Leptin increases sympathetic nerve activity via induction of its own receptor in the paraventricular nucleus.

Zhigang Shi,Jennifer Wong,Andrei D Sdrulla,Nicole E Pelletier,Christopher J Madden,Daniel L Marks,Virginia L Brooks,Baoxin Li

doi:10.7554/elife.55357

Zhigang Shi, Jennifer Wong + Show 6 more

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https://doi.org/10.7554/elife.55357

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Abstract

Whether leptin acts in the paraventricular nucleus (PVN) to increase sympathetic nerve activity (SNA) is unclear, since PVN leptin receptors (LepR) are sparse. We show in rats that PVN leptin slowly increases SNA to muscle and brown adipose tissue, because it induces the expression of its own receptor and synergizes with local glutamatergic neurons. PVN LepR are not expressed in astroglia and rarely in microglia; instead, glutamatergic neurons express LepR, some of which project to a key presympathetic hub, the rostral ventrolateral medulla (RVLM). In PVN slices from mice expressing GCaMP6, leptin excites glutamatergic neurons. LepR are expressed mainly in thyrotropin-releasing hormone (TRH) neurons, some of which project to the RVLM. Injections of TRH into the RVLM and dorsomedial hypothalamus increase SNA, highlighting these nuclei as likely targets. We suggest that this neuropathway becomes important in obesity, in which elevated leptin maintains the hypothalamic pituitary thyroid axis, despite leptin resistance.

Highlights

Obesity activates the sympathetic nervous system, which can lead to hypertension, in part due to the central actions of adipose-derived leptin (Hall et al, 2010; Bell and Rahmouni, 2016)
We show that paraventricular nucleus (PVN) leptin slowly, but dose-dependently, increased lumbar SNA (LSNA); PVN leptin activated brown adipose tissue (BAT) sympathetic nerve activity (SNA)
Using GCaMP6, we further show that PVN leptin excited glutamatergic neurons, which contributed to its local excitatory effects on LSNA

Summary

Introduction

Obesity activates the sympathetic nervous system, which can lead to hypertension, in part due to the central actions of adipose-derived leptin (Hall et al, 2010; Bell and Rahmouni, 2016). Examined sections from animals (n = 3) treated with unilateral leptin and aCSF injections (Figure 11) Using both ihc and RNAScope for iba-1 to identify microglial cells, we again found rare overlap of the LepR and iba-1 signals in the PVN. ACSF injections 90 min after PVN leptin were not associated with further significant increases in LSNA (the response had stabilized as in Figure 1; Figure 13D) These results indicate that the reduced DHK response after PVN leptin was due to the injection itself (same as after aCSF); these data do not support the hypothesis that leptin directly or indirectly inhibits astroglial GLT-1 and glutamate uptake, thereby activating PVN pre-sympathetic neurons. DMH TRH increased LSNA, HR, and MAP, as well as BAT SNA, BAT temperature, and CO2; again, DMH aCSF was without effect on these variables (Figure 18B,C)

Discussion

Findings

Summary

Materials and methods