Environmental enrichment reverses reduction in glucocorticoid receptor expression in the hippocampus of and improves behavioral responses of anxiety in early malnourished rats.

We compared glucocorticoid receptor (GR) gene expression in the hippocampus of rats subjected to a low protein, "malnourished" diet (M; 6% protein) or a control, "well-nourished" diet (W; 16% protein), exposed to different environmental stimulation (environmental enrichment, E; no enrichment, N) between postnatal day 8 (P8) and P35. Rats were tested on the elevated plus maze (EPM) on P36. Male Wistar rats were split into two groups at birth according to diet (M or W) and subdivided according to environmental stimulation (E or N). GR expression was determined using real-time polymerase chain reaction and GR immunohistochemistry in the hippocampus. Our results showed that MN rats spent more time and made more entries into the open arms of the EPM compared to W rats. On the other hand, ME rats spent a similar percentage of time, and made a similar number of entries, in the open arms as WN rats. Following the EPM test, GR mRNA expression in the hippocampus was different in MN rats compared to W rats; expression was also different between M and ME rats; mRNA and expression of GR receptors in WN rats was similar to that observed in WE rats. These data also show that the effects of malnutrition on risk assessment in the EPM were reversed by E. Early malnutrition may alter GR expression in the hippocampus and environmental enrichment may exert a neuroprotective effect on malnutrition-induced brain injury.

Protein tyrosine phosphatase-1B contributes to LPS-induced leptin resistance in male rats.

Leptin resistance is induced by the feedback inhibitors tyrosine phosphatase-1B (PTP1B) and decreased Src homology 2 domain-containing tyrosine phosphatase-2 (SHP-2) signaling. To investigate the participation of PTP1B and SHP-2 in LPS-induced leptin resistance, we injected repeated (6-LPS) intraperitoneal LPS doses (100 µg/kg ip) for comparison with a single (1-LPS) treatment and evaluated the expression of SHP-2, PTP1B, p-ERK1/2, and p-STAT3 in the hypothalamus of male Wistar rats. The single LPS treatment increased the expression of p-STAT3 and PTP1B but not SHP-2. The repeated LPS treatment reduced SHP-2, increased PTP1B, and did not change p-STAT3. We observed that the PTP1B expression induced by the endotoxin was highly colocalized with leptin receptor cells in the hypothalamus of LepRb-IRES-Cre-tdTomato reporter mice. The single, but not the repeated, LPS treatment decreased the food intake and body weight. Leptin had no stimulatory effect on the hypophagia, body weight loss, or pSTAT3 expression in 6-LPS rats, indicating leptin unresponsiveness. Notably, the PTP1B inhibitor (3.0 nmol/rat in 5 µl icv) restored the LPS-induced hypophagia in 6-LPS rats and restored the ability of leptin to reduce food intake and body weight as well as to phosphorylate STAT3 in the arcuate, paraventricular, and ventromedial nuclei of the hypothalamus. The present data suggest that an increased PTP1B expression in the hypothalamus underlies the development of leptin resistance during repeated exposure to LPS. Our findings contribute to understanding the mechanisms involved in leptin resistance during low-grade inflammation as seen in obesity.