of rats and INS­1 cells was significantly decreased in response to vitexin treatment. In addition, pretreatment with vitexin decreased the levels of the pro­inflammatory cytokines tumor necrosis factor­α and high mobility group box 1 (HMGB1) in LPS­induced rats. Further experiments demonstrated that vitexin pretreatment suppressed the activation of P38 mitogen­activated protein kinase signaling pathways in LPS­induced INS­1 cells. In conclusion, the results indicated that vitexin prevented LPS­induced islet tissue damage in rats, and INS­1 cells injury and apoptosis by inhibiting HMGB1 release. Therefore, the present study provided clear evidence indicating that vitexin may be a viable therapeutic strategy for the treatment of DM.

Inhibiting autophagy promotes endoplasmic reticulum stress and the ROS­induced nod­like receptor 3­dependent proinflammatory response in HepG2 cells.

Inflammation and endoplasmic reticulum (ER) stress are key contributors to insulin resistance and metabolic disease, and interleukin (IL)­1ß is involved in insulin resistance. The present study aimed to investigated the role of autophagy in LPS­induced ER stress and inflammation, which may provide evidence for controlling metabolic disease associated with inflammation. Lipopolysaccharide (LPS) induced the activation of ER stress and the nod­like receptor 3­dependent expression of IL­1ß and caspase­1, as shown by western blotting, which contributed to HepG2 cell death. This also involved the generation of mitochondrial reactive oxygen species and the autophagy signaling response, which are derived from the ER stress pathway. The percentage of apoptotic cells was measured by flow cytometry with fluorescein isothiocyanate/propidium iodide staining. Reactive oxygen species formation was detected by flow cytometry using the peroxide sensitive fluorescent probe 2',7'­dichlorofluorescin diacetate. Autophagy activation was measured by western blotting and confirmed using transmission electron microscopy. Furthermore, inhibiting autophagy promoted ER stress and the proinflammatory response in addition to cell death. These findings provide insights into the protective role of autophagy in LPS­induced cell death and ER stress, and further identified the association of autophagy, ER stress and inflammation in HepG2 cells.

Identification of a Novel Function of Adipocyte Plasma Membrane-Associated Protein (APMAP) in Gestational Diabetes Mellitus by Proteomic Analysis of Omental Adipose Tissue.

Gestational diabetes mellitus (GDM) is considered as an early stage of type 2 diabetes mellitus. In this study, we compared demographic and clinical data between six GDM subjects and six normal glucose tolerance (NGT; healthy controls) subjects and found that homeostasis model of assessment for insulin resistance index (HOMA-IR) increased in GDM. Many previous studies demonstrated that omental adipose tissue dysfunction could induce insulin resistance. Thus, to investigate the cause of insulin resistance in GDM, we used label-free proteomics to identify differentially expressed proteins in omental adipose tissues from GDM and NGT subjects (data are available via ProteomeXchange with identifier PXD003095). A total of 3528 proteins were identified, including 66 significantly changed proteins. Adipocyte plasma membrane-associated protein (APMAP, a.k.a. C20orf3), one of the differentially expressed proteins, was down-regulated in GDM omental adipose tissues. Furthermore, mature 3T3-L1 adipocytes were used to simulate omental adipocytes. The inhibition of APMAP expression by RNAi impaired insulin signaling and activated NFκB signaling in these adipocytes. Our study revealed that the down-regulation of APMAP in omental adipose tissue may play an important role in insulin resistance in the pathophysiology of GDM.

Spexin peptide is expressed in human endocrine and epithelial tissues and reduced after glucose load in type 2 diabetes.

Spexin mRNA and protein are widely expressed in rat tissues and associate with weight loss in rodents of diet-induced obesity. Its location in endocrine and epithelial cells has also been suggested. Spexin is a novel peptide that involves weight loss in rodents of diet-induced obesity. Therefore, we aimed to examine its expression in human tissues and test whether spexin could have a role in glucose and lipid metabolism in type 2 diabetes mellitus (T2DM). The expression of the spexin gene and immunoreactivity in the adrenal gland, skin, stomach, small intestine, liver, thyroid, pancreatic islets, visceral fat, lung, colon, and kidney was higher than that in the muscle and connective tissue. Immunoreactive serum spexin levels were reduced in T2DM patients and correlated with fasting blood glucose (FBG, r=-0.686, P<0.001), hemoglobin A1c (HbA1c, r=-0.632, P<0.001), triglyceride (TG, r=-0.236, P<0.001) and low density lipoprotein-cholesterol (LDL-C, r=-0.382, P<0.001). A negative correlation of blood glucose with spexin was observed during oral glucose tolerance test (OGTT). Spexin is intensely expressed in normal human endocrine and epithelial tissues, indicating that spexin may be involved in physiological functions of endocrine and in several other tissues. Circulating spexin levels are low in T2DM patients and negatively related to blood glucose and lipids suggesting that the peptide may play a role in glucose and lipid metabolism in T2DM.

Palmitate induces endoplasmic reticulum stress and autophagy in mature adipocytes: implications for apoptosis and inflammation.

Endoplasmic reticulum (ER) stress and inflammation induced by obesity lead to adipocyte dysfunction, with the impairment of the insulin pathway. Recent studies have indicated that understanding the physiological role of autophagy is of great significance. In the present study, an in vitro model was used in which 3T3-L1 adipocytes were pre-loaded with palmitate (PA) to generate artificially hypertrophied mature adipocytes. PA induced an autophagic flux, determined by an increased microtubule-associated protein 1 light chain 3 (LC3)-II formation, as shown by western blot analysis and fluorescence microscopy, and was confirmed using transmission electron microscopy (TEM). Using TEM and western blot analysis, we observed increased ER stress in response to PA, as indicated by the increased levels of the ER stress markers, BiP, activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), and the phosphoralytion of eukaryotic translation initiation factor 2α and c-Jun N-terminal kinase (JNK). Of note, we observed that the PA-induced ER stress occurred prior to the activation of autophagy. We confirmed that autophagy was induced in response to JNK-dependent ER stress, as autophagy was suppressed by treatment with the ER stress inhibitor, 4-phenyl butyrate (4-PBA), and the JNK inhibitor, SP600125. Upon the inhibition of autophagy using chloroquine (CQ), we observed exacerbated ER stress and an increased level of cell death. Importantly, to determine whether autophagy is linked to inflammation, the autophagy inhibitor, 3-methyladenine (3-MA) was used. The inhibition of autophagy led to a further increase in the PA-induced expression of monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6). Consistently, such an increase was also observed following treatment with SP600125. In conclusion, our data indicate that PA elicits a ER stress-JNK-autophagy axis, and that this confers a pro-survival effect against PA-induced cell death and stress in hypertrophied adipocytes. The JNK-dependent activation of autophagy diminishes PA-induced inflammation. Therefore, the stimulation of autophagy may become a method with which to attenuate adipocyte dysfunction and inflammation.

Rapamycin improves palmitate-induced ER stress/NF κ B pathways associated with stimulating autophagy in adipocytes.

Obesity-induced endoplasmic reticulum (ER) stress and inflammation lead to adipocytes dysfunction. Autophagy helps to adapt to cellular stress and involves in regulating innate inflammatory response. In present study, we examined the activity of rapamycin, a mTOR kinase inhibitor, against endoplasmic reticulum stress and inflammation in adipocytes. An in vitro model was used in which 3T3-L1 adipocytes were preloaded with palmitate (PA) to generate artificial hypertrophy mature adipocytes. Elevated autophagy flux and increased number of autophagosomes were observed in response to PA and rapamycin treatment. Rapamycin attenuated PA-induced PERK and IRE1-associated UPR pathways, evidenced by decreased protein levels of eIF2α phosphorylation, ATF4, CHOP, and JNK phosphorylation. Inhibiting autophagy with chloroquine (CQ) exacerbated these ER stress markers, indicating the role of autophagy in ameliorating ER stress. In addition, cotreatment of CQ abolished the anti-ER stress effects of rapamycin, which confirms the effect of rapamycin on ERs is autophagy-dependent. Furthermore, rapamycin decreased PA-induced nuclear translocation of NFκB P65 subunit, thereby NFκB-dependent inflammatory cytokines MCP-1 and IL-6 expression and secretion. In conclusion, rapamycin attenuated PA-induced ER stress/NFκB pathways to counterbalance adipocytes stress and inflammation. The beneficial of rapamycin in this context partly depends on autophagy. Stimulating autophagy may become a way to attenuate adipocytes dysfunction.

Toll-like receptor 2/4 links to free fatty acid-induced inflammation and ß-cell dysfunction.

T2D is a metabolic and inflammatory disease characterized by deteriorating ß-cell function and increased levels of inflammatory cytokines. Low-grade inflammation and innate immune system activation lead to ß-cell failure. Recently, SFAs have been proposed as triggers of metabolism-associated inflammation through the TLR family of PRRs. In this review, recent progress in defining the molecular basis of FFA-associated TLR2/4 activation and signaling in ß-cell dysfunction and apoptosis is summarized. Furthermore, we highlight links between TLRs and diabetic complications, insulin resistance, and autophagy. This knowledge may facilitate novel strategies to abrogate inflammation in T2D.

Follistatin-like 1: a potential mediator of inflammation in obesity.

Obesity is associated with a state of chronic low-grade inflammation, which contributes to insulin resistance and type 2 diabetes. However, the molecular mechanisms that link obesity to inflammation are not fully understood. Follistatin-like 1 (FSTL1) is a novel proinflammatory cytokine that is expressed in adipose tissue and secreted by preadipocytes/adipocytes. We aimed to test whether FSTL1 could have a role in obesity-induced inflammation and insulin resistance. It was found that FSTL1 expression was markedly decreased during differentiation of 3T3-L1 preadipocytes but reinduced by TNF-α. Furthermore, a significant increase in FSTL1 levels was observed in adipose tissue of obese ob/ob mice, as well as in serum of overweight/obese subjects. Mechanistic studies revealed that FSTL1 induced inflammatory responses in both 3T3-L1 adipocytes and RAW264.7 macrophages. The expression of proinflammatory mediators including IL-6, TNF-α, and MCP-1 was upregulated by recombinant FSTL1 in a dose-dependent manner, paralleled with activation of the IKKß-NFκB and JNK signaling pathways in the two cell lines. Moreover, FSTL1 impaired insulin signaling in 3T3-L1 adipocytes, as revealed by attenuated phosphorylation of both Akt and IRS-1 in response to insulin stimulation. Together, our results suggest that FSTL1 is a potential mediator of inflammation and insulin resistance in obesity.