Exacerbated Blood Pressure Response to Sensory Neurons Stimulation in Fat Increases the Renal Sympathetic Outflow in Obese Male Mice Exposed to Early Life Stress

Abstract

Experimental stimulation of sensory nerves from white adipose tissue contributes to the increased sympathetic activation associated with obesity-induced hypertension as part of a mechanism called adipose afferent reflex (AAR). Previously, we have demonstrated that male mice exposed to maternal separation and early weaning (MSEW), a mouse model of early life stress display increased mean arterial pressure (MAP) and sympathetic activation compared to control mice when fed a high fat diet (HF). Moreover, MSEW-HF males display exacerbated blood pressure responses to the acute stimulation of the AAR in epididymal white adipose tissue (eWAT) compared to control mice. Thus, the aim of this study was to investigate the contribution of the renal nerves in the chronic increase in MAP and in the acute AAR stimulation in MSEW males fed HF. Male C57BL/6J mice pups were separated from the dams from postnatal day (PD) 2 to PD 16 and weaned early on PD 17. Control litters remained undisturbed with the dams and were weaned on PD 21. After weaning, Control and MSEW mice were placed on HF (60% Kcal from fat) for six months. Two weeks before the experiments a set of mice (n=4) were implanted with radiotelemetry. At six months, MAP was recorded at baseline and 6 days after bilateral renal denervation (RDNX, 10% phenol in ethanol). MSEW mice fed a HF displayed significantly increased chronic baseline MAP compared to controls (122±2 vs. 114±2 mmHg respectively, p<0.05). RDNX decreased MAP in both groups and abolished the differences between groups (MSEW: 112±2 vs. Control: 110±2 mmHg, p<0.05). Another set of mice was subjected to sham or RDNX surgery 4 days prior to the acute AAR stimulation with capsaicin (CAP; 0.5 nmol/ul; 4 sites; 4ul/min; 2 min; bilateral; n=7) to determine the MAP response. Mice were anesthetized, fitted with carotid catheters, and epididymal white adipose tissue (eWAT) was exposed for saline and CAP infusions. In these experiments, only in obese sham MSEW displayed increased MAP in response to CAP (baseline: 98±1 vs. CAP: 104±2 mmHg, p<0.05). RDNX significantly decreased baseline MAP in Control (baseline sham: 93±1 vs. baseline RDNX: 78±4 mmHg, p<0.05) and in MSEW (baseline sham: 98±1 vs. baseline RDNX: 80±3 mmHg, p<0.05) obese male mice. Moreover, CAP infusion in eWAT failed to increase MAP after RDNX in obese MSEW male mice (baseline RDNX: 80±3 vs. CAP RDNX: 75±6 mmHg). Taken together these results show that the renal nerves display an important contribution to the mechanism by which male mice exposed to early life stress in combination with an obesogenic diet present an overactivation of the fat-brain-blood pressure axis in response to capsaicin.