IL-6 ameliorates defective leptin sensitivity in DIO ventromedial hypothalamic nucleus neurons.

Rats selectively bred to develop diet-induced obesity (DIO) have an early onset reduction in the sensitivity of their ventromedial hypothalamic nucleus (VMN) neurons to leptin compared with diet-resistant (DR) rats. This reduced sensitivity includes decreased leptin receptor (Lepr-b) mRNA expression, leptin receptor binding, leptin-induced phosphorylation of STAT3 (pSTAT3), and impaired leptin excitation (LepE) of VMN neurons. When administered exogenously, the pancreatic peptide, amylin, acts synergistically to reduce food intake and body weight in obese, leptin-resistant DIO rats by increasing VMN leptin signaling, likely by stimulation of microglia IL-6, which acts on its receptor to increase leptin-induced pSTAT3. Here, we demonstrate that incubation of cultured VMN neurons of outbred rats with IL-6 increases their leptin sensitivity. Control, dissociated DIO VMN neurons express 66% less Lepr-b and 75% less Bardet Biedl Syndrome-6 (BBS6) mRNA and have reduced leptin-induced activation of LepE neurons compared with DR neurons. Incubation for 4 days with IL-6 increased DIO neuron Lepr-b expression by 77% and BBS6 by 290% and corrected their defective leptin activation of LepE neurons to DR levels. Since BBS6 enhances trafficking of Lepr-b to the cell membrane, the increases in Lepr-b and BBS6 expression appear to account for correction of the reduced leptin excitation of DIO LepE neurons to that of control DR rats. These data support prior findings suggesting that IL-6 mediates the leptin-sensitizing effects of amylin on VMN neurons and that the inherent leptin resistance of DIO rats can be effectively reversed at a cellular level by IL-6.

Suppression of natural killer cell cytotoxicity following chronic electrical stimulation of the ventromedial hypothalamic nucleus in rats.

In our previous study we found that chronic electrical stimulation of the lateral hypothalamus (LH) enhances and its lesion suppresses natural killer cell cytotoxicity (NKCC) and a large granular lymphocyte (LGL) number in conscious, freely behaving rats. Since the ventromedial nucleus of the hypothalamus (VMH) is regarded as behaviorally and physiologically opposite to LH, in our present study we investigated whether this antagonism also holds for the immune functions. Chronic electrical VMH stimulation effect on 1) immune parameters: both spleen and blood NKCC (chromium release assay and single-cell agarose assay) and the number of large granular lymphocytes (LGL; a morphological method), and 2) endocrine parameters: immunosuppressive-corticosterone (COR) and testosterone (TST) and immunostimulative-growth hormone (GH) and prolactin (PRL) plasma levels (RIA) was assessed. Twenty-one days of electrical stimulation of VMH caused significant decrease in both spleen and blood NKCC at the population level (chromium release assay) but not at the single cell level (agarose assay) with a simultaneous fall in the LGL number. Rats responding to the VMH stimulation with behavioral inactivation (BIN) showed a significantly lower depression of NKCC and LGL number than those responding with an aversive reaction (AVE). Depression of NKCC coexisted with various hormonal changes: increase of PRL, increase (AVE) or fall (BIN) of COR, decrease of GH (BIN), and increase of TST (VMH-stimulated and VMH-sham). There were significant differences in all measured plasma hormones between BIN and AVE groups. The results obtained indicate that VMH decreases cell-mediated immune response, represented by NK cell activity. The immunosuppressive effect is dependent on the behavioral outcome of VMH stimulation (BIN/AVE) rather than tested endocrine variables. Moreover, the present results indicate that the VMH and LH are antagonistically engaged in the regulation of NK cell cytotoxicity.

Immunological study of the rat hypothalamic ventromedial nucleus.

Specific anti-sera were prepared by injecting the homogenates of rat ventromedial nucleus (VMH) and caudate nucleus (Cd) into the rabbit. Anti-VMH serum, after absorption of common components in rat normal serum and anti-Cd serum, reacted specifically to the rat VMH with only one precipitation line. Anti-VMH serum was successfully applied to 80 VMH neurons by electrophoresis through 5 barreled micropipettes. Fresh anti-VMH serum caused an irreversible response (increase and subsequent sudden cessation of firing) in 8 of the 25 VMH neurons tested. Anti-VMH serum reversibly inhibited 32 of 80 VMH neurons and 13 of these were also tested with glucose. Discharge rates of 12 of the 13 neurons increased by glucose. Most of these neurons were not affected by anti-Cd serum or normal rabbit serum. Results of these immunological and electrophysiological studies suggest the existence of specific membrane receptor binding sites on the glucoreceptor neurons in the VMH. These sites afford one route for producing the excitatory effect that glucose has on VMH neurons.

[The effect of hypothalamic lesions on the immune response in rats].

The nervous and immune systems are thought to have important roles in the host defence mechanism. Recent reports have suggested that presence of common antigens between the nervous and immune systems. It would be of interest to know the possibility of mutual relations between both systems. For the purpose of examining the relations, the author investigated peripheral blood lymphocyte blastogenesis, growth curves of inoculated subcutaneous tumor and serum levels of catecholamine and corticosterone, 2 weeks after the bilateral stereotaxic destruction of WKA rat medial hypothalamic nuclei. As a result of hypothalamic destruction, lower stimulation indices to PHA of the lymphocytes in the peripheral blood were obtained in rats with anterior hypothalamic lesions, premamillary lesions and mamillary lesions, and higher stimulation indices in those with dorsomedial hypothalamic lesions. On the other hand, lower stimulation indices to PWM were obtained in rats with dorsomedial hypothalamic lesions and higher ones in those with mamillary lesions. These results may suggest the existence of reciprocal function between the dorsomedial hypothalamic nucleus and mamillary nucleus. To examine the effect of hypothalamic lesions on tumor immunity, subcutaneous tumor inoculation and its growth curves were studied. As the tumor cells of KMT-17 are allogeneic in WKA rats, inoculated subcutaneous tumors grew temporarily and disappeared within 15 days. The peak of the growth curves was raised in rats with anterior hypothalamic lesions. Rats with other hypothalamic lesions and controls showed almost the same growth curves. From the results, it is suggested that the anterior hypothalamic nucleus may have some effect on tumor immunity.(ABSTRACT TRUNCATED AT 250 WORDS)

[Steady potential dynamics in hypothalamic structures in response to a tolerogen and an immunogen]. / Dinamika postoiannogo potentsiala v strukturakh gipotalamusa pri vvedenii toleragena i immunogena.

DC potential shifts due to induction of immune tolerance and immune memory were studied in hypothalamic structures. The lost capability of immune cooperation after tolerogen administration was accompanied by a monophasic negative shift of DC potential. Immunogen administration induced a positive shift of DC potential within 1-3 days. An immunogen fraction induced a pyrogenic response. There seems to be a correlation between the pyrogenic and immunogenic actions of antigens and the reorganization of hypothalamic neurons function.

Central adiponectin acutely improves glucose tolerance in male mice.

Adiponectin, an adipocyte-derived hormone, regulates glucose and lipid metabolism. It is also antiinflammatory. During obesity, adiponectin levels and sensitivity are reduced. Whereas the action of adiponectin in the periphery is well established the neuroendocrine role of adiponectin is largely unknown. To address this we analyzed the expression of adiponectin and the 2 adiponectin receptors (AdipoR1 and AdipoR2) in response to fasting and to diet-induced and genetic obesity. We also investigated the acute impact of adiponectin on central regulation of glucose homeostasis. Adiponectin (1 µg) was injected intracerebroventricularly (ICV), and glucose tolerance tests were performed in dietary and genetic obese mice. Finally, the influence of ICV adiponectin administration on central signaling cascades regulating glucose homeostasis and on markers of hypothalamic inflammation was assessed. Gene expression of adiponectin was down-regulated whereas AdipoR1 was up-regulated in the arcuate nucleus of fasted mice. High-fat (HF) feeding increased AdipoR1 and AdipoR2 gene expression in this region. In mice on a HF diet and in leptin-deficient mice acute ICV adiponectin improved glucose tolerance 60 minutes after injection, whereas normoglycemia in control mice was unaffected. ICV adiponectin increased pAKT, decreased phospho-AMP-activated protein kinase, and did not change phospho-signal transducer and activator of transcription 3 immunoreactivity. In HF-fed mice, ICV adiponectin reversed parameters of hypothalamic inflammation and insulin resistance as determined by the number of phospho-glycogen synthase kinase 3 ß(Ser9) and phospho-c-Jun N-terminal kinase (Thr183/Tyr185) immunoreactive cells in the arcuate nucleus and ventromedial hypothalamus. This study demonstrates that the insulin-sensitizing properties of adiponectin are at least partially based on a neuroendocrine mechanism that involves centrally synthesized adiponectin.

Changes of the expressions of immune-related genes after ventromedial hypothalamic lesioning. Systematic review of the literature.

Over the past 20 years, the functional autonomy of both the immune and central nervous systems has been successfully challenged. Although the ventromedial hypothalamus (VMH) is one of the centers of parasympathetic nervous system, to date, there has been little reported regarding the role of the hypothalamus in directly changing the expression of immune-related genes. Recently, it has been reported that VMH lesions can directly change the expression of immune-related gene families. The present review focuses on the relationships between the VMH and the expressions of immune-related genes.