Biology subjects

Czech, M.

Publications and source records attributed to Czech, M..

4 recordsLinked to original sources

bioRxiv2025

Thermogenic adipocytes alleviate hepatic steatosis and insulin resistance via macrophage cytokine secretion in obese mice

The Nrip1 gene encodes the protein Rip140, which suppresses nuclear receptors that regulate energy metabolism. Here we show adipocyte-selective deficiency of Nrip1 (AdNrip1KO) in mice causes a striking expansion of alternatively activated, M2-like macrophages within subcutaneous inguinal adipose tissue (iWAT) in addition to the appearance of thermogenic adipocytes expressing uncoupling protein 1 (UCP1). AdNrip1KO mice are less cold sensitive but showed no differences in whole body energy expenditure or food intake compared to control mice at 22 {degrees}C. Strikingly, AdNrip1KO mice on HFD display markedly attenuated hepatic steatosis and insulin resistance compared to control mice on HFD. Secreted factors that might mediate this crosstalk from adipose tissue to liver were searched for by iWAT RNAseq. Unexpectedly, upregulation of genes associated with cytokines and cytokine receptor signaling were the most highly correlated with adipocyte-selective Nrip1 loss in obese mice. Furthermore, the top upregulated genes that encode secreted proteins in AdNrip1KO iWAT are most highly expressed in macrophages, not adipocytes. This list included the IL-1b antagonist IL-1rn, known to attenuate hepatic steatosis and insulin resistance. Indeed, the IL-1rn protein in AdNrip1KO mice was found to circulate at levels we previously reported strongly attenuates hepatic steatosis and glucose tolerance in obese mice. Taken together, these results suggest a paradigm for metabolic crosstalk from thermogenic adipose tissue to liver that is mediated by IL-1rn and potentially other factors secreted from M2-like macrophages within beige adipose tissues. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/667482v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@15fb086org.highwire.dtl.DTLVardef@13e6689org.highwire.dtl.DTLVardef@1bde77borg.highwire.dtl.DTLVardef@a83f2e_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIAdipocyte Nrip1 deficiency (AdNrip1KO) strongly promotes adipose browning C_LIO_LIMouse AdNrip1KO polarizes adipose tissue macrophages towards M2-like C_LIO_LIAdNrip1KO reduces the hepatic fat and insulin resistance of obese mice C_LIO_LIAdNrip1KO adipose tissue macrophages secrete IL-1rn, known to mitigate hepatic fat and insulin resistance C_LI

physiology↗

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↗

bioRxiv2023

Low level of antioxidant capacity biomarkers but not target overexpression predicts vulnerability to ROS-inducing drugs

Despite a strong rationale for why cancer cells are susceptible to redox-targeting drugs, such drugs often face tumor resistance or dose-limiting toxicity in preclinical and clinical studies. An important reason is the lack of specific biomarkers to better select susceptible cancer entities and stratify patients. Using a large panel of lung cancer cell lines, we identified a set of "antioxidant-capacity" biomarkers (ACB), which were tightly repressed, partly by STAT3 and STAT5A/B in sensitive cells, rendering them susceptible to multiple redox-targeting and ferroptosis-inducing drugs. Contrary to expectation, constitutively low ACB expression was not associated with an increased steady state level of reactive oxygen species (ROS) but a high level of nitric oxide, which is required to sustain high replication rates. Using ACBs, we identified cancer entities with a high percentage of patients with favorable ACB expression pattern, making it likely that more responders to ROS-inducing drugs could be stratified for clinical trials.

cancer biology↗

bioRxiv2022

Paradoxical activation of SREBP1c and de novo lipogenesis by hepatocyte-selective ACLY depletion in obese mice.

Hepatic steatosis associated with high fat diets, obesity and type 2 diabetes is thought to be the major driver of severe liver inflammation, fibrosis, and cirrhosis. Cytosolic acetyl-coenzyme A (AcCoA), a central metabolite and substrate for de novo lipogenesis (DNL), is produced from citrate by ATP-citrate lyase (ACLY) and from acetate through AcCoA synthase short chain family member 2 (ACSS2). However, the relative contributions of these two enzymes to hepatic AcCoA pools and DNL rates in response to high fat feeding is unknown. We report here that hepatocyte-selective depletion of either ACSS2 or ACLY caused similar 50% decreases in liver AcCoA levels in obese mice, showing that both pathways contribute to generation of this DNL substrate. Unexpectedly however, the hepatocyte ACLY depletion in obese mice paradoxically increased total DNL flux measured by D2O incorporation into palmitate, while in contrast ACSS2 depletion had no effect. The increase in liver DNL upon ACLY depletion was associated with increased expression of nuclear sterol regulatory element-binding protein 1c (SREBP1c) and of its target DNL enzymes. This upregulated DNL enzyme expression explains the increased rate of palmitate synthesis in ACLY depleted livers. Furthermore, this increased flux through DNL may also contribute to the observed depletion of AcCoA levels due to its increased conversion to Malonyl CoA (MalCoA) and palmitate. Together, these data indicate that in HFD fed obese mice, hepatic DNL is not limited by its immediate substrates AcCoA or MalCoA, but rather by activities of DNL enzymes.

molecular biology↗