Biology subjects

Chelikani, P. K.

Publications and source records attributed to Chelikani, P. K..

3 recordsLinked to original sources

bioRxiv2025

Pan-EphB tyrosine kinase inhibitor mitigates diabetic cardiomyopathy

Diabetic cardiomyopathy (DCM) is characterized by myocardial fibrosis, excessive collagen deposition, decline in ejection fraction and diastolic dysfunction in diabetic subjects. As current pharmaceuticals have varying efficacy and adverse effects, there is an unmet need for new therapeutics. We recently identified STA-013, a pan-EphB tyrosine kinase inhibitor sparing EphB3, that resulted in whole-body weight loss, restored glucose homeostasis, and mitigated insulin resistance in diet-induced obese mouse models. Here, we now show in a streptozotocin (STZ)-high-fat diet-induced mouse model that STA-013 decreased body weight and restored glucose homeostasis while mitigating insulin resistance. Importantly, STA-013 significantly improved cardiac function in part by increasing ejection fraction and fractional shortening, and reduced collagen deposition suggestive of decreased cardiac fibrosis. This was associated with a significant downregulation of key molecular intermediaries including phosphorylation EphB tyrosine kinase signaling, insulin receptor signal, and TGF-{beta} levels in STA-013 treated STZ-HFD mice. Together, our preclinical findings support the development of pan-EphB tyrosine kinase inhibitors as novel therapeutics to mitigate DCM and associated complications.

pharmacology and toxicology↗

bioRxiv2023

Sex dimorphism in the aged metabolic phenotype of smoothelin-like 1 (SMTNL1) deficient mice

Smoothelin-like 1 (SMTNL1) is expressed in smooth and skeletal muscle tissues as well as a variety of steroid hormone-sensitive tissues. SMTNL1 can play a sex-dependent regulatory role in skeletal muscle metabolism in mice. Previous studies have documented appreciable changes in muscle morphology and metabolic function of young male mice with genetic deletion of Smtnl1. SMTNL1 can also impact the energy metabolism and insulin sensitivity of female mice during pregnancy. Therefore, we investigated the metabolic outcome of global SMTNL1 knockout (KO) in male and female mice with advancing age using a comprehensive lab animal monitoring system (CLAMS). With ageing, body weight gain was markedly higher with a concomitant increase in whole body adiposity as well as specific white adipose depots in the absence of SMTNL1. Moreover, this genotypic difference in whole body adiposity was greater in the female cohort. The deletion of SMTNL1 was also associated with delayed satiety in mice fed a high fat diet, which was more pronounced in the female mice. A significant genotypic difference was also revealed for the metabolic energy balance in 12 month old animals of both sexes. The KO animals were metabolically less efficient and displayed a preference for carbohydrate catabolism. However, reduced glucose tolerance was observed only in the female group with the deletion of SMTNL1. Taken together, the current findings establish a novel role for SMTNL1 in modulating adiposity and energy metabolism with ageing in a sex dimorphic way.

biochemistry↗

bioRxiv2022

A Genetic Variant of Fatty Acid Amide Hydrolase (FAAH) Exacerbates Hormone- Mediated Orexigenic Feeding in Mice

Fatty acid amide hydrolase (FAAH) degrades the endocannabinoid anandamide. A polymorphism in FAAH (FAAH C385A) reduces FAAH expression, increases anandamide levels, and increases the risk of obesity. Nevertheless, some studies have found no association between FAAH C385A and obesity. We investigated whether the environmental context governs the impact of FAAH C385A on metabolic outcomes. Using a C385A knock-in mouse model, we found that under basal conditions, there was no effect of the FAAH C385A polymorphism on body weight or composition. By contrast, FAAH A/A mice are more susceptible to glucocorticoid-induced hyperphagia, weight gain, and activation of hypothalamic AMPK. AMPK inhibition occluded the amplified hyperphagic response to glucocorticoids in FAAH A/A mice. FAAH knockdown exclusively in AgRP neurons mimicked the exaggerated feeding response of FAAH A/A mice to glucocorticoids. FAAH A/A mice likewise presented exaggerated orexigenic responses to ghrelin, while FAAH knockdown in AgRP neurons blunted leptin anorectic responses. Together, the FAAH A/A genotype amplifies orexigenic responses and decreases anorexigenic responses, providing a putative mechanism explaining the diverging human findings.

neuroscience↗