gw9662 and Hyperglycemia

Obesity is one of the most serious public health problems. Peroxisome proliferator-activated receptor γ (PPARγ) plays the master role in adipocyte differentiation for obesity development. However, optimum anti-obesity drug has yet been developed, mandating more investigation to identify novel regulator in obesity pathogenesis. Heat shock protein 12A (HSPA12A) encodes a novel member of the HSP70 family. Here, we report that obese patients showed increased adipose HSPA12A expression, which was positively correlated with increase of body mass index. Intriguingly, knockout of HSPA12A (Hspa12a

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adipose Tissue, White; Adiposity; Anilides; Animals; Body Mass Index; Cell Line; Diet, High-Fat; DNA-Binding Proteins; HSP70 Heat-Shock Proteins; Humans; Hyperglycemia; Hyperlipidemias; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; PPAR gamma; Promoter Regions, Genetic

Uncontrolled hyperglycemia accelerates endothelial damage and vascular inflammation caused by proinflammatory cytokines including tumor necrosis factor α (TNFα), which leads to arteriosclerotic cardiovascular diseases such as myocardial infarction. Telmisartan, an angiotensin II type 1 receptor blocker (ARB), is prescribed for treatment of hypertensive patients with concurrent diabetes mellitus (DM). Although a few clinical trials have suggested that telmisartan decreases cardiovascular complications in diabetic patients, the molecular mechanism for the beneficial effects remains elusive. Here, we investigated a molecular mechanism and effects of telmisartan on the expression of vascular cell adhesion molecule-1 (VCAM-1) and attachment of monocytes onto endothelial cells induced by TNFα in hyperglycemia-treated bovine aortic endothelial cells (BAEC). Telmisartan dose-dependently decreased hyperglycemia-aggravated IκB kinase β (IKKβ) expression and nuclear factor-κB (NF-κB) p65-Ser(536) phosphorylation, which accompanied a decrease in VCAM-1 expression and THP-1 monocytes adhesion. Among ARBs, including losartan and fimasartan, only telmisartan showed the inhibitory effects on expression of VCAM-1 and IKKβ, and phosphorylation of NF-κB p65-Ser(536). The telmisartan's beneficial effects were not changed by pretreatment with GW9662, a specific and irreversible peroxisome proliferator-activated receptor γ (PPARγ) antagonist, although GW9662 clearly inhibited rosiglitazone-induced CD36 expression. Finally, ectopic expression of wild type (WT)-IKKβ significantly restored telmisartan-attenuated VCAM-1 expression, NF-κB p65-Ser(536) phosphorylation, and THP-1 monocytes adhesion. Taken together, our findings demonstrate that telmisartan ameliorates hyperglycemia-exacerbated vascular inflammation, at least in part, by decreasing expression of IKKβ and VCAM-1 independently of PPARγ. Telmisartan may be useful for the treatment of DM-associated vascular inflammation and cardiovascular diseases.

Topics: Angiotensin II Type 1 Receptor Blockers; Anilides; Animals; Benzimidazoles; Benzoates; Cattle; Cell Adhesion; Diabetes Mellitus; Endothelial Cells; Humans; Hyperglycemia; I-kappa B Kinase; Inflammation; Monocytes; PPAR gamma; Rosiglitazone; Telmisartan; Thiazolidinediones; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Diabetes mellitus is associated with increased risk and incidence of cardiovascular morbidity and mortality, independently of other risk factors typically associated with diabetes such as coronary artery disease and hypertension. This promotes the development of a distinct condition of the heart muscle known as diabetic cardiomyopathy. We have previously shown that conjugated linoleic acid (CLA) prevents endothelin-1-induced cardiomyocyte hypertrophy. However, the effects of CLA in preventing alterations in cardiomyocyte structure and function due to high glucose are unknown. We therefore hypothesized that CLA will have protective effects in an in vitro model of diabetic cardiomyopathy using adult rat cardiomyocytes exposed to high glucose. Our results demonstrate that subjecting adult rat cardiomyocytes to high glucose (25 mmol/L) for 24 hours significantly impaired the contractile function as evidenced by decreases in maximal velocity of shortening, peak shortening, and maximal velocity of relengthening. High glucose-induced contractile dysfunction was inhibited by pretreatment with CLA (30 μmol/L; 1 hour). In addition to contractile aberrations, exposing adult rat cardiomyocytes to high glucose for 48 hours induced cardiomyocyte hypertrophy. High glucose-induced cardiomyocyte hypertrophy was likewise prevented by CLA. The antihypertrophic effects of CLA were abolished when cardiomyocytes were pretreated with the pharmacologic inhibitor of peroxisome proliferator-activated receptor γ, GW9662 (1 μmol/L). In conclusion, our findings show that exposing cardiomyocytes to high glucose results in cardiomyocyte functional and structural abnormalities, and these abnormalities are prevented by pretreatment with CLA and mediated, in part, by peroxisome proliferator-activated receptor γ activation.

Topics: Anilides; Animals; Cardiomyopathy, Hypertrophic; Cell Shape; Cell Size; Cell Survival; Cells, Cultured; Diabetic Cardiomyopathies; Dietary Fats, Unsaturated; Gene Expression Regulation; Hyperglycemia; Kinetics; Linoleic Acids, Conjugated; Male; Muscle Proteins; Myocardial Contraction; Myocytes, Cardiac; Oxidative Stress; PPAR gamma; Rats, Sprague-Dawley

Huntington's disease (HD) is a devastating genetic neurodegenerative disease caused by CAG trinucleotide expansion in the exon-1 region of the huntingtin gene. Currently, no cure is available. It is becoming increasingly apparent that mutant Huntingtin (HTT) impairs metabolic homeostasis and causes transcriptional dysregulation. The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a transcriptional factor that plays a key role in regulating genes involved in energy metabolism; recent studies demonstrated that PPAR-γ activation prevented mitochondrial depolarization in cells expressing mutant HTT and attenuated neurodegeneration in various models of neurodegenerative diseases. PPAR-γ-coactivator 1α (PGC-1 α) transcription activity is also impaired by mutant HTT. We now report that the PPAR-γ agonist, rosiglitazone (RSG), significantly attenuated mutant HTT-induced toxicity in striatal cells and that the protective effect of RSG is mediated by activation of PPAR-γ. Moreover, chronic administration of RSG (10 mg/kg/day, i.p) significantly improved motor function and attenuated hyperglycemia in N171-82Q HD mice. RSG administration rescued brain derived neurotrophic factor(BDNF) deficiency in the cerebral cortex, and prevented loss of orexin-A-immunopositive neurons in the hypothalamus of N171-82Q HD mice. RSG also prevented PGC-1α reduction and increased Sirt6 protein levels in HD mouse brain. Our results suggest that modifying the PPAR-γ pathway plays a beneficial role in rescuing motor function as well as glucose metabolic abnormalities in HD.

Topics: Adenosine Triphosphate; Anilides; Animals; Brain; Brain-Derived Neurotrophic Factor; Cell Line; Disease Models, Animal; Gene Expression Regulation; Glutamates; Humans; Huntingtin Protein; Huntington Disease; Hyperglycemia; Intracellular Signaling Peptides and Proteins; L-Lactate Dehydrogenase; Male; Mice; Mice, Transgenic; Movement Disorders; Nerve Tissue Proteins; Neurons; Neuropeptides; Neuroprotective Agents; Orexins; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PPAR gamma; RNA, Messenger; Rosiglitazone; Sirtuins; Thiazolidinediones; Trans-Activators; Transcription Factors; Transfection; Trinucleotide Repeat Expansion

Nesfatin-1 is recently reported as a satiety molecule to suppress food intake via the melanocortin signaling in hypothalamus when injected centrally and peripherally. Here we report that nesfatin-1 is also anti-hyperglycemic. It was found that the intravenous injection of nesfatin-1 significantly reduced blood glucose in hyperglycemic db/db mice. This anti-hyperglycemic effect of nesfatin-1 was time-, dose-, insulin-dependent and peripheral.

Topics: Anilides; Animals; Appetite Depressants; Blood Glucose; Calcium-Binding Proteins; DNA-Binding Proteins; Eating; Hyperglycemia; Hypolipidemic Agents; Insulin; Mice; Mice, Mutant Strains; Nerve Tissue Proteins; Nucleobindins; Peptide Hormones; Pyrazoles; Pyrimidines; Receptors, Leptin; Rosiglitazone; Thiazolidinediones