Adipose Afferent Reflex Stimulation Increases The Activation Of The Organum Vasculosum Of The Lamina Terminalis (OVLT) In Obese Male Mice Exposed To Early Life Stress

Abstract

Experimental stimulation of sensory nerves from adipose tissue contributes to increase sympathetic activation associated with obesity‐induced hypertension as part of a mechanism called adipose afferent reflex (AAR). We have reported that male mice exposed to maternal separation and early weaning (MSEW) when fed a high fat diet (HF) display exacerbated neuronal activation in the posterior paraventricular nucleus of the hypothalamus (PVN) and blood pressure response to white adipose tissue (WAT) stimulation with capsaicin (CAP). Thus, the aim of this study was to determine the neuronal activation in other brain areas that receive afferent signals from WAT: neuroendocrine neurons of PVN, magnocellular neurons of PVN (PaLM), supraoptic nucleus (SON), OVLT and subfornical organ (SFO). At weaning, Control and MSEW C57BL/6J males were fed low fat diet (LF) or HF for 16 weeks (10% and 60% Kcal from fat, respectively). A set of HF‐fed mice was implanted with carotid catheters to measure mean arterial pressure (MAP) in response to epididymal WAT (eWAT) stimulation with 0.9% saline (resting, 8ul/2 min; 4 sites; bilateral; n=4/group) or CAP (2 nmol/8ul/2 min; 4 sites; bilateral; n=6/group). At resting, MAP was not different between groups. In control‐HF males, MAP did not change in response to CAP (from 91±1 to 89±3 mmHg; p=ns). However, CAP increased MAP from baseline in MSEW‐HF males (from 92±2 to 98±2 mmHg; p<0.01). In another set of mice not subjected to catheter implantation, eWAT was microinfused with 0.9% saline (n=4) or capsaicin (n=3–5) for quantification of neuronal activation by immunohistochemistry. MSEW‐LF mice showed a significant increase in Fos positive cells in OVLT and SFO at resting (p<0.05). Moreover, MSEW‐LF mice displayed increased glomerular filtration rate, sodium excretion and ENaC alpha expression when compared with C‐LF (p<0.05). However, this positive correlation between hyperfiltration, hypernatriuresis and activation of neurons in OVLT and SFO nuclei was not observed in HF‐fed mice at resting. In response to CAP stimulation, HF‐fed MSEW increased Fos expression in OVLT from resting (from 21±5 to 36±3 number of positive cells; p<0.05), while OVLT neuronal activation did not changed in controls. No significant differences due separation was observed in PaML and SON at resting, while CAP stimulation similarly increased Fos positive cells of in PaML and SON in controls and MSEW LF‐fed mice (p<0.05). HF did not increase further the effect of CAP on Fos expression in PaML and SON (p<0.05) in either group. In addition to the already shown increased neuronal activation in posterior PVN, the number of neuroendocrine neurons in anterior PVN (Fos‐fluorogold positive cells) was unchanged due to diet, separation or CAP stimulation. Taken together, these results suggest that AAR could play an important role increasing MAP in male MSEW mice via neuronal activation of brain areas that are known to receive sensory signals from the fat and regulate sympathetic outflow such as OVLT and posterior PVN. In addition, an exacerbated capacity to excrete sodium in MSEW mice suggests a profound impairment of water and electrolyte homeostasis.Support or Funding InformationR01 HL135158, R01 HL135158S1