Role and mechanism of PVN–sympathetic–adipose circuit in depression and insulin resistance induced by chronic stress

Abstract

Chronic stress induces depression and insulin resistance, between which there is a bidirectional relationship. However, the mechanisms underlying this comorbidity remain unclear. White adipose tissue (WAT), innervated by sympathetic nerves, serves as a central node in the interorgan crosstalk through adipokines. Abnormal secretion of adipokines is involved in mood disorders and metabolic morbidities. We describe here a brain–sympathetic nerve–adipose circuit originating in the hypothalamic paraventricular nucleus (PVN) with a role in depression and insulin resistance induced by chronic stress. PVN neurons are labelled after inoculation of pseudorabies virus (PRV) into WAT and are activated under restraint stress. Chemogenetic manipulations suggest a role for the PVN in depression and insulin resistance. Chronic stress increases the sympathetic innervation of WAT and downregulates several antidepressant and insulin‐sensitizing adipokines, including leptin, adiponectin, Angptl4 and Sfrp5. Chronic activation of the PVN has similar effects. β‐adrenergic receptors translate sympathetic tone into an adipose response, inducing downregulation of those adipokines and depressive‐like behaviours and insulin resistance. We finally show that AP‐1 has a role in the regulation of adipokine expression under chronic stress. image Under chronic stress, the PVN increases sympathetic innervation of adipose tissues and represses adipokine expression through AP‐1, which contributes to the development of depression and insulin resistance. Chronic activation of PVN neurons responding to restraint stress contributes to the development of depression and insulin resistance. Chronic activation of PVN neurons responding to restraint stress increases sympathetic innervation of adipose tissues. The β‐adrenergic receptors translate sympathetic tone into the expression regulation of some adipokines, including leptin, adiponectin, Angptl4, Sfrp5 and Fbn1. AP‐1 proteins have a role in the regulation of adipokine expression by the PVN–sympathetic nerve pathway.