Contribution of Fat‐derived Sensory Signals to Sympathetic Activation During Obesity‐hypertension

Abstract

Blood pressure regulation in health and disease involves a balance between afferent and efferent signals from multiple organs and tissues. Numerous studies have addressed the role of sympathetic nerves in different models of hypertension; however, few have focused on the contribution of afferent nerves innervating the adipose tissue and their role in the development of obesity‐induced hypertension. Thus, the aim of this study was to determine the changes in blood pressure in response to sensory stimulation of the fat pads and the subsequent neuronal activation in brain areas that receive afferent signals from white adipose tissue (WAT). Male C57BL/6J mice were fed low fat diet (LF), regular chow, or high fat diet (HF) for 16 weeks (10%, 18% and 60% Kcal from fat, respectively). First, using radiotelemetry, we determined that mice fed HF display increased mean arterial pressure (MAP), heart rate and sympathetic index compared with LF‐fed mice (p<0.05). The selective afferent denervation of visceral fat using resiniferotoxin (RTX, 20 pmol/ul, 6 sites, 1 ul per site; bilateral) reduced mean arterial pressure (MAP). In addition, capsaicin‐induced increases in MAP were measured in anesthetized mice via carotid catheter. Capsaicin was infused in the intravascular space or skeletal muscle (2 nmol/μl, 8 μl/2 min), and subcutaneous WAT or epidydimal WAT (2 nmol/μl, 8 μl/2 min, 4 sites, bilateral). MAP did not change from baseline after capsaicin infusion into the blood stream via the jugular vein, adjacent skeletal muscle or subcutaneous WAT; whereas the infusion induced a significant increase on MAP in response to epidydimal WAT stimulation (p<0.05). Subcutaneous or epidydimal WAT stimulation with saline solution (0.9% NaCl, 8 μl/2 minutes, 4 sites, bilateral) did not influence baseline MAP in either fat depots. In a different set of mice not subjected to catheter implantation, epidydimal WAT was infused with 0.9% saline (resting, n=4) or capsaicin (n=3–5) for Fos+ cells quantification by immunohistochemistry. We quantified the posterior paraventricular nucleus of the hypothalamus (PVN), magnocellular subdivision of PVN (PaLM), supraoptic nucleus (SON), organum vasculosum of the lamina terminalis (OVLT), median preoptic nucleus (MnPO) and subfornical organ (SFO). HF increased the number of Fos+ cells in the SFO and SON at resting when compared with LF‐fed mice (p<0.05). However, no changes in nonendocrine neurons in the posterior PVN, PaLM, SON, OVLT and MnPO were observed in response to HF at resting. Capsaicin stimulation in epidydimal WAT significantly decreased Fos expression in OVLT and MnPO in HF fed males compared to LF‐fed mice (p<0.05). However, no significant changes were observed in nonendocrine neurons in the posterior PVN, PaLM, SON and SFO in response to diet. Thus, this data shows that adipose tissue‐blood pressure axis response is fat depot‐specific and exacerbated in HF. In addition, although several brain areas are overactivated in response to acute stimulation with capsaicin, the OVLT and MnPO decreased its activation in mice fed a chronic HF.Support or Funding InformationR01 HL135158