Chronic unpredictable stress regulates visceral adipocyte-mediated glucose metabolism and inflammatory circuits in male rats.

Chronic psychological stress is a prominent risk factor involved in the pathogenesis of many complex diseases, including major depression, obesity, and type II diabetes. Visceral adipose tissue is a key endocrine organ involved in the regulation of insulin action and an important component in the development of insulin resistance. Here, we examined for the first time the changes on visceral adipose tissue physiology and on adipocyte-associated insulin sensitivity and function after chronic unpredictable stress in rats. Male rats were subjected to chronic unpredictable stress for 35 days. Total body and visceral fat was measured. Cytokines and activated intracellular kinase levels were determined using high-throughput multiplex assays. Adipocyte function was assessed via tritiated glucose uptake assay. Stressed rats showed no weight gain, and their fat/lean mass ratio increased dramatically compared to control animals. Stressed rats had significantly higher mesenteric fat content and epididymal fat pad weight and demonstrated reduced serum glucose clearing capacity following glucose challenge. Alterations in fat depot size were mainly due to changes in adipocyte numbers and not size. High-throughput molecular screening in adipocytes isolated from stressed rats revealed activation of intracellular inflammatory, glucose metabolism, and MAPK networks compared to controls, as well as significantly reduced glucose uptake capacity in response to insulin stimulation. Our study identifies the adipocyte as a key regulator of the effects of chronic stress on insulin resistance, and glucose metabolism, with important ramifications in the pathophysiology of several stress-related disease states.

Chronic stress-induced changes in pro-inflammatory cytokines and spinal glia markers in the rat: a time course study.

BACKGROUND/AIMS: Spinal glia activation has been proposed as one mechanism underlying visceral hyperalgesia in a rodent model of chronic stress. In order to assess the possible role of changes in circulating cytokines and in blood-spinal cord barrier (BSCB) permeability in spinal glia activation, we studied the time course of peripheral and spinal pro-inflammatory cytokines and of spinal and satellite glia markers in response to repeated water avoidance (WA) stress. METHODS: Spinal cords and dorsal root ganglion cells (DRGs) were collected from control rats, rats exposed to 1-hour WA, or 1-hour WA daily for 5 days or 1-hour WA daily for 10 days. RESULTS: We demonstrated a time-dependent change in circulating IL-1ß and spinal IL-1ß, IL-6 and TNF-α in stressed animals compared with controls. We found altered expression of the astrocyte markers GFAP and Connexin 43 in spinal and DRG samples at different time points. Finally, WA was associated with increased BSCB permeability. CONCLUSIONS: These findings confirm the concept that both peripheral and spinal immune markers are altered after chronic WA and suggest a possible link between stress-induced increase of peripheral pro-inflammatory cytokines, changes in satellite glial cells, increase in BSCB permeability and increase in spinal pro-inflammatory mediators suggesting glia activation.

Role of astrocytes and altered regulation of spinal glutamatergic neurotransmission in stress-induced visceral hyperalgesia in rats.

Glutamate (Glu) is the primary excitatory neurotransmitter in the central nervous system and plays a critical role in the neuroplasticity of nociceptive networks. We aimed to examine the role of spinal astroglia in the modulation of glutamatergic neurotransmission in a model of chronic psychological stress-induced visceral hyperalgesia in male Wistar rats. We assessed the effect of chronic stress on different glial Glu control mechanisms in the spinal cord including N-methyl-d-aspartate receptors (NMDARs), glial Glu transporters (GLT1 and GLAST), the Glu conversion enzyme glutamine synthetase (GS), and glial fibrillary acidic protein (GFAP). We also tested the effect of pharmacological inhibition of NMDAR activation, of extracellular Glu reuptake, and of astrocyte function on visceral nociceptive response in naive and stressed rats. We observed stress-induced decreased expression of spinal GLT1, GFAP, and GS, whereas GLAST expression was upregulated. Although visceral hyperalgesia was blocked by pharmacological inhibition of spinal NMDARs, we observed no stress effects on NMDAR subunit expression or phosphorylation. The glial modulating agent propentofylline blocked stress-induced visceral hyperalgesia, and blockade of GLT1 function in control rats resulted in enhanced visceral nociceptive response. These findings provide evidence for stress-induced modulation of glia-controlled spinal Glu-ergic neurotransmission and its involvement in chronic stress-induced visceral hyperalgesia. The findings reported in this study demonstrate a unique pattern of stress-induced changes in spinal Glu signaling and metabolism associated with enhanced responses to visceral distension.