Biology subjects

Korobkina, E.

Publications and source records attributed to Korobkina, E..

4 recordsLinked to original sources

bioRxiv2025

UCP1 Mitigates Hepatic Steatosis and Fibrosis Independent of Cold Exposure

Non-shivering thermogenesis by brown adipose tissue (BAT) is a promising target for anti-obesity therapies, making its regulatory mechanisms of significant translational interest. While cold-induced BAT thermogenesis (CIT) is well characterized, certain high-calorie diets can also activate BAT in the absence of cold, a process known as diet-induced thermogenesis (DIT). Despite its potential relevance to modern human diets and lifestyles, the mechanisms and physiological relevance underlying DIT remain poorly understood. Here, we show that DIT reduces adiposity and protects against hepatic steatosis and fibrosis in males but not female mice. Moreover, adipose tissue-specific ablation of uncoupling protein 1 (UCP1) reveals that BAT is the primary mediator of DIT but that non-adipocyte UCP1 also contributes to body weight regulation. Transcriptome analysis suggests that DIT is triggered by intrinsic metabolic stress, distinguishing it from CIT, which is driven by sympathetic tone. Finally, BAT-specific arteriovenous metabolomics identifies glucose as the predominant circulating fuel for DIT. These findings uncover distinct molecular and metabolic features of DIT, highlighting opportunities to harness BAT activity for treating obesity and metabolic diseases without requiring cold exposure.

physiology↗

bioRxiv2025

Rag GTPases Suppress Renal Cystic Disease by Inhibiting TFEB Independently of mTORC1

Aberrant mTORC1 activation in renal tubular epithelial cells (rTECs) is implicated as a critical driver of renal cystic diseases (RCDs), including autosomal dominant polycystic kidney disease (ADPKD) and tuberous sclerosis (TSC), yet its precise role remains unclear. Rag GTPases recruit mTORC1 to lysosomes, its intracellular activation site. Unexpectedly, we found that deleting RagA/B in rTECs, despite inhibiting mTORC1, triggers renal cystogenesis and kidney failure. We identify TFEB as the key driver of cystogenesis downstream of RagA/B loss and show that Rag GTPases, rather than mTORC1, are the primary suppressors of TFEB in vivo. We further highlight increased nuclear TFEB as a shared feature of several RCD models, whereas differences in mTORC1 activity may explain the variable efficacy of mTORC1 inhibitors. Finally, we provide evidence that nuclear TFEB, rather than mTORC1 activation, is a more consistent biomarker of cyst-lining epithelial cells in ADPKD. Overall, these findings challenge the prevailing view that mTORC1 hyperactivation is required for renal cystogenesis, which has important translational implications. TeaserA serendipitous finding uncovers the Rag GTPases as strong suppressors of renal cystogenesis with important disease implications.

cell biology↗

bioRxiv2025

Pancreatic cancer cachexia is mediated by PTHrP-driven disruption of adipose de novo lipogenesis

Pancreatic cancer patients have the highest rates and most severe forms of cancer cachexia, yet cachexia etiologies remain largely elusive, leading to a lack of effective intervening therapies. Parathyroid hormone-related protein (PTHrP) has been clinically implicated as a putative regulator of cachexia, with serum PTHrP levels correlating with increased weight loss in PDAC patients. Here we show that cachectic PDAC patients have high expression of tumor PTHrP and use a genetically engineered mouse model to functionally demonstrate that loss of PTHrP blocks cachectic wasting, dramatically extending overall survival. The re-expression of PTHrP in lowly cachectic models is sufficient to induce wasting and reduce survival in mice, which is reversed by the conditional deletion of the PTHrP receptor, Pth1r, in adipocytes. Mechanistically, tumor-derived PTHrP suppresses de novo lipogenesis in adipocytes, leading to a molecular rewiring of adipose depots to promote wasting in the cachectic state. Finally, the pharmacological disruption of the PTHrP-PTH1R signaling axis abrogates wasting, highlighting that a targeted disruption of tumor-adipose crosstalk is an effective means to limit cachexia. STATEMENT OF SIGNIFICANCEPancreatic ductal adenocarcinoma (PDAC) is the prototypical cancer type associated with cancer cachexia, a debilitating wasting syndrome marked by adipose tissue loss and muscle atrophy. Herein, we establish that PTHrP is a tumor-derived factor that facilitates cachexia by downregulating de novo lipogenesis in adipocytes and that blocking PTHrP is an effective means to limit wasting in preclinical mouse models.

cancer biology↗

bioRxiv2019

Reversal of ageing- and injury-induced vision loss by Tet-dependent epigenetic reprogramming

Ageing is a degenerative process leading to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise, which disrupts youthful gene expression patterns that are required for cells to function optimally and recover from damage1-3. Changes to DNA methylation patterns over time form the basis of an ageing clock4, 5, but whether old individuals retain information to reset the clock and, if so, whether this would improve tissue function is not known. Of all the tissues in the body, the central nervous system (CNS) is one of the first to lose regenerative capacity6, 7. Using the eye as a model tissue, we show that expression of Oct4, Sox2, and Klf4 genes (OSK) in mice resets youthful gene expression patterns and the DNA methylation age of retinal ganglion cells, promotes axon regeneration after optic nerve crush injury, and restores vision in a mouse model of glaucoma and in normal old mice. This process, which we call recovery of information via epigenetic reprogramming or REVIVER, requires the DNA demethylases Tet1 and Tet2, indicating that DNA methylation patterns dont just indicate age, they participate in ageing. Thus, old tissues retain a faithful record of youthful epigenetic information that can be accessed for functional age reversal.

molecular biology↗