cyclin-d1 and Insulin-Resistance

Obesity with dysfunctional adipose cells is the major cause of the current epidemic of type 2 diabetes (T2D). We examined senescence in human adipose tissue cells from age- and BMI-matched individuals who were lean, obese, and obese with T2D. In obese individuals and, more pronounced, those with T2D, we found mature and fully differentiated adipose cells to exhibit increased senescence similar to what we previously have shown in the progenitor cells. The degree of adipose cell senescence was positively correlated with whole-body insulin resistance and adipose cell size. Adipose cell protein analysis revealed dysfunctional cells in T2D with increased senescence markers reduced PPAR-γ, GLUT4, and pS473AKT. Consistent with a recent study, we found the cell cycle regulator cyclin D1 to be increased in obese cells and further elevated in T2D cells, closely correlating with senescence markers, ambient donor glucose, and, more inconsistently, plasma insulin levels. Furthermore, fully differentiated adipose cells were susceptible to experimentally induced senescence and to conditioned medium increasing cyclin D1 and responsive to senolytic agents. Thus, fully mature human adipose cells from obese individuals, particularly those with T2D become senescent, and SASP secretion by senescent progenitor cells can play an important role in addition to donor hyperinsulinemia.

Topics: Adipose Tissue; Biomarkers; Culture Media, Conditioned; Cyclin D1; Diabetes Mellitus, Type 2; Glucose; Humans; Insulin Resistance; Insulins; Obesity; Peroxisome Proliferator-Activated Receptors

Vascular remodeling induced by long‑term hyperglycaemia is the main pathological process in diabetic vascular complications. Thus, vascular remodeling may be a potential therapeutic target in diabetes mellitus (DM) with macrovascular disease. The present study aimed to investigate the effect of RING finger protein 10 (RNF10) on vascular remodeling under conditions of chronic hyperglycaemia stimulation. We found that overexpression of RNF10 clearly decreased intimal thickness and attenuated vascular remodeling in DM. TUNEL staining showed that apoptosis was clearly inhibited, an effect that may be mediated by decreases in Bcl‑2 protein expression. Quantitative analysis demonstrated that overexpression of RNF10 could suppress inflammation by reducing the levels of TNF‑α, and MCP‑1 mRNA and NF‑κB protein. Meanwhile, overexpression of RNF10 prevented vascular smooth muscle cell (VSMC) hyperproliferation through the downregulation of cyclin D1 and CDK4 proteins. Notably, short hairpin RNF10 (shRNF10) greatly aggravated the pathological responses of diabetic vascular remodeling. These outcomes revealed that the differential expression of RNF10 had a completely opposite effect on vascular damage under hyperglycaemia, further displaying the core function of RNF10 in regulating vascular remodeling induced by diabetes. Consequently, RNF10 could be a novel target for the treatment of diabetic vascular complications.

Topics: Animals; Apoptosis; Carotid Arteries; Carrier Proteins; Chemokine CCL2; Cyclin D1; Cyclin-Dependent Kinase 4; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Diet, High-Fat; Gene Expression Regulation; Humans; Hyperglycemia; Insulin Resistance; Male; Myocytes, Smooth Muscle; Nerve Tissue Proteins; NF-kappa B; Rats; Rats, Sprague-Dawley; RNA, Small Interfering; Signal Transduction; Tumor Necrosis Factor-alpha

Childhood obesity is associated with renal diseases. Maternal obesity is a risk factor linked to increased adipocytokines and metabolic disorders in the offspring. Therefore, we studied the impact of maternal obesity on renal-intrinsic insulin and adipocytokine signaling and on renal function and structure. To induce maternal obesity, female mice were fed a high-fat diet (HFD) or a standard diet (SD; control group) prior to mating, during gestation, and throughout lactation. A third group of dams was fed HFD only during lactation (HFD-Lac). After weaning at postnatal day (P)21, offspring of all groups received SD. Clinically, HFD offspring were overweight and insulin resistant at P21. Although no metabolic changes were detected at P70, renal sodium excretion was reduced by 40%, and renal matrix deposition increased in the HFD group. Mechanistically, two stages were differentiated. In the early stage (P21), compared with the control group, HFD showed threefold increased white adipose tissue, impaired glucose tolerance, hyperleptinemia, and hyperinsulinemia. Renal leptin/Stat3-signaling was activated. In contrast, the Akt/ AMPKα cascade and Krüppel-like factor 15 expression were decreased. In the late stage (P70), although no metabolic differences were detected in HFD when compared with the control group, leptin/Stat3-signaling was reduced, and Akt/AMPKα was activated in the kidneys. This effect was linked to an increase of proliferative (cyclinD1/D2) and profibrotic (ctgf/collagen IIIα1) markers, similar to leptin-deficient mice. HFD-Lac mice exhibited metabolic changes at P21 similar to HFD, but no other persistent changes. This study shows a link between maternal obesity and metabolic programming of renal structure and function and intrinsic-renal Stat3/Akt/AMPKα signaling in the offspring.

Topics: Adipokines; Adipose Tissue, White; AMP-Activated Protein Kinases; Animals; Collagen Type III; Connective Tissue Growth Factor; Cyclin D1; Cyclin D2; Diet, High-Fat; DNA-Binding Proteins; Female; Glucose Intolerance; Insulin; Insulin Resistance; Kidney; Kruppel-Like Transcription Factors; Leptin; Male; Mice; Obesity; Overweight; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Proto-Oncogene Proteins c-akt; Signal Transduction; Sodium; STAT3 Transcription Factor; Transcription Factors

To investigate the change of plasma nesfatin-1 concentration in a nonalcoholic fatty liver disease rat model induced by high-fat diet, and explore its effect on the dysfunction of glucose and lipid metabolism.. The nonalcoholic fatty liver disease rat model was established through introduction of a high-fat diet, and four weeks later, the intraperitoneal glucose tolerance test was conducted. Serum concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), total cholesterol (TC) triglyceride (TG), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C) were detected using chemiluminescence technique. The plasma levels of nesfatin-1, leptin, and insulin (INS) were measured via enzyme-linked immunosorbent assay (ELISA), the histological changes of the liver was observed via HE staining, and the protein expressions of beta-catenin, p-beta-catenin and cyclin D1 in the liver were detected using western blot and compared with beta-actin.. The bodyweight, liver weight, liver index, and area under the curve of the intraperitoneal glucose tolerance test were all higher in the model rats than those in the controls. Compared with the control, serum concentrations of ALT, TBIL, IBIL, TC and LDL-C in the model rats were all increased. The plasma nesfatin-1 level was increased in model rats while the plasma concentrations of leptin and insulin were decreased, and a negative correlation was found between the plasma concentration of nesfatin-1 and leptin. Inflammation and hepatocyte steatosis were detected in the livers of model rats, and the protein expression of cyclinD1 was upregulated while the phosphorylation of beta-catenin was decreased in the livers of the model rats.. Post-creation of nonalcoholic fatty liver disease rat models through high fat diets, changes were observed in plasma nesfatin-1 concentration, perhaps a vital part of glucose and lipid metabolism dysfunction.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; beta Catenin; Bilirubin; Body Weight; Calcium-Binding Proteins; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cyclin D1; Diet, High-Fat; DNA-Binding Proteins; Enzyme-Linked Immunosorbent Assay; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Nerve Tissue Proteins; Non-alcoholic Fatty Liver Disease; Nucleobindins; Rats; Triglycerides

Bisphenol A (BPA) is a widespread endocrine-disrupting chemical used as the building block for polycarbonate plastics. Epidemiological evidence has correlated BPA exposure with higher risk of heart disease and type 2 diabetes. However, it remains unknown whether there are critical windows of susceptibility to BPA exposure on the development of dysglycemia. This study was an attempt to investigate the critical windows and the long-term consequences of perinatal exposure to BPA on glucose homeostasis. Pregnant mice were given either vehicle or BPA (100 µg/kg/day) at different time of perinatal stage: 1) on days 1-6 of pregnancy (P1-P6, preimplantation exposure); 2) from day 6 of pregnancy until postnatal day (PND) 0 (P6-PND0, fetal exposure); 3) from lactation until weaning (PND0-PND21, neonatal exposure); and 4) from day 6 of gestation until weaning (P6-PND21, fetal and neonatal exposure). At 3, 6 and 8 months of age, offspring in each group were challenged with glucose and insulin tolerance tests. Then islet morphometry and β-cell function were measured. The glucose homeostasis was impaired in P6-PND0 mice from 3 to 6 months of age, and this continued to 8 months in males, but not females. While in PND0-PND21 and P6-PND21 BPA-treated groups, only the 3-month-old male offspring developed glucose intolerance. Moreover, at the age of 3 months, perinatal exposure to BPA resulted in the increase of β-cell mass mainly due to the coordinate changes in cell replication, neogenesis, and apoptosis. The alterations of insulin secretion and insulin sensitivity, rather than β-cell mass, were consistent with the development of glucose intolerance. Our findings suggest that BPA may contribute to metabolic disorders relevant to glucose homeostasis and the effects of BPA were dose, sex, and time-dependent. Fetal development stage may be the critical window of susceptibility to BPA exposure.

Topics: Adult; Animals; Benzhydryl Compounds; Blood Glucose; Body Weight; Caspase 3; Cyclin D1; Estrogens, Non-Steroidal; Female; Glucose; Homeostasis; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Male; Mice; Phenols; Phenotype; Pregnancy; Pregnancy Outcome; Prenatal Exposure Delayed Effects; Sex Factors

The deadenylase nocturnin (Noc, Ccrn4l) has been recently found to regulate lipid metabolism and to control preadipocyte differentiation. Here, we showed that among the five deadenylases tested, Noc and Pan2 exhibited a biphasic expression which is out of phase to each other during adipocyte differentiation of 3T3-L1 cells. The expression levels of other deadenylases, including Parn, Ccr4, and Caf1, were relatively unchanged or reduced. The immediate early expressed Noc during 3T3-L1 adipogenesis was involved in regulating mitotic clonal expansion (MCE) and cyclin D1 expression, as demonstrated in Noc-silenced 3T3-L1 cells and Noc(-/-) primary mouse embryonic fibroblasts (MEFs). Transcriptional profiling of Noc-depleted 3T3-L1 adipocytes revealed that most of the differentially expressed genes were related to cell growth and proliferation. In human adipose tissue, NOC mRNA level negatively associated with both fasting serum insulin and homeostasis model assessment of insulin resistance, and positively associated with both adiponectin mRNA levels and circulating adiponectin levels. Taken together, these results suggest the role of Noc in the modulation of early adipogenesis as well as systemic insulin sensitivity.

Topics: 3T3-L1 Cells; Adipogenesis; Adiponectin; Adipose Tissue; Adult; Animals; Cell Proliferation; Cyclin D1; Fasting; Fibroblasts; Gene Expression; Humans; Insulin; Insulin Resistance; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitosis; Nuclear Proteins; Obesity; RNA, Messenger; Transcription Factors; Transcriptome

A major determinant of the progression from insulin resistance to the development of overt type 2 diabetes is a failure to mount an appropriate compensatory beta-cell hyperplastic response to maintain normoglycemia. We undertook the present study to directly explore the significance of the cell cycle protein cyclin D2 in the expansion of beta-cell mass in two different models of insulin resistance.. We created compound knockouts by crossing mice deficient in cyclin D2 (D2KO) with either the insulin receptor substrate 1 knockout (IRS1KO) mice or the insulin receptor liver-specific knockout mice (LIRKO), neither of which develops overt diabetes on its own because of robust compensatory beta-cell hyperplasia. We phenotyped the double knockouts and used RT-qPCR and immunohistochemistry to examine beta-cell mass.. Both compound knockouts, D2KO/LIRKO and D2KO/IRS1KO, exhibited insulin resistance and hyperinsulinemia and an absence of compensatory beta-cell hyperplasia. However, the diabetic D2KO/LIRKO group rapidly succumbed early compared with a relatively normal lifespan in the glucose-intolerant D2KO/IRS1KO mice.. This study provides direct genetic evidence that cyclin D2 is essential for the expansion of beta-cell mass in response to a spectrum of insulin resistance and points to the cell-cycle protein as a potential therapeutic target that can be harnessed for preventing and curing type 2 diabetes.

Topics: Animals; Cyclin D1; Cyclin D2; Diabetes Mellitus, Experimental; Genotype; Homozygote; Hyperglycemia; Hyperplasia; Insulin Resistance; Insulin-Secreting Cells; Liver; Mice; Mice, Knockout; Receptor, Insulin; Reverse Transcriptase Polymerase Chain Reaction

Sex-determining region Y-box (SOX) 6 negatively regulates glucose-stimulated insulin secretion from beta-cells and is a down-regulated transcription factor in the pancreatic islet cells of hyperinsulinemic obese mice. To determine the contribution of SOX6 to insulin resistance, we analyzed the effects of SOX6 on cell proliferation. Small interfering RNA-mediated attenuation of SOX6 expression stimulated the proliferation of insulinoma INS-1E and NIH-3T3 cells, whereas retroviral overexpression resulted in inhibition of cell growth. Quantitative real time-PCR analysis revealed that the levels of cyclin D1 transcripts were markedly decreased by SOX6 overexpression. Luciferase-reporter assay with beta-catenin showed that SOX6 suppresses cyclin D1 promoter activities. In vitro binding experiments showed that the LZ/Q domain of SOX6 physically interacts with armadillo repeats 1-4 of beta-catenin. Furthermore, chromatin immunoprecipitation assay revealed that increased SOX6 expression significantly reduced the levels of acetylated histones H3 and H4 at the cyclin D1 promoter. By using a histone deacetylase (HDAC) inhibitor and co-immunoprecipitation analysis, we showed that SOX6 suppressed cyclin D1 activities by interacting withbeta-catenin and HDAC1. The data presented suggest that SOX6 may be an important factor in obesity-related insulin resistance.

Topics: Animals; beta Catenin; Cell Division; Cell Line, Tumor; Cyclin D1; DNA-Binding Proteins; Down-Regulation; High Mobility Group Proteins; Histone Deacetylase 1; Histone Deacetylases; Histones; Humans; Hyperinsulinism; Insulin Resistance; Insulin-Secreting Cells; Insulinoma; Kidney; Leucine Zippers; Mice; NIH 3T3 Cells; Obesity; Pancreatic Neoplasms; Promoter Regions, Genetic; Protein Structure, Tertiary; Rats; SOXD Transcription Factors; Transcription Factors; Transduction, Genetic