Epididymal Fat-Derived Sympathoexcitatory Signals Exacerbate Neurogenic Hypertension in Obese Male Mice Exposed to Early Life Stress

Abstract

Previously, we have shown that male mice exposed to maternal separation and early weaning (MSEW)—a mouse model of early life stress—display increased mean arterial pressure compared with controls when fed a high-fat diet. As the stimulation of sensory nerves from fat has been shown to trigger the adipose afferent reflex, we tested whether MSEW male mice show obesity-associated hypertension via the hyperactivation of this sympathoexcitatory mechanism. After 16 weeks on high-fat diet, MSEW mice displayed increased blood pressure, sympathetic activation, and greater depressor response to an α-adrenergic blocker when compared with controls ( P <0.05; n=8), despite no differences in adiposity and plasma leptin. The acute infusion of capsaicin in epididymal white adipose tissue (1.5 pmol/μL of capsaicin, 8 μL/per site, 4 sites, bilaterally) increased the total pressor response in MSEW mice compared with controls (110±19 versus 284±33 mm Hg×30 minutes; P <0.05; n=8). This response was associated with neuronal activation in OVLT, posterior paraventricular nucleus of the hypothalamus, and RVLM ( P <0.05 versus control; n=6–7). Renal denervation abolished both the acute and chronic elevated mean arterial pressure in obese MSEW mice. Moreover, selective sensory denervation of epididymal white adipose tissue using resiniferatoxin (10 pmol/µL solution; n=6) decreased mean arterial pressure in obese MSEW mice only ( P <0.05 versus control). Obese MSEW mice displayed increased epididymal white adipose tissue levels of both tryptophan hydroxylase (Tph1) mRNA expression and its synthesis product serotonin (8.3±1.9 versus 16.6±1.7 ug/mg tissue; P <0.05 versus control). Thus, afferent sensory signals from epididymal white adipose tissue may contribute to the exacerbated fat–brain–blood pressure axis displayed by obese male mice exposed to early life stress.

Neural Circuits Underlying Reciprocal Cardiometabolic Crosstalk: 2023 Arthur C. Corcoran Memorial Lecture

“…An increase in cFos, a marker of neuronal activation, after activation of adipose afferents was documented in different nuclei, including the rostral ventrolateral medulla, organum vasculosum of the lamina terminalis, and paraventricular nucleus of the hypothalamus (PVN). 88,90 Adipose afferent reflexinduced increase in discharge activity of individual PVN neurons was confirmed using direct recording. 92 Moreover, chemically mediated lesioning of the PVN neurons with kainic acid abolished the adipose afferent reflex induced by injection of capsaicin into the inguinal fat depot.…”

“…Moreover, in these mice, selective denervation of afferents emanating from the epididymal fat reduced blood pressure and attenuated the sympathetic index. Denervation of the kidneys also blunted the chronic blood pressure elevation and the acute capsaicin-induced pressor response in diet-obese mice exposed to early life stress, 90 implicating the renal nerves in mediating the changes observed in these mice.…”

“…87,89 In addition, the adipose sensory reflex was implicated in early life stress, based on an exaggerated increase in arterial pressure in response to stimulation of epididymal adipose tissue with capsaicin in high-fat diet fed male mice that had been subjected to maternal separation and early weaning. 90 Interestingly, the adipose sensory reflex-induced blood pressure increase in these mice is fat depot specific, as capsaicin injection into subcutaneous adipose tissue did not elicit a response. Moreover, in these mice, selective denervation of afferents emanating from the epididymal fat reduced blood pressure and attenuated the sympathetic index.…”

Disrupted Circadian Rhythm of Epinephrine in Males With Youth-Onset Type 2 Diabetes

“…Male and female mice that have undergone early-life stress develop hypertension after placement on a high-fat diet. However, they appear to develop hypertension differently, with male mice displaying increased sympathetic activation, and female mice showing greater adiposity and metabolic compromise [ 52 ]. The higher PHQ-2 and PHQ-9 scores in our male participants with T2D might reflect increased stress and may be associated with sympathetic activation.…”

Emerging topics on basic research in hypertension: interorgan communication and the need for interresearcher collaboration

“…Dalmasso et al recently demonstrated that the stimulation of afferent sensory nerves from visceral white adipose tissue could increase blood pressure in normal mice [ 11 ]. They further showed that afferent signals from visceral white adipose tissue contributed to sympathetic activation and hypertension in male mice exposed to early life stress when fed an obesogenic diet [ 12 ]. This enhanced sympathetic outflow was most likely mediated by increased afferent signals from epididymal white adipose tissue projecting to brain areas with a pivotal role in developing neurogenic hypertension, such as the hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM).…”