28 research outputs found
Review: Peroxisome Proliferator-Activated Receptor-Ī³ and Its Role in the Development and Treatment of Diabetes
Since its identification as the receptor for antidiabetic
thiazolidinedione drugs, peroxisome proliferator-activated
receptor-Ī³ (PPARĪ³) has been the focus of pharmaceutical
drug discovery programs directed toward finding better
drugs for the treatment of diabetes, as well as the object
of basic research aimed at understanding its role in
the regulation of metabolism. We now understand a great
deal about the crucial role that PPARĪ³ plays in adipocyte
differentiation and development, and are rapidly gaining
knowledge about the role of the receptor in the regulation
of metabolism. However, many crucial aspects of the molecular
mechanism by which modulation of PPARĪ³ activity
affects insulin resistance and glucose homeostasis are still
not clearly understood. Here the authors review the current
status of PPARĪ³ research, with an emphasis on its role in
the causes and treatment of type 2 diabetes
Gene Expression Analysis in Rats Treated with Experimental Acetyl-Coenzyme A Carboxylase Inhibitors Suggests Interactions with the Peroxisome Proliferator-Activated Receptor ā£ Pathway
ABSTRACT Acetyl CoA carboxylase (ACC) 2, which catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA, has been identified as a potential target for type 2 diabetes and obesity. Small-molecule inhibitors of ACC2 would be expected to reduce de novo lipid synthesis and increase lipid oxidation. Treatment of ob/ob mice with compound A-908292 (S) ({(S)-3-[2-(4-isopropoxy-phenoxy)-thiazol-5-yl]-1-methylprop-2-ynyl}-carbamic acid methyl ester), a small-molecule inhibitor with an IC 50 of 23 nM against ACC2, resulted in a reduction of serum glucose and triglyceride levels. However, compound A-875400 (R) ({(R)-3-[2-(4-isopropoxy-phenoxy)-thiazol-5-yl]-1-methyl-prop-2-ynyl}-carbamic acid methyl ester), an inactive enantiomer of A-908292 (S) with approximately 50-fold less activity against ACC2, also caused a similar reduction in glucose and triglycerides, suggesting that the glucose-lowering effects in ob/ob mice may be mediated by other metabolic pathways independent of ACC2 inhibition. To characterize the pharmacological activity of these experimental compounds at a transcriptional level, rats were orally dosed for 3 days with either A-908292 (S) or A-875400 (R), and gene expression analysis was performed. Gene expression analysis of livers showed that treatment with A-908292 (S) or A-875400 (R) resulted in gene expression profiles highly similar to known peroxisome proliferator-activated receptor (PPAR)-ā£ activators. The results suggest that, in vivo, both A-908292 (S) and A-875400 (R) stimulated the PPAR-ā£-dependent signaling pathway. These results were further supported by both an in vitro genomic evaluation using rat hepatocytes and immunohistochemical evaluation using 70-kDa peroxisomal membrane protein. Overall, the gene expression analysis suggests a plausible mechanism for the similar pharmacological findings with active and inactive enantiomers of an ACC2 inhibitor
Comorbidity Burden Among Patients with Vitiligo in the United States: A Large-Scale Retrospective Claims Database Analysis
Abstract Introduction Vitiligo is often associated with comorbid conditions that may increase economic burden and affect patientsā health-related quality of life. No large-scale study has been published to date using claims databases to evaluate the burden of comorbidities among patients with vitiligo. Herein, we evaluate the comorbidity burden among patients diagnosed with vitiligo from the US. Methods This retrospective cohort analysis used the Merative MarketScan Commercial Database. Eligible patients were diagnosed with vitiligo between January 2008 and December 2020 and matched 1:4 (vitiligo:control) with control subjects with no diagnosis of vitiligo between January 2007 and December 2021. Study outcomes were the incidence of comorbidities after matching, adjusted hazard ratios of comorbidity incidence among patients with vitiligo relative to matched control subjects, and time to comorbidity diagnosis or incidence. Results Baseline demographics were well balanced between matched vitiligo (nā=ā13,687) and control cohorts (nā=ā54,748). Incidence rates of comorbidities were higher among patients compared with control subjects (psychiatric, 28.4% vs 22.8%; autoimmune, 13.4% vs 5.1%; and non-autoimmune, 10.0% vs 7.0%). The most common psychiatric and autoimmune comorbidities in patients with vitiligo compared with control subjects included anxiety (14.3% vs 11.0%, respectively), sleep disturbance (9.1% vs 7.1%), depression (8.0% vs 6.3%), atopic dermatitis (3.1% vs 1.1%), psoriasis (2.7% vs 0.6%), and linear morphea (1.5% vs 0.1%). The risk of developing any psychiatric (hazard ratio 1.31; Pā<ā0.01), autoimmune (hazard ratio 2.77; Pā<ā0.01), or non-autoimmune (hazard ratio 1.45; Pā<ā0.01) comorbidity was significantly higher among patients with vitiligo. Time to diagnosis of most vitiligo comorbidities was 1ā3Ā years, although linear morphea was diagnosed atā<ā1Ā year. Conclusion Results of this retrospective analysis demonstrated that patients were much more likely to be diagnosed with autoimmune or psychiatric comorbidities following a vitiligo diagnosis, which likely contributed to increased economic burden and lower quality of life
PPARĪ³ knockdown by engineered transcription factors: exogenous PPARĪ³2 but not PPARĪ³1 reactivates adipogenesis
To determine functional differences between the two splice variants of PPARĪ³ (Ī³1 and Ī³2), we sought to selectively repress Ī³2 expression by targeting engineered zinc finger repressor proteins (ZFPs) to the Ī³2-specific promoter, P2. In 3T3-L1 cells, expression of ZFP55 resulted in >50% reduction in Ī³2 expression but had no effect on Ī³1, whereas adipogenesis was similarly reduced by 50%. However, ZFP54 virtually abolished both Ī³2 and Ī³1 expression, and completely blocked adipogenesis. Overexpression of exogenous Ī³2 in the ZFP54-expressing cells completely restored adipogenesis, whereas overexpression of Ī³1 had no effect. This finding clearly identifies a unique role for the PPARĪ³2 isoform