Fat Nerve Recording in Mice

My proposal aim is to establish a novel approach to study the contribution of adipose tissue afferent nerves in the development of obesity-induced hypertension in a model of Early Life Stress (ELS). We will do this by learning how to record white adipose tissue afferent nerve activity (WANA), a technique dominated by Dr. Kamal Rahmouni at the University of Iowa. Our ultimate goal is to bring this technique to our laboratory in order to investigate the mechanism by which a mouse model of ELS displays exacerbated blood pressure in response to a chronic high fat diet. During the last decade, I have gathered compelling information on the effect of ELS activating the sympathetic nervous system. We have measured the sympathetic index and baroreflex sensitivity in awake rats and mice. In addition, we analyzed plasma, tissue and urinary norepinephrine. Our data showed that ELS reduces GFR in male rats, while renal nerve ablation normalized it, suggesting an increased sympathetic outflow to the kidney. Furthermore, we measure cFos expression, a marker of neuronal activation, in different brain areas involved in blood pressure regulation. Recent studies in my lab showed that afferent signals from adipose tissue could be a significant contributor to increases in the sympathetic tone in mice exposed to ELS via a sympatho-excitatory mechanism called adipose afferent reflex (AAR). We found that the acute stimulation of neuro-adipose connections increase blood pressure response in mice exposed to ELS. Specifically, we showed that the acute stimulation of subcutaneous (scWAT) or perigonadal fat (gWAT) with 0.9% saline does not increase mean arterial pressure; however, a capsaicin infusion (0.5 nmol/ul; 4 sites; 4ul/min; 2 min; bilateral) in perigonadal fat, but not subcutaneous, significantly increased MAP in ELS mice compared with controls. After MAP responses, fat depots from these mice were removed to measure capsaicin-induced CGRP release in tissue explants (1 ìM capsaicin) by EIA bioassay. We observed that MSEW increased capsaicin-induced CGRP levels in gWAT compared to controls. In addition, the number of Fos positive neurons in the posterior part of paraventricular nucleus of the hypothalamus (PVN) was increased in MSEW mice fed a high fat diet after capsaicin infusion. Thus, the results reveal that male MSEW mice display afferent signals that influence the acute MAP control in a depot-specific fashion. These data suggest that AAR could play an important role in the heightened response to high fat diet-induced increases in sympathetic tone and MAP observed in male MSEW mice. Despite these results showing that the fat-brain-blood pressure axis is overactivated in MSEW mice, we still need to demonstrate that there is a direct effect of early life stress on afferent nerve activity. We are confident that our technical expertise in whole animal physiology warrants significant advances in understanding the contribution of less traditional risk factors, such as early life stress, to obesity-induced hypertension. Moreover, it will allow us to pinpoint potential therapeutic targets for the treatment of hypertension.