Biology subjects

Eeda, V.

Publications and source records attributed to Eeda, V..

3 recordsLinked to original sources

bioRxiv2025

Small molecule inhibitor of PPARγ acetylation promotes insulin sensitization and browning of white adipose tissue with improved safety

The nuclear receptor PPAR{gamma} is a primary therapeutic target for insulin resistance and type 2 diabetes (T2D); however, its thiazolidinedione (TZD) class of PPAR{gamma} agonists have substantial safety concerns in clinical utilization. Genetic inhibition of PPAR{gamma} acetylation at K268 and K293 dissociates the major adverse effects of TZDs from insulin sensitization and other metabolic improvements. We therefore posit that chemical inhibition of PPAR{gamma} acetylation would elicit insulin sensitization with improved safety. Here we describe the identification of a synthetic thiopyrimidine derivative (TPMD) that acts as a small molecule inhibitor of PPAR{gamma} acetylation. TPMD improves insulin sensitivity, promotes brown remodeling of white adipose tissue (WAT), increases energy expenditure, and decreases adiposity in dietary and genetic mouse models of T2D. Importantly, TPMD is deprived of the major side effects of TZDs, including weight gain, fluid retention, cardiac hypertrophy, bone marrow adiposity, and bone loss. X-ray crystallography at 2.0 [A] resolution reveals a unique binding mode of TPMD molecules to the PPAR{gamma} ligand-binding domain and provides structural and molecular basis for the acetylation inhibitory activity of TPMD together with site-directed mutagenesis studies. These findings identify TPMD as a first-in-class compound that specifically targets PPAR{gamma} acetylation and possesses the potential of developing into a safe insulin sensitizer to treat and prevent T2D and obesity.

cell biology↗

bioRxiv2024

Targeting IRE1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in obesity

Overnutrition engenders the expansion of adipose tissue and the accumulation of immune cells, in particular, macrophages, in the adipose tissue, leading to chronic low-grade inflammation and insulin resistance. In obesity, several proinflammatory subpopulations of adipose tissue macrophages (ATMs) identified hitherto include the conventional "M1-like" CD11C-expressing ATM and the newly discovered metabolically activated CD9-expressing ATM; however, the relationship among ATM subpopulations is unclear. The ER stress sensor inositol-requiring enzyme 1 (IRE1) is activated in the adipocytes and immune cells under obesity. It is unknown whether targeting IRE1 is capable of reversing insulin resistance and obesity and modulating the metabolically activated ATMs. We report that pharmacological inhibition of IRE1 RNase significantly ameliorates insulin resistance and glucose intolerance in male mice with diet-induced obesity. IRE1 inhibition also increases thermogenesis and energy expenditure, and hence protects against high fat diet-induced obesity. Our study shows that the "M1-like" CD11c+ ATMs are largely overlapping with but yet non-identical to CD9+ ATMs in obese white adipose tissue. Notably, IRE1 inhibition diminishes the accumulation of obesity-induced metabolically activated ATMs and "M1-like" ATMs, resulting in the curtailment of adipose inflammation and ensuing reactivation of thermogenesis, without augmentation of the alternatively activated M2 macrophage population. Our findings suggest the potential of targeting IRE1 for the therapeutic treatment of insulin resistance and obesity.

cell biology↗

bioRxiv2020

Inhibition of inositol-requiring enzyme 1 RNase activity protects pancreatic beta cell and improves diabetic condition in insulin mutation-induced diabetes

Proinsulin misfolding in the endoplasmic reticulum (ER) plays an important role in {beta}-cell dysfunction and death and the pathogenesis of mutant INS-gene-induced diabetes of youth (MIDY). There is no effective treatment for MIDY except the insulin administration. Here, we found that the ER stress sensor inositol-requiring enzyme 1 (IRE1) was activated in the Akita mice, a mouse model of MIDY. Normalization of IRE1 RNase hyperactivity by pharmacological inhibitors significantly ameliorated the hyperglycemic conditions and increased serum insulin levels in Akita mice. These benefits were accompanied by a concomitant protection of functional {beta}-cell mass, as shown by the suppression of {beta}-cell apoptosis, increase in mature insulin production and reduction of proinsulin level. At the molecular level, we observed that the expression of genes associated with {beta}-cell identity and function was significantly up-regulated and ER stress and its associated inflammation and oxidative stress were suppressed in islets from Akita mice treated with IRE1 RNase inhibitors. This study provides the first evidence of the in vivo efficacy of IRE1 RNase inhibition in Akita mice, pointing to the possibility of targeting IRE1 RNase as a therapeutic direction for the treatment of MIDY diabetes.

pharmacology and toxicology↗