Biology subjects

Nicoloro, S. M.

Publications and source records attributed to Nicoloro, S. M..

3 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↗

bioRxiv2023

Regulation of lipolysis by 14-3-3 proteins on human adipocyte lipid droplets.

Adipocyte lipid droplets (LDs) play a crucial role in systemic lipid metabolism by storing and releasing lipids to meet the organisms energy needs. Hormonal signals such as catecholamines and insulin act on adipocyte LDs, and impaired responsiveness to these signals can lead to uncontrolled lipolysis, lipotoxicity, and a higher risk of metabolic diseases. To investigate the mechanisms that control LD function in human adipocytes, we employed techniques to obtain mesenchymal progenitor cells on a large scale and applied proximity labeling mediated by enhanced ascorbate peroxidase (APEX2) to identify the interactome of PLIN1 in differentiated adipocytes. We identified 70 proteins that interact specifically with PLIN1, including PNPLA2 and LIPE, which are the primary effectors of regulated triglyceride hydrolysis, and four members of the 14-3-3 protein family (YWHAB, YWHAE, YWHAZ, and YWHAG), which are known to regulate diverse signaling pathways. Functional studies showed that YWHAB is required for maximum cAMP-stimulated lipolysis and helps to mitigate the anti-lipolytic effects of insulin. These findings reveal new regulatory mechanisms that control lipolysis in human metabolism. SIGNIFICANCE STATEMENTLipid droplets are ubiquitous cytoplasmic organelles that store metabolic energy and play a key role in cellular lipid metabolism (1). Adipocyte LDs play an additional, crucial role, as they supply the energy needs of the whole body through hormonally regulated triglyceride synthesis, storage, and release. The mechanisms by which adipocyte lipid droplets release lipids for systemic use has been mostly studied in mouse models and cell lines. To understand how lipid mobilization is controlled in human adipocytes, we used proximity labeling to identify proteins that interact with PLIN1, a major component of the lipid droplet, in adipocytes generated from primary human progenitor cells. Our study catalogues the interactome of human PLIN1 and identifies previously unrecognized potential mechanism for control of human adipocyte lipolysis through 14-3-3 proteins.

cell biology↗

bioRxiv2018

CRISPR delivery particles for developing therapeutic strategies in metabolic disease

RNA-guided engineered nucleases derived from a prokaryotic adaptive immune system known as CRISPR-Cas represent a promising platform for gene deletion and editing. As a therapeutic approach, direct delivery of Cas9 protein and guide RNA could circumvent the safety problems associated with plasmid delivery and therefore represents an attractive tool for genome engineering. Gene deletion or editing in adipose tissue to enhance its energy expenditure, fat oxidation and secretion of bioactive factors through a \"browning\" process presents a potential therapeutic strategy to alleviate metabolic disease. Here, we developed novel CRISPR delivery particles, denoted CriPs, composed of nano-size complexes of Cas9 protein and single guide (sg)RNA, coated with an amphipathic peptide called Endo-Porter that mediates entry into cells. Efficient CRISPR-Cas9 mediated gene deletion of ectopically expressed Green fluorescent protein (GFP) by CriPs was achieved in multiple cell types including a macrophage cell line, primary macrophages and primary pre-adipocytes. Significant GFP loss was also observed in peritoneal exudate cells with minimum systemic toxicity in GFP expressing mice following intraperitoneal injection of CriPs containing sgRNA targeting Gfp. Furthermore, the disruption of the Nrip1 gene in white adipocytes by CriPs enhanced adipocyte \"browning\" with a marked increase of UCP1 expression. Deletion of Nrip1 by CriPs did not produce detectable off-target effects. Thus CriPs represent a novel CRISPR delivery system for Cas9 and sgRNA that is effective for ablating targeted gene products in cultured cells and in vivo, and provide a potential therapeutic strategy for metabolic disease.

bioengineering↗