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Molecular Research on Obesity and Diabetes

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2016) | Viewed by 182104

Special Issue Editor

Prof. Dr. Toshiro Arai

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Guest Editor
Department of Veterinary Bioscience, School of Veterinary Medicine, Nippon Veterinary and Life Science University, 1-7-1 Kyonancho, Musashino, Tokyo 180-8602, Japan
Interests: clinical biochemistry; molecular and biochemical analysis of onset mechanism of obesity and diabetes; comparative endocrinology; nutrition and metabolism in animals; prophylactic veterinary medicine and disease control in animals
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Obesity and diabetes are disorders in energy metabolism and are observed in most animals, including humans, dogs, cats, ruminants, and birds. The prevalence of obesity and diabetes has increased in all species in recent years. Obesity is defined as the accumulation of excessive amounts of adipose tissue in the body, and is associated with a variety of conditions, including osteoarthritis, respiratory distress, glucose intolerance and diabetes mellitus, hypertension, dystocia, decreased heat tolerance, some types of cancer, and increased risks for anesthetic and surgical complications. Obesity is also associated with inflammation and immune cell recruitment to adipose tissue, muscle, and the intima of atherosclerotic blood vessels. Diabetes mellitus (DM) is one of the most frequently diagnosed endocrinopathies in cats and dogs. Obesity has been clearly identified as a major risk factor for diabetes in cats and for type 2 DM in humans. The autoimmune destruction of pancreatic beta cells, a feature of type 1 DM in human, is common in dogs. There is also evidence for the role of genetic and environmental factors in the occurrences of different types of DM between species. DM is also characterized as a disorder involving the signal transduction of hormones and cytokines. Diagnosis at early stages is important for decreasing the prevalences of obesity and DM. This Special Issue will center on reviews and primary data manuscripts that focus on defining (1) comparative studies in carbohydrate and lipid metabolism in various species; (2) abnormalities in signal transduction related to the onsets of obesity and DM; (3) metabolic syndrome and lipotoxicity; (4) changes in molecules in obese and diabetic animals; (5) the detection of new diagnostic molecules for obesity and DM; (6) the molecular science of insulin resistance and metabolic syndrome; (7) new concepts for treating obesity and DM.

Prof. Dr. Toshiro Arai
Guest Editor

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Keywords

  • Diabetes
  • Obesity
  • Metabolic syndrome
  • Insulin resistance
  • Inflammatory cytokines
  • Lipotoxicity
  • Adiponectin
  • Gene expression
  • Cardiovascular disease
  • Lipid metabolism
  • High calorie diet
  • Physical inactivity

Published Papers (22 papers)

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4599 KiB  
Article
MicroRNA-24 Attenuates Neointimal Hyperplasia in the Diabetic Rat Carotid Artery Injury Model by Inhibiting Wnt4 Signaling Pathway
by Jian Yang, Zhixing Fan, Jun Yang, Jiawang Ding, Chaojun Yang and Lihua Chen
Int. J. Mol. Sci. 2016, 17(6), 765; https://doi.org/10.3390/ijms17060765 - 24 May 2016
Cited by 28 | Viewed by 5108
Abstract
The long-term stimulation of hyperglycemia greatly increases the incidence of vascular restenosis (RS) after angioplasty. Neointimal hyperplasia after vascular injury is the pathological cause of RS, but its mechanism has not been elucidated. MicroRNA-24 (miR-24) has low expression in the injured carotid arteries [...] Read more.
The long-term stimulation of hyperglycemia greatly increases the incidence of vascular restenosis (RS) after angioplasty. Neointimal hyperplasia after vascular injury is the pathological cause of RS, but its mechanism has not been elucidated. MicroRNA-24 (miR-24) has low expression in the injured carotid arteries of diabetic rats. However, the role of miR-24 in the vascular system is unknown. In this study, we explore whether over-expression of miR-24 could attenuate neointimal formation in streptozotocin (STZ)-induced diabetic rats. Adenovirus (Ad-miR-24-GFP) was used to deliver the miR-24 gene to injured carotid arteries in diabetic rats. The level of neointimal hyperplasia was examined by hematoxylin-eosin (HE) staining. Vascular smooth muscle cell (VSMC) proliferation in the neointima was evaluated by immunostaining for proliferating cell nuclear antigen (PCNA). The mRNA levels of miR-24, PCNA, wingless-type MMTV integration site family member 4 (Wnt4), disheveled-1 (Dvl-1), β-catenin and cell cycle-associated molecules (Cyclin D1, p21) were determined by Quantitative Real-Time PCR (qRT-PCR). PCNA, Wnt4, Dvl-1, β-catenin, Cyclin D1 and p21 protein levels were measured by Western blotting analysis. STZ administration decreased plasma insulin and increased fasting blood glucose in Sprague-Dawley (SD) rats. The expression of miR-24 was decreased in the carotid artery after a balloon injury in diabetic rats, and adenoviral transfection (Ad-miR-24-GFP) increased the expression of miR-24. Over-expression of miR-24 suppressed VSMC proliferation and neointimal hyperplasia in diabetic rats at 14 days. Furthermore, compared with Sham group, the mRNA and protein levels of PCNA, Wnt4, Dvl-1, β-catenin, and Cyclin D1 were strikingly up-regulated in the carotid arteries of diabetic rats after a balloon injury. Interestingly, up-regulation of miR-24 significantly reduced the mRNA and protein levels of these above molecules. In contrast, the change trend in p21 mRNA and protein levels was opposite after a balloon injury. However, over-expression of miR-24 after gene delivery increased the mRNA and protein levels of p21. We conclude that over-expression of miR-24 could attenuate VSMC proliferation and neointimal hyperplasia after vascular injuries in diabetic rats. This result is possibly related to the regulation of the expression of Cyclin D1 and p21 through the Wnt4/Dvl-1/β-catenin signaling pathway. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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2007 KiB  
Article
Thrombin Receptor-Activating Protein (TRAP)-Activated Akt Is Involved in the Release of Phosphorylated-HSP27 (HSPB1) from Platelets in DM Patients
by Haruhiko Tokuda, Gen Kuroyanagi, Masanori Tsujimoto, Rie Matsushima-Nishiwaki, Shigeru Akamatsu, Yukiko Enomoto, Hiroki Iida, Takanobu Otsuka, Shinji Ogura, Toru Iwama, Kumi Kojima and Osamu Kozawa
Int. J. Mol. Sci. 2016, 17(5), 737; https://doi.org/10.3390/ijms17050737 - 14 May 2016
Cited by 13 | Viewed by 4863
Abstract
It is generally known that heat shock protein 27 (HSP27) is phosphorylated through p38 mitogen-activated protein (MAP) kinase. We have previously reported that HSP27 is released from human platelets associated with collagen-induced phosphorylation. In the present study, we conducted an investigation into the [...] Read more.
It is generally known that heat shock protein 27 (HSP27) is phosphorylated through p38 mitogen-activated protein (MAP) kinase. We have previously reported that HSP27 is released from human platelets associated with collagen-induced phosphorylation. In the present study, we conducted an investigation into the effect of thrombin receptor-activating protein (TRAP) on the release of HSP27 in platelets in type 2 diabetes mellitus (DM) patients. The phosphorylated-HSP27 levels induced by TRAP were directly proportional to the aggregation of platelets. The levels of phosphorylated-HSP27 (Ser-78) were correlated with the levels of phosphorylated-p38 MAP kinase and phosphorylated-Akt in the platelets stimulated by 10 µM TRAP but not with those of phosphorylated-p44/p42 MAP kinase. The levels of HSP27 released from the TRAP (10 µM)-stimulated platelets were correlated with the levels of phosphorylated-HSP27 in the platelets. The released platelet-derived growth factor-AB (PDGF-AB) levels were in parallel with the HSP27 levels released from the platelets stimulated by 10 µM TRAP. Although the area under the curve (AUC) of small aggregates (9–25 µm) induced by 10 µM TRAP showed no significant correlation with the released HSP27 levels, AUC of medium aggregates (25–50 µm), large aggregates (50–70 µm) and light transmittance were significantly correlated with the released HSP27 levels. TRAP-induced phosphorylation of HSP27 was truly suppressed by deguelin, an inhibitor of Akt, in the platelets from a healthy subject. These results strongly suggest that TRAP-induced activation of Akt in addition to p38 MAP kinase positively regulates the release of phosphorylated-HSP27 from human platelets, which is closely related to the platelet hyper-aggregation in type 2 DM patients. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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207 KiB  
Communication
Plasma Lipoprotein-Associated Phospholipase A2 Levels Correlated with the Cardio-Ankle Vascular Index in Long-Term Type 2 Diabetes Mellitus Patients
by Kazuhiko Kotani
Int. J. Mol. Sci. 2016, 17(5), 634; https://doi.org/10.3390/ijms17050634 - 27 Apr 2016
Cited by 6 | Viewed by 5303
Abstract
The circulating levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) can be a simple, but practical and useful marker of cardiovascular disease (CVD). As limited studies are available in patients with diabetes mellitus (DM), further studies are needed to establish the clinical [...] Read more.
The circulating levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) can be a simple, but practical and useful marker of cardiovascular disease (CVD). As limited studies are available in patients with diabetes mellitus (DM), further studies are needed to establish the clinical application of Lp-PLA2 in DM practice. The present study investigated the correlation between Lp-PLA2 and the cardio-ankle vascular index (CAVI), a recent marker of arterial stiffness, in DM patients according to their diabetes duration. Clinical data, including the plasma Lp-PLA2 mass and CAVI values, were collected from CVD-free type 2 DM female patients (n = 65, mean age 62 years, mean hemoglobin A1c 7.0%). The Lp-PLA2 level of patients with a diabetes duration of <10 years (n = 40:20.2 IU/mL) was not significantly different from that of patients with a diabetes duration of ≥10 years (n = 25:20.5 IU/mL), while the CAVI level was significantly higher in patients with ≥10 years (9.0) than in those with <10 years (8.1; p < 0.05). A stepwise multiple regression analysis found a positive correlation between the Lp-PLA2 and CAVI levels (β = 0.43, p < 0.01) in patients with a diabetes duration of ≥10 years. This correlation between Lp-PLA2 and CVAI suggests the possible use of Lp-PLA2 in DM patients with long-term disease. Further studies on Lp-PLA2 are warranted in DM practice in relation to the disease duration. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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6184 KiB  
Article
Regulation of Adipogenesis by Quinine through the ERK/S6 Pathway
by Xiaomin Ning, Jingjing He, Xin’e Shi and Gongshe Yang
Int. J. Mol. Sci. 2016, 17(4), 504; https://doi.org/10.3390/ijms17040504 - 13 Apr 2016
Cited by 20 | Viewed by 5955
Abstract
Quinine is a bitter tasting compound that is involved in the regulation of body weight as demonstrated in in vivo animal models and in vitro models of the adipogenic system. Arguments exist over the positive or negative roles of quinine in both in [...] Read more.
Quinine is a bitter tasting compound that is involved in the regulation of body weight as demonstrated in in vivo animal models and in vitro models of the adipogenic system. Arguments exist over the positive or negative roles of quinine in both in vivo animal models and in vitro cell models, which motivates us to further investigate the functions of quinine in the in vitro adipogenic system. To clarify the regulatory functions of quinine in adipogenesis, mouse primary preadipocytes were induced for differentiation with quinine supplementation. The results showed that quinine enhanced adipogenesis in a dose dependent manner without affecting lipolysis. The pro-adipogenic effect of quinine was specific, as other bitter tasting agonists had no effect on adipogenesis. Moreover, the pro-adipogenic effect of quinine was mediated by activation of ERK/S6 (extracellular-signal-regulated kinase/Ribosomal protein S6) signaling. Knockdown of bitter taste receptor T2R106 (taste receptor, type 2, member 106) impaired the pro-adipogenic effect of quinine and suppressed the activation of ERK/S6 signaling. Taken together, quinine stimulates adipogenesis through ERK/S6 signaling, which at least partly functions via T2R106. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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2814 KiB  
Article
Pancreatic Transdifferentiation and Glucose-Regulated Production of Human Insulin in the H4IIE Rat Liver Cell Line
by Binhai Ren, Chang Tao, Margaret Anne Swan, Nichole Joachim, Rosetta Martiniello-Wilks, Najah T. Nassif, Bronwyn A. O’Brien and Ann M. Simpson
Int. J. Mol. Sci. 2016, 17(4), 534; https://doi.org/10.3390/ijms17040534 - 08 Apr 2016
Cited by 3 | Viewed by 6592
Abstract
Due to the limitations of current treatment regimes, gene therapy is a promising strategy being explored to correct blood glucose concentrations in diabetic patients. In the current study, we used a retroviral vector to deliver either the human insulin gene alone, the rat [...] Read more.
Due to the limitations of current treatment regimes, gene therapy is a promising strategy being explored to correct blood glucose concentrations in diabetic patients. In the current study, we used a retroviral vector to deliver either the human insulin gene alone, the rat NeuroD1 gene alone, or the human insulin gene and rat NeuroD1 genes together, to the rat liver cell line, H4IIE, to determine if storage of insulin and pancreatic transdifferentiation occurred. Stable clones were selected and expanded into cell lines: H4IIEins (insulin gene alone), H4IIE/ND (NeuroD1 gene alone), and H4IIEins/ND (insulin and NeuroD1 genes). The H4IIEins cells did not store insulin; however, H4IIE/ND and H4IIEins/ND cells stored 65.5 ± 5.6 and 1475.4 ± 171.8 pmol/insulin/5 × 106 cells, respectively. Additionally, several β cell transcription factors and pancreatic hormones were expressed in both H4IIE/ND and H4IIEins/ND cells. Electron microscopy revealed insulin storage vesicles in the H4IIE/ND and H4IIEins/ND cell lines. Regulated secretion of insulin to glucose (0–20 mmol/L) was seen in the H4IIEins/ND cell line. The H4IIEins/ND cells were transplanted into diabetic immunoincompetent mice, resulting in normalization of blood glucose. This data shows that the expression of NeuroD1 and insulin in liver cells may be a useful strategy for inducing islet neogenesis and reversing diabetes. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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2084 KiB  
Article
Programming Effects of Prenatal Glucocorticoid Exposure with a Postnatal High-Fat Diet in Diabetes Mellitus
by Jiunn-Ming Sheen, Chih-Sung Hsieh, You-Lin Tain, Shih-Wen Li, Hong-Ren Yu, Chih-Cheng Chen, Miao-Meng Tiao, Yu-Chieh Chen and Li-Tung Huang
Int. J. Mol. Sci. 2016, 17(4), 533; https://doi.org/10.3390/ijms17040533 - 08 Apr 2016
Cited by 20 | Viewed by 5592
Abstract
Increasing evidence has shown that many chronic diseases originate from early life, even before birth, through what are termed as fetal programming effects. Glucocorticoids are frequently used prenatally to accelerate the maturation of the lungs of premature infants. High-fat diets are associated with [...] Read more.
Increasing evidence has shown that many chronic diseases originate from early life, even before birth, through what are termed as fetal programming effects. Glucocorticoids are frequently used prenatally to accelerate the maturation of the lungs of premature infants. High-fat diets are associated with insulin resistance, but the effects of prenatal glucocorticoid exposure plus a postnatal high-fat diet in diabetes mellitus remain unclear. We administered pregnant Sprague-Dawley rats’ intraperitoneal dexamethasone (0.1 mg/kg body weight) or vehicle at gestational days 14–20. Male offspring were administered a normal or high-fat diet starting from weaning. We assessed the effects of prenatal steroid exposure plus postnatal high-fat diet on the liver, pancreas, muscle and fat at postnatal day 120. At 15 and 30 min, sugar levels were higher in the dexamethasone plus high-fat diet (DHF) group than the vehicle plus high-fat diet (VHF) group in the intraperitoneal glucose tolerance test (IPGTT). Serum insulin levels at 15, 30 and 60 min were significantly higher in the VHF group than in the vehicle and normal diet group. Liver insulin receptor and adenosine monophosphate-activated protein kinase mRNA expressions and protein levels were lower in the DHF group. Insulin receptor and insulin receptor substrate-1 mRNA expressions were lower in the epididymal adipose tissue in the VHF and DHF groups. “Programming” of liver or epididymal adipose tissue resulted from prenatal events. Prenatal steroid exposure worsened insulin resistance in animals fed a high-fat diet. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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3481 KiB  
Article
Interleukin-17A Differentially Induces Inflammatory and Metabolic Gene Expression in the Adipose Tissues of Lean and Obese Mice
by Yine Qu, Qiuyang Zhang, Siqi Ma, Sen Liu, Zhiquan Chen, Zhongfu Mo and Zongbing You
Int. J. Mol. Sci. 2016, 17(4), 522; https://doi.org/10.3390/ijms17040522 - 07 Apr 2016
Cited by 21 | Viewed by 8035
Abstract
The functions of interleukin-17A (IL-17A) in adipose tissues and adipocytes have not been well understood. In the present study, male mice were fed with a regular diet (n = 6, lean mice) or a high-fat diet (n = 6, obese mice) [...] Read more.
The functions of interleukin-17A (IL-17A) in adipose tissues and adipocytes have not been well understood. In the present study, male mice were fed with a regular diet (n = 6, lean mice) or a high-fat diet (n = 6, obese mice) for 30 weeks. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were analyzed for IL-17A levels. SAT and VAT were treated with IL-17A and analyzed for inflammatory and metabolic gene expression. Mouse 3T3-L1 pre-adipocytes were differentiated into adipocytes, followed with IL-17A treatment and analysis for inflammatory and metabolic gene expression. We found that IL-17A levels were higher in obese SAT than lean SAT; the basal expression of inflammatory and metabolic genes was different between SAT and VAT and between lean and obese adipose tissues. IL-17A differentially induced expression of inflammatory and metabolic genes, such as tumor necrosis factor α, Il-6, Il-1β, leptin, and glucose transporter 4, in adipose tissues of lean and obese mice. IL-17A also differentially induced expression of inflammatory and metabolic genes in pre-adipocytes and adipocytes, and IL-17A selectively activated signaling pathways in adipose tissues and adipocytes. These findings suggest that IL-17A differentially induces inflammatory and metabolic gene expression in the adipose tissues of lean and obese mice. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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1583 KiB  
Article
MicroRNAs in Hyperglycemia Induced Endothelial Cell Dysfunction
by Maskomani Silambarasan, Jun Rong Tan, Dwi Setyowati Karolina, Arunmozhiarasi Armugam, Charanjit Kaur and Kandiah Jeyaseelan
Int. J. Mol. Sci. 2016, 17(4), 518; https://doi.org/10.3390/ijms17040518 - 07 Apr 2016
Cited by 65 | Viewed by 8086
Abstract
Hyperglycemia is closely associated with prediabetes and Type 2 Diabetes Mellitus. Hyperglycemia increases the risk of vascular complications such as diabetic retinopathy, diabetic nephropathy, peripheral vascular disease and cerebro/cardiovascular diseases. Under hyperglycemic conditions, the endothelial cells become dysfunctional. In this study, we investigated [...] Read more.
Hyperglycemia is closely associated with prediabetes and Type 2 Diabetes Mellitus. Hyperglycemia increases the risk of vascular complications such as diabetic retinopathy, diabetic nephropathy, peripheral vascular disease and cerebro/cardiovascular diseases. Under hyperglycemic conditions, the endothelial cells become dysfunctional. In this study, we investigated the miRNA expression changes in human umbilical vein endothelial cells exposed to different glucose concentrations (5, 10, 25 and 40 mM glucose) and at various time intervals (6, 12, 24 and 48 h). miRNA microarray analyses showed that there is a correlation between hyperglycemia induced endothelial dysfunction and miRNA expression. In silico pathways analyses on the altered miRNA expression showed that the majority of the affected biological pathways appeared to be associated to endothelial cell dysfunction and apoptosis. We found the expression of ten miRNAs (miR-26a-5p, -26b-5p, 29b-3p, -29c-3p, -125b-1-3p, -130b-3p, -140-5p, -192-5p, -221-3p and -320a) to increase gradually with increasing concentration of glucose. These miRNAs were also found to be involved in endothelial dysfunction. At least seven of them, miR-29b-3p, -29c-3p, -125b-1-3p, -130b-3p, -221-3p, -320a and -192-5p, can be correlated to endothelial cell apoptosis. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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1220 KiB  
Article
Downregulation of de Novo Fatty Acid Synthesis in Subcutaneous Adipose Tissue of Moderately Obese Women
by Esther Guiu-Jurado, Teresa Auguet, Alba Berlanga, Gemma Aragonès, Carmen Aguilar, Fàtima Sabench, Sandra Armengol, José Antonio Porras, Andreu Martí, Rosa Jorba, Mercè Hernández, Daniel Del Castillo and Cristóbal Richart
Int. J. Mol. Sci. 2015, 16(12), 29911-29922; https://doi.org/10.3390/ijms161226206 - 16 Dec 2015
Cited by 17 | Viewed by 6053
Abstract
The purpose of this work was to evaluate the expression of fatty acid metabolism-related genes in human adipose tissue from moderately obese women. We used qRT-PCR and Western Blot to analyze visceral (VAT) and subcutaneous (SAT) adipose tissue mRNA expression involved in de [...] Read more.
The purpose of this work was to evaluate the expression of fatty acid metabolism-related genes in human adipose tissue from moderately obese women. We used qRT-PCR and Western Blot to analyze visceral (VAT) and subcutaneous (SAT) adipose tissue mRNA expression involved in de novo fatty acid synthesis (ACC1, FAS), fatty acid oxidation (PPARα, PPARδ) and inflammation (IL6, TNFα), in normal weight control women (BMI < 25 kg/m2, n = 35) and moderately obese women (BMI 30–38 kg/m2, n = 55). In SAT, ACC1, FAS and PPARα mRNA expression were significantly decreased in moderately obese women compared to controls. The downregulation reported in SAT was more pronounced when BMI increased. In VAT, lipogenic-related genes and PPARα were similar in both groups. Only PPARδ gene expression was significantly increased in moderately obese women. As far as inflammation is concerned, TNFα and IL6 were significantly increased in moderate obesity in both tissues. Our results indicate that there is a progressive downregulation in lipogenesis in SAT as BMI increases, which suggests that SAT decreases the synthesis of fatty acid de novo during the development of obesity, whereas in VAT lipogenesis remains active regardless of the degree of obesity. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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2858 KiB  
Article
Leptin Promotes cPLA2 Gene Expression through Activation of the MAPK/NF-κB/p300 Cascade
by Pei-Sung Hsu, Chi-Sheng Wu, Jia-Feng Chang and Wei-Ning Lin
Int. J. Mol. Sci. 2015, 16(11), 27640-27658; https://doi.org/10.3390/ijms161126045 - 18 Nov 2015
Cited by 17 | Viewed by 5769
Abstract
Hyperplasia or hypertrophy of adipose tissues plays a crucial role in obesity, which is accompanied by the release of leptin. Recently, obesity was determined to be associated with various pulmonary diseases including asthma, acute lung injury, and chronic obstructive pulmonary disease. However, how [...] Read more.
Hyperplasia or hypertrophy of adipose tissues plays a crucial role in obesity, which is accompanied by the release of leptin. Recently, obesity was determined to be associated with various pulmonary diseases including asthma, acute lung injury, and chronic obstructive pulmonary disease. However, how obesity contributes to pulmonary diseases and whether leptin directly regulates lung inflammation remains unclear. We used cell and animal models to study the mechanisms of leptin mediation of pulmonary inflammation. We found that leptin activated de novo synthesis of cytosolic phospholipase A2-α (cPLA2-α) in vitro in the lung alveolar type II cells, A549, and in vivo in ICR mice. Upregulated cPLA2-α protein was attenuated by pretreatment with an OB-R blocking antibody, U0126, SB202190, SP600125, Bay11-7086, garcinol, and p300 siRNA, suggesting roles of p42/p44 MAPK, p38 MAPK, JNK1/2, NF-κB, and p300 in leptin effects. Leptin enhanced the activities of p42/p44 MAPK, p38 MAPK, JNK1/2, and p65 NF-κB in a time-dependent manner. Additional studies have suggested the participation of OB-R, p42/p44 MAPK, and JNK1/2 in leptin-increased p65 phosphorylation. Furthermore, p300 phosphorylation and histone H4 acetylation were reduced by blockage of OB-R, p42/p44 MAPK, p38 MAPK, JNK1/2, and NF-κB in leptin-stimulated cells. Similarly, blockage of the MAPKs/NF-κB/p300 cascade significantly inhibited leptin-mediated cPLA2-α mRNA expression. Our data as a whole showed that leptin contributed to lung cPLA2-α expression through OB-R-dependent activation of the MAPKs/NF-κB/p300 cascade. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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1072 KiB  
Article
Interleukins 6 and 15 Levels Are Higher in Subcutaneous Adipose Tissue, but Obesity Is Associated with Their Increased Content in Visceral Fat Depots
by Marta Izabela Jonas, Alina Kurylowicz, Zbigniew Bartoszewicz, Wojciech Lisik, Maurycy Jonas, Zbigniew Wierzbicki, Andrzej Chmura, Piotr Pruszczyk and Monika Puzianowska-Kuznicka
Int. J. Mol. Sci. 2015, 16(10), 25817-25830; https://doi.org/10.3390/ijms161025817 - 28 Oct 2015
Cited by 43 | Viewed by 7680
Abstract
Excess adiposity is associated with chronic inflammation, which takes part in the development of obesity-related complications. The aim of this study was to establish whether subcutaneous (SAT) or visceral (VAT) adipose tissue plays a major role in synthesis of pro-inflammatory cytokines. Concentrations of [...] Read more.
Excess adiposity is associated with chronic inflammation, which takes part in the development of obesity-related complications. The aim of this study was to establish whether subcutaneous (SAT) or visceral (VAT) adipose tissue plays a major role in synthesis of pro-inflammatory cytokines. Concentrations of interleukins (IL): 1β, 6, 8 and 15 were measured at the protein level by an ELISA-based method and on the mRNA level by real-time PCR in VAT and SAT samples obtained from 49 obese (BMI > 40 kg/m2) and 16 normal-weight (BMI 20–24.9 kg/m2) controls. IL-6 and IL-15 protein concentrations were higher in SAT than in VAT for both obese (p = 0.003 and p < 0.0001, respectively) and control individuals (p = 0.004 and p = 0.001, respectively), while for IL-1β this was observed only in obese subjects (p = 0.047). What characterized obese individuals was the higher expression of IL-6 and IL-15 at the protein level in VAT compared to normal-weight controls (p = 0.047 and p = 0.016, respectively). Additionally, obese individuals with metabolic syndrome had higher IL-1β levels in VAT than did obese individuals without this syndrome (p = 0.003). In conclusion, concentrations of some pro-inflammatory cytokines were higher in SAT than in VAT, but it was the increased pro-inflammatory activity of VAT that was associated with obesity and metabolic syndrome. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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2667 KiB  
Article
Expression of PD-1 Molecule on Regulatory T Lymphocytes in Patients with Insulin-Dependent Diabetes Mellitus
by Valentina Perri, Benedetta Russo, Antonino Crinò, Riccardo Schiaffini, Ezio Giorda, Marco Cappa, Maria Manuela Rosado and Alessandra Fierabracci
Int. J. Mol. Sci. 2015, 16(9), 22584-22605; https://doi.org/10.3390/ijms160922584 - 18 Sep 2015
Cited by 39 | Viewed by 6340
Abstract
Type 1 diabetes is caused by autoreactive T cells that destroy pancreatic beta cells. Animal models suggested that a CD4+CD25+ population has a regulatory function capable of preventing activation and effector functions of autoreactive T cells. However, the role of [...] Read more.
Type 1 diabetes is caused by autoreactive T cells that destroy pancreatic beta cells. Animal models suggested that a CD4+CD25+ population has a regulatory function capable of preventing activation and effector functions of autoreactive T cells. However, the role of CD4+CD25high T cells in autoimmunity and their molecular mechanisms remain the subject of investigation. We therefore evaluated T regulatory cell frequencies and their PD-1 expression in the peripheral blood of long-standing diabetics under basal conditions and after CD3/CD28 stimulation. Under basal conditions, the percentages of T regulatory cells were significantly higher while that of T effector cells were significantly lower in patients than in controls. The ratio of regulatory to effector T cells was higher in patients than that in controls, suggesting that T regulatory cells were functional in patients. Percentages of total PD-1+, PD-1low and PD-1high expressing T regulatory cells did not change in patients and in controls. After stimulation, a defect in T regulatory cell proliferation was observed in diabetics and the percentages of total PD-1+, PD-1low and PD-1high expressing cells were lower in patients. Our data suggest a defective activation of T regulatory cells in long-standing diabetics due to a lower expression of PD-1 on their surface. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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Article
Protective Effects of MDG-1, a Polysaccharide from Ophiopogon japonicus on Diabetic Nephropathy in Diabetic KKAy Mice
by Yuan Wang, Lin-Lin Shi, Ling-Yi Wang, Jin-Wen Xu and Yi Feng
Int. J. Mol. Sci. 2015, 16(9), 22473-22484; https://doi.org/10.3390/ijms160922473 - 17 Sep 2015
Cited by 19 | Viewed by 5717
Abstract
Ophiopogon japonicus is a traditional Chinese medicine that might be effective for treating type 2 diabetes. Recent research confirmed that MDG-1, a polysaccharide from O. japonicas, activates the PI3K/Akt signaling pathway and improves insulin sensitivity in a diabetic KKAy mouse model, [...] Read more.
Ophiopogon japonicus is a traditional Chinese medicine that might be effective for treating type 2 diabetes. Recent research confirmed that MDG-1, a polysaccharide from O. japonicas, activates the PI3K/Akt signaling pathway and improves insulin sensitivity in a diabetic KKAy mouse model, but little is known about its effects on diabetic nephropathy. In this study, KKAy mice were orally administered distilled water (control group), MDG-1, or rosiglitazone for 12 weeks. Blood glucose levels were tested every two weeks for the fed mice. At 6 and 12 weeks, blood samples were collected for biochemical examination. At the end of the experiment, all kidney tissues were collected for histological examination and western blot analysis. Results show that MDG-1 (300 mg/kg) significantly decreased the levels of blood glucose, triglycerides, blood urine nitrogen and albumin, and significantly inhibited the expression of transforming growth factor-beta 1 and connective tissue growth factor. Moreover, MDG-1 could alleviate glomerular mesangial expansion and tubulointerstitial fibrosis in the diabetic mice, as confirmed by histopathological examination. These data indicated that MDG-1 ameliorates renal disease in diabetic mice by reducing hyperglycemia, hyperinsulinemia, and hyperlipidemia, and by inhibiting intracellular signaling pathways. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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859 KiB  
Article
Interleukin-17A Gene Expression in Morbidly Obese Women
by Fernando Zapata-Gonzalez, Teresa Auguet, Gemma Aragonès, Esther Guiu-Jurado, Alba Berlanga, Salomé Martinez, Andreu Martí, Fátima Sabench, Mercé Hernandez, Carmen Aguilar, Joan Josep Sirvent, Rosa Jorba, Daniel Del Castillo and Cristóbal Richart
Int. J. Mol. Sci. 2015, 16(8), 17469-17481; https://doi.org/10.3390/ijms160817469 - 30 Jul 2015
Cited by 23 | Viewed by 5664
Abstract
Data from recent studies conducted in rodent models and humans suggest that interleukin-17A (IL-17A) plays a role in the induction of inflammation in adipose tissue during obesity. The aim of this study was to assess the gene expression of IL-17A in adipose tissue [...] Read more.
Data from recent studies conducted in rodent models and humans suggest that interleukin-17A (IL-17A) plays a role in the induction of inflammation in adipose tissue during obesity. The aim of this study was to assess the gene expression of IL-17A in adipose tissue of morbidly obese patients. We used RT-PCR to evaluate the expression of IL-17A and several adipo/cytokines in the visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) of 10 normal-weight control women (BMI < 25 kg/m2) and 30 morbidly obese women (MO, BMI > 40 kg/m2). We measured serum levels of IL-17A and adipo/cytokines in MO and normal weight women. IL-17A expression was significantly higher in VAT than in SAT in MO patients (p = 0.0127). It was very low in normal-weight controls in both VAT and SAT tissues. We found positive correlations between IL-17A and IL-6, lipocalin-2 and resistin in VAT of MO patients. The circulating level of IL-17A was higher in the normal-weight group than the MO patients (p = 0.032), and it was significantly related to adiponectin and TNFRII levels. In conclusion, IL-17A expression in VAT is increased in morbidly obese women, which suggests a link between obesity and innate immunity in low-grade chronic inflammation in morbidly obese women. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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2982 KiB  
Article
Expression of Human DNAJ (Heat Shock Protein-40) B3 in Humanized UDP-glucuronosyltransferase 1 Mice
by Ryo Mitsugi, Tomoo Itoh and Ryoichi Fujiwara
Int. J. Mol. Sci. 2015, 16(7), 14997-15008; https://doi.org/10.3390/ijms160714997 - 02 Jul 2015
Cited by 6 | Viewed by 5350
Abstract
The human DNAJB3 gene encodes a DNAJ (Heat shock protein 40; Hsp40) homolog, subfamily B, member 3 chaperone protein (DNAJB3), which can be down-regulated in disease conditions, as observed in decreased expression of DNAJB3 mRNA in peripheral blood mononuclear cells (PBMC) of obese [...] Read more.
The human DNAJB3 gene encodes a DNAJ (Heat shock protein 40; Hsp40) homolog, subfamily B, member 3 chaperone protein (DNAJB3), which can be down-regulated in disease conditions, as observed in decreased expression of DNAJB3 mRNA in peripheral blood mononuclear cells (PBMC) of obese patients. Recently, humanized UDP-glucuronosyltransferase (UGT) 1 mice (hUGT1 mice) were developed, in which the introduced human UGT1 gene contained a gene encoding human DNAJB3. In the present study, we analyzed the expression of human DNAJB3 mRNA in hUGT1 mice. Among the examined tissues, the testis had the highest expression of human DNAJB3 mRNA, while the lowest expression was observed in the liver. We found that the pattern of tissue-specific expression of mouse Dnajb3 in hUGT1 mice was very similar to that of human DNAJB3. We further demonstrated that the expression of human DNAJB3 in the liver was significantly reduced in high-fat-diet-fed hUGT1 mice compared to the expression level in the control mice, indicating that the expression of human DNAJB3 in hUGT1 mice could be similarly regulated in disease conditions such as obesity. Humanized UGT1 mice might therefore be useful to investigate the physiological role of human DNAJB3 in vivo. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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Review

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232 KiB  
Review
Type 1 Diabetes in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Syndrome (APECED): A “Rare” Manifestation in a “Rare” Disease
by Alessandra Fierabracci
Int. J. Mol. Sci. 2016, 17(7), 1106; https://doi.org/10.3390/ijms17071106 - 12 Jul 2016
Cited by 31 | Viewed by 5482
Abstract
Type 1 autoimmune polyglandular syndrome (APS1) is a rare autosomal recessive disease, caused by mutations in the autoimmune regulator gene (AIRE); the encoded Aire protein plays an important role in the establishment of the immunological tolerance acting as a transcriptional regulator [...] Read more.
Type 1 autoimmune polyglandular syndrome (APS1) is a rare autosomal recessive disease, caused by mutations in the autoimmune regulator gene (AIRE); the encoded Aire protein plays an important role in the establishment of the immunological tolerance acting as a transcriptional regulator of the expression of organ-specific antigens within the thymus in perinatal age. While a high prevalence for this rare syndrome is reported in Finland and Scandinavia (Norway), autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) cohorts of patients are also detected in continental Italy and Sardinia, among Iranian Jews, as well as in other countries. The syndrome is diagnosed when patients present at least two out of the three fundamental disorders including chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison’s disease. Among the associated conditions insulin-dependent diabetes mellitus (Type 1 diabetes) has been rarely reported in different series of patients and occurring more frequently in Finnish APECED patients. In this review, we analyze the incidence of Type 1 diabetes as a clinical manifestation of APECED in different populations highlighting the peculiar genetic and immunological features of the disease when occurring in the context of this syndrome. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
1717 KiB  
Review
Cell Models and Their Application for Studying Adipogenic Differentiation in Relation to Obesity: A Review
by Francisco Javier Ruiz-Ojeda, Azahara Iris Rupérez, Carolina Gomez-Llorente, Angel Gil and Concepción María Aguilera
Int. J. Mol. Sci. 2016, 17(7), 1040; https://doi.org/10.3390/ijms17071040 - 30 Jun 2016
Cited by 261 | Viewed by 16784
Abstract
Over the last several years, the increasing prevalence of obesity has favored an intense study of adipose tissue biology and the precise mechanisms involved in adipocyte differentiation and adipogenesis. Adipocyte commitment and differentiation are complex processes, which can be investigated thanks to the [...] Read more.
Over the last several years, the increasing prevalence of obesity has favored an intense study of adipose tissue biology and the precise mechanisms involved in adipocyte differentiation and adipogenesis. Adipocyte commitment and differentiation are complex processes, which can be investigated thanks to the development of diverse in vitro cell models and molecular biology techniques that allow for a better understanding of adipogenesis and adipocyte dysfunction associated with obesity. The aim of the present work was to update the different animal and human cell culture models available for studying the in vitro adipogenic differentiation process related to obesity and its co-morbidities. The main characteristics, new protocols, and applications of the cell models used to study the adipogenesis in the last five years have been extensively revised. Moreover, we depict co-cultures and three-dimensional cultures, given their utility to understand the connections between adipocytes and their surrounding cells in adipose tissue. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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895 KiB  
Review
Postprandial C-Peptide to Glucose Ratio as a Marker of β Cell Function: Implication for the Management of Type 2 Diabetes
by Yoshifumi Saisho
Int. J. Mol. Sci. 2016, 17(5), 744; https://doi.org/10.3390/ijms17050744 - 17 May 2016
Cited by 60 | Viewed by 13860
Abstract
C-peptide is secreted from pancreatic β cells at an equimolar ratio to insulin. Since, in contrast to insulin, C-peptide is not extracted by the liver and other organs, C-peptide reflects endogenous insulin secretion more accurately than insulin. C-peptide is therefore used as a [...] Read more.
C-peptide is secreted from pancreatic β cells at an equimolar ratio to insulin. Since, in contrast to insulin, C-peptide is not extracted by the liver and other organs, C-peptide reflects endogenous insulin secretion more accurately than insulin. C-peptide is therefore used as a marker of β cell function. C-peptide has been mainly used to assess the presence of an insulin-dependent state for the diagnosis of type 1 diabetes. However, recent studies have revealed that β cell dysfunction is also a core deficit of type 2 diabetes, and residual β cell function is a key factor in achieving optimal glycemic control in patients with type 2 diabetes. This review summarizes the role of C-peptide, especially the postprandial C-peptide to glucose ratio which likely better reflects maximum β cell secretory capacity compared with the fasting ratio in assessing β cell function, and discusses perspectives on its clinical utility for managing glycemic control in patients with type 2 diabetes. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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283 KiB  
Review
In Search of New Therapeutic Targets in Obesity Treatment: Sirtuins
by Alina Kurylowicz
Int. J. Mol. Sci. 2016, 17(4), 572; https://doi.org/10.3390/ijms17040572 - 19 Apr 2016
Cited by 39 | Viewed by 6869
Abstract
Most of the available non-invasive medical therapies for obesity are non-efficient in a long-term evaluation; therefore there is a constant need for new methods of treatment. Research on calorie restriction has led to the discovery of sirtuins (silent information regulators, SIRTs), enzymes regulating [...] Read more.
Most of the available non-invasive medical therapies for obesity are non-efficient in a long-term evaluation; therefore there is a constant need for new methods of treatment. Research on calorie restriction has led to the discovery of sirtuins (silent information regulators, SIRTs), enzymes regulating different cellular pathways that may constitute potential targets in the treatment of obesity. This review paper presents the role of SIRTs in the regulation of glucose and lipid metabolism as well as in the differentiation of adipocytes. How disturbances of SIRTs’ expression and activity may lead to the development of obesity and related complications is discussed. A special emphasis is placed on polymorphisms in genes encoding SIRTs and their possible association with susceptibility to obesity and metabolic complications, as well as on data regarding altered expression of SIRTs in human obesity. Finally, the therapeutic potential of SIRTs-targeted strategies in the treatment of obesity and related disorders is discussed. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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6236 KiB  
Review
Molecular Mechanisms of the Anti-Obesity and Anti-Diabetic Properties of Flavonoids
by Mohammed Kawser Hossain, Ahmed Abdal Dayem, Jihae Han, Yingfu Yin, Kyeongseok Kim, Subbroto Kumar Saha, Gwang-Mo Yang, Hye Yeon Choi and Ssang-Goo Cho
Int. J. Mol. Sci. 2016, 17(4), 569; https://doi.org/10.3390/ijms17040569 - 15 Apr 2016
Cited by 334 | Viewed by 25193
Abstract
Obesity and diabetes are the most prevailing health concerns worldwide and their incidence is increasing at a high rate, resulting in enormous social costs. Obesity is a complex disease commonly accompanied by insulin resistance and increases in oxidative stress and inflammatory marker expression, [...] Read more.
Obesity and diabetes are the most prevailing health concerns worldwide and their incidence is increasing at a high rate, resulting in enormous social costs. Obesity is a complex disease commonly accompanied by insulin resistance and increases in oxidative stress and inflammatory marker expression, leading to augmented fat mass in the body. Diabetes mellitus (DM) is a metabolic disorder characterized by the destruction of pancreatic β cells or diminished insulin secretion and action insulin. Obesity causes the development of metabolic disorders such as DM, hypertension, cardiovascular diseases, and inflammation-based pathologies. Flavonoids are the secondary metabolites of plants and have 15-carbon skeleton structures containing two phenyl rings and a heterocyclic ring. More than 5000 naturally occurring flavonoids have been reported from various plants and have been found to possess many beneficial effects with advantages over chemical treatments. A number of studies have demonstrated the potential health benefits of natural flavonoids in treating obesity and DM, and show increased bioavailability and action on multiple molecular targets. This review summarizes the current progress in our understanding of the anti-obesity and anti-diabetic potential of natural flavonoids and their molecular mechanisms for preventing and/or treating obesity and diabetes. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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401 KiB  
Review
Diabetes Mellitus Induces Alzheimer’s Disease Pathology: Histopathological Evidence from Animal Models
by Nobuyuki Kimura
Int. J. Mol. Sci. 2016, 17(4), 503; https://doi.org/10.3390/ijms17040503 - 05 Apr 2016
Cited by 89 | Viewed by 13139
Abstract
Alzheimer’s disease (AD) is the major causative disease of dementia and is characterized pathologically by the accumulation of senile plaques (SPs) and neurofibrillary tangles (NFTs) in the brain. Although genetic studies show that β-amyloid protein (Aβ), the major component of SPs, is the [...] Read more.
Alzheimer’s disease (AD) is the major causative disease of dementia and is characterized pathologically by the accumulation of senile plaques (SPs) and neurofibrillary tangles (NFTs) in the brain. Although genetic studies show that β-amyloid protein (Aβ), the major component of SPs, is the key factor underlying AD pathogenesis, it remains unclear why advanced age often leads to AD. Interestingly, several epidemiological and clinical studies show that type II diabetes mellitus (DM) patients are more likely to exhibit increased susceptibility to AD. Moreover, growing evidence suggests that there are several connections between the neuropathology that underlies AD and DM, and there is evidence that the experimental induction of DM can cause cognitive dysfunction, even in rodent animal models. This mini-review summarizes histopathological evidence that DM induces AD pathology in animal models and discusses the possibility that aberrant insulin signaling is a key factor in the induction of AD pathology. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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1275 KiB  
Review
Molecular Pathways Regulating Macrovascular Pathology and Vascular Smooth Muscle Cells Phenotype in Type 2 Diabetes
by Sara Casella, Alessandra Bielli, Alessandro Mauriello and Augusto Orlandi
Int. J. Mol. Sci. 2015, 16(10), 24353-24368; https://doi.org/10.3390/ijms161024353 - 14 Oct 2015
Cited by 33 | Viewed by 7388
Abstract
Type 2 diabetes mellitus (T2DM) is a disease reaching a pandemic proportion in developed countries and a major risk factor for almost all cardiovascular diseases and their adverse clinical manifestations. T2DM leads to several macrovascular and microvascular alterations that influence the progression of [...] Read more.
Type 2 diabetes mellitus (T2DM) is a disease reaching a pandemic proportion in developed countries and a major risk factor for almost all cardiovascular diseases and their adverse clinical manifestations. T2DM leads to several macrovascular and microvascular alterations that influence the progression of cardiovascular diseases. Vascular smooth muscle cells (VSMCs) are fundamental players in macrovascular alterations of T2DM patients. VSMCs display phenotypic and functional alterations that reflect an altered intracellular biomolecular scenario of great vessels of T2DM patients. Hyperglycemia itself and through intraparietal accumulation of advanced glycation-end products (AGEs) activate different pathways, in particular nuclear factor-κB and MAPKs, while insulin and insulin growth-factor receptors (IGFR) are implicated in the activation of Akt and extracellular-signal-regulated kinases (ERK) 1/2. Nuclear factor-κB is also responsible of increased susceptibility of VSMCs to pro-apoptotic stimuli. Down-regulation of insulin growth-factor 1 receptors (IGFR-1R) activity in diabetic vessels also influences negatively miR-133a levels, so increasing apoptotic susceptibility of VSMCs. Alterations of those bimolecular pathways and related genes associate to the prevalence of a synthetic phenotype of VSMCs induces extracellular matrix alterations of great vessels. A better knowledge of those biomolecular pathways and related genes in VSMCs will help to understand the mechanisms leading to macrovascular alterations in T2DM patients and to suggest new targeted therapies. Full article
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
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