Transcriptional Landscape in Epididymal White Adipose Tissue and Dorsal Root Ganglia in Obese Male Mice Exposed to Early Life Stress
Authors: Dalmasso Carolina , Leachman Jacqueline , Ahmed Nermin , Ghuneim Sundus , Blalock Eric , Loria Analia 
Published: May 2023

We have shown that male mice exposed to maternal separation and early weaning (MSEW), a mouse model of early life stress, display increased blood pressure and sympathetic activation compared to controls (C) when fed a high fat diet (HF). Obese MSEW males also show exacerbated pressor response to the acute stimulation of epididymal white adipose tissue (eWAT) with capsaicin, a transient receptor potential cation channel subfamily V member 1 (TrpV1) ligand. Further, selective afferent denervation reduces blood pressure in MSEW mice only. We also reported that increases in serotonin (5-HT) levels in eWAT could serve as a potential endogenous factor stimulating sensory neurons. The goal of this study was to identify whether MSEW induces changes in the transcriptomes of eWAT and dorsal root ganglia (DRG) that could be associated with sensory neuron stimulation. In addition, we investigated MSEW-induced changes in lipid class and kinases activity. After weaning, C57BL/6J male C and MSEW pups (n=4/group) were placed on HF (60% Kcal from fat) for 16 weeks. Then, mice were euthanized and eWAT and DRGs were collected for tissue analysis. Pamstation12 instrument (PamGene International, Netherlands) was used for kinase activity profiles. For lipidomic analysis, lipids were extracted using acidified organic solvents, and dry residues were reconstituted for analysis using a Shimadzu Nexera UHPLC system coupled with an AB Sciex 6500+ Q-Trap linear ion trap/triple quadrupole mass spectrometer. RNA-sequencing was performed by Novogene Corp Inc.Overall, MSEW decreased the phosphorylation of ~20 kinases in eWAT (e.g. AKT, SGK, PKA, PKG, JNK, PAKA, ERK, AMPK), while increasing phosphatidylglycerols (PG) in eWAT (p<0.05 vs. control). Among the 1124 eWAT genes altered by MSEW, propionyl-Coenzyme A carboxylase and synthetase short-chain (family members 1, 2 and 3); potassium voltage-gated channel (H, G, K, Shal- and shaker-related subfamilies); sodium voltage-gated channel (type III, VII); TrpV1 and TrpC1 were upregulated in MSEW (p<0.05 vs. C). On the other hand, 5-HT receptor 2B (5-HT2B) gene was downregulated in MSEW (p<0.05 vs. C). From the 17 DRG genes affected by MSEW, potassium voltage-gated channel F1; sodium channel, voltage-gated, XI alpha and acid-sensing ion channel 3 were significantly upregulated (p<0.05 vs. C). Thus, our data shows increased enzymes involved in the catabolism of odd chain fatty acids, elevated PG (shown to bind to and stabilize ligand-gated ion channels) and upregulation of cation channels that could be expressed in the axons of the sensory neurons innervating fat. These findings suggest that MSEW induces metabolic alterations that could activate the sensory neurons through various mechanisms. Moreover, the 5-HT2B receptor also works as a transporter and its activation could be protective against elevated extracellular 5-HT levels. Therefore, reduced levels of this receptor may contribute to increase serotonin in eWAT. HL135158 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.