Increased Serotonin In Visceral Adipose Tissue May Contribute To Stimulate Sensory Neurons Mediating Obesity Hypertension In Mice Exposed To Early Life Stress

Male C57BL/6J mice exposed to maternal separation and early weaning (MSEW), a mouse model of early life stress, display increased blood pressure (BP) and sympathetic activation compared to obese controls when fed a high fat diet (HF). Moreover, HF-fed MSEW males display exacerbated BP responses to the acute stimulation of the adipose afferent reflex (AAR) in epididymal white adipose tissue (eWAT). The aim of this study was to investigate the contribution of endogenous factors that could stimulate fat sensory neurons. MSEW and control (C) mice (n=8/group) were placed on a LF or HF (10% and 60% Kcal from fat, respectively) for 16 weeks. Then, serum obtained by decapitation and adipose tissue samples were collected to measure mRNA and protein expression of 15 factors and receptors known to activate sensory neurons. No differences were found across measurements on LF. Plasma AGT and AngII were decreased in HF-fed MSEW compared to C (AGT: 760±48 vs. 1267±161 ng/ml, p<0.05; AngII; 413±57 vs. 1082±340 pmol/l, p<0.07, Attoquant) and no differences were found in leptin (103±6 vs. 104±4 ng/ml, p<0.87). In eWAT, MSEW and C showed similar AGT (2.1±0.4 vs. 1.9±0.3 ng/ml per g tissue), AngII (1.7±0.2 vs. 2.3±0.5 pg AngII/mg tissue), ACE 1 activity (21.5±1.2 vs. 20.0±0.9 RFU/min/μg protein, p<0.33) and leptin (102.8±6.1 vs. 104.5±6.8 ng/mg of tissue, p<0.87). However, HF-fed MSEW showed increased eWAT mRNA expression of tryptophan hydroxylase 1 (Tph1), the rate limiting enzyme in serotonin (5-HT) synthesis (10.2±2.9 vs. 1.6±0.3 2 -ΔΔct , p<0.03). SERT-Tph1-MAO signaling pathway protein expression was activated, and fat serotonin concentration was also increased in eWAT from obese MSEW mice compared to C (16.58±1.5 vs. 8.5±2.1 ug/mg of tissue, p<0.01). Acute stimulation of eWAT with serotonin (10-6 M, 4 sites, 2 ul/site) tend to increase pressor response in MSEW mice (p<0.066, n=2-3). Unlike in female MSEW mice, our study demonstrates that MSEW does not increase circulating and tissue AGT, Ang II and leptin in male mice. Taken together, these data suggest that increased local serotonin could be endogenously sensitizing the sensory neurons in obese MSEW mice contributing to chronic AAR stimulation, directly via TRPV1 channels, or indirectly, via acid-sensing ion channels.