Teasaponin reduces inflammation and central leptin resistance in diet-induced obese male mice.

Chronic inflammation is involved in the pathogenesis of obesity and type 2 diabetes. Recently teasaponin, an extract from tea, has been shown to have antiinflammatory effects. We examined the effect of teasaponin on obesity, inflammation, glucose metabolism, and central leptin sensitivity in obese mice fed a high-fat (HF) diet for 16 weeks. Intraperitoneal injections of teasaponin (10 mg/kg, daily) for 21 days significantly decreased the food intake and body weight of HF diet-induced obese mice. Teasaponin treatment also reduced the protein levels of proinflammatory cytokines (TNF-α, IL-6, and/or IL-1ß) and nuclear factor-κB signaling (phosphorylated inhibitory-κB kinase and phosphorylated inhibitory-κBα) in adipose tissue and the liver. The antiinflammatory effects of teasaponin were associated with improved glycemic status in the treated animals, evidenced by improved glucose tolerance, homeostasis model assessment, and fasting plasma insulin. In the hypothalamus, teasaponin decreased both proinflammatory cytokines and inflammatory signaling in the mediobasal hypothalamus. Teasaponin treatment also enhanced the anorexigenic effect of central leptin administration, restored leptin phosphorylated signal transducer and activator of transcription-3 (p-STAT3) signaling in the arcuate nucleus, and increased hypothalamic expression of the anorexigenic peptide proopiomelanocortin. These results identify a potential novel application for teasaponin as an antiobesity and antiinflammatory agent.

Neural substrates for behaviorally conditioned immunosuppression in the rat.

We have previously demonstrated behaviorally conditioned immunosuppression using cyclosporin A as an unconditioned stimulus and saccharin as a conditioned stimulus. In the current study, we examined the central processing of this phenomenon generating excitotoxic lesions before and after acquisition to discriminate between learning and memory processes. Three different brain areas were analyzed: insular cortex (IC), amygdala (Am), and ventromedial nucleus of the hypothalamus (VMH). The results demonstrate that IC lesions performed before and after acquisition disrupted the behavioral component of the conditioned response (taste aversion). In contrast, Am and VMH lesions did not affect conditioned taste aversion. The behaviorally conditioned suppression of splenocyte proliferation and cytokine production (interleukin-2 and interferon-gamma) was differentially affected by the excitotoxic lesions, showing that the IC is essential to acquire and evoke this conditioned response of the immune system. In contrast, the Am seems to mediate the input of visceral information necessary at the acquisition time, whereas the VMH appears to participate within the output pathway to the immune system necessary to evoke the behavioral conditioned immune response. The present data reveal relevant neural mechanisms underlying the learning and memory processes of behaviorally conditioned immunosuppression.

A mechanism underlying the sexually dimorphic ACTH response to lipopolysaccharide in rats: sex steroid modulation of cytokine binding sites in the hypothalamus.

It is well established that the hypothalamic-pituitary-adrenal responses to immune stressors are sexually dimorphic in rodents (females > males), but the underlying mechanism is still unclear. To investigate the mechanism, in this study we examined whether the sex steroid environment affects the following variables in male and female rats: (1) plasma levels of ACTH, interleukin (IL)-1beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha) after systemic lipopolysaccharide (LPS) administration; (2) static concentrations of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) in the mediobasal hypothalamus (MBH) and those of ACTH in the anterior pituitary (AP); and (3) the binding characteristics of IL-1beta, IL-6 and TNF-alpha in the MBH and AP. LPS-induced ACTH release was significantly higher in female than in male rats, and this sexual difference was abolished by performing gonadectomy in both sexes. Administration of physiological doses of testosterone and oestradiol to gonadectomized males and females, respectively, restored the altered ACTH responses to normal. Changes in the sex steroid milieu did not affect plasma cytokine responses to LPS, tissue contents of CRH, AVP and ACTH, or the IL-6 binding characteristics in the MBH and AP. However, the number of IL-1beta and TNF-alpha binding sites, but not their binding affinities, in the MBH showed significant changes according to altered sex hormone milieu, in the same direction as the LPS-induced ACTH response. These results suggest that the hypothalamic sensitivity to peripheral IL-1beta and TNF-alpha may be an important mechanism underlying the sexually dimorphic ACTH response to LPS in rats.

Interleukin-1 inhibits NMDA-stimulated GnRH secretion: associated effects on the release of hypothalamic inhibitory amino acid neurotransmitters.

Immune system activation is often accompanied by alterations in the reproductive axis. Interleukin-1 (IL-1), a polypeptide cytokine, has been postulated as a chemical messenger between the immune and the neuroendocrine systems. Using superfused hypothalamic fragments explanted from intact male rats, we evaluated the effects of IL-1 (0. 5 and 5 nM) on basal and N-methyl-D-aspartate (NMDA)-stimulated release of gonadotropin-releasing hormone (GnRH), and the associated modifications in the output of inhibitory amino acid neurotransmitters involved in the control of GnRH secretion. IL-1 did not modify basal GnRH release, but markedly restrained the stimulatory effect of NMDA on GnRH secretion. gamma-Aminobutyric acid, glycine and taurine concentrations significantly increased in the superfusion medium only after pretreatment with the higher dose of IL-1 (p < 0.05). Our results indicate that this cytokine inhibits NMDA- stimulated GnRH release, affecting the activity and/or the release of hypothalamic excitatory and inhibitory amino acid neurotransmitters participating in the regulation of GnRH secretion.

Electrolytic lesions of the lateral hypothalamus influence peripheral blood NK cytotoxicity in rats.

Bilateral electrolytic lesions of the lateral hypothalamic (LH) area in Wistar rats result in a time-dependent blood NK cytotoxicity changes as measured by the 51Cr-release (for entire cell population) and agarose (for a single-cell) assays. NK activity against YAC-1 and K-562 cells shifts from depression through enhancement to another depression on the 2nd, 5th and 21st post-lesion day, respectively, as compared to both LH sham-operated animals and the pre-lesion baselines. This effect is not attributable to malnutrition and dehydration resulting from ingestive impairments evoked by LH lesions. No significant change in NK cytotoxicity was found after destruction of the medial hypothalamus (MH). The results indicate that LH, under normal conditions, which may be considered as a dynamogenic and stressogenic hypothalamic area is essential for proper regulations of NK cytotoxicity at both population and single-cell level.

The postnatal developmental localization of pro-opiomelanocortin and alpha melanocyte stimulating hormone in the medio-basal hypothalamus of the rat.

This immunocytochemical study of the late postnatal development of the medio-basal hypothalamus revealed the presence of ACTH 1-39 like positivity in neurons of the arcuate nucleus form the begin of this study (day E 18-20) onwards. Alpha MSH positivity, on the contrary, is not present in cells of the same area before day P 16. No other areas in the developing medio-basal hypothalamus contain perikaryal positivity for alpha M-SH or ACTH 1-39. The pituitary contains ACTH 1-39 like positivity from the begin of this study (day E 18-20) onwards. Fibers are positive for alpha MSH during the fetal development of the medio-basal hypothalamus, demonstrating an overal reactivity without varicosities and restricted to bundles or neuropil areas. Towards P 16 the alpha MSH positivity diminishes in the whole medio-basal hypothalamus, remaining present only in large fibre systems like the fornix. ACTH 1-39 like fiber positivity is already distributed in arcuate and periventricular regions at days E 20-PO, reaching its mature extension at day P2. After P16 alpha MSH positive threads, possessing varicosities are restricted to the same areas as ACTH 1-39 like fiber positivity is.

Cholecystokinin-like immunoreactivity of rat medial basal hypothalamus: investigations on a possible hypophysiotropic function.

Studies on the cholecystokinin-like immunoreactivity (CCK-IR), of the medial basal hypothalamus (MBH) were performed in rats. In immunohistochemical studies, a dense CCK-IR-positive staining was found in the external layer of the median eminence adjacent to portal capillaries. Either high potassium (56 mM) or veratridine (1-50 micrograms/ml) stimulated the release of CCK-IR from MBH incubated in vitro. This increase in CCK-IR release depended on the presence of calcium. In vivo, the content of CCK-IR in the MBH was reduced after bilateral adrenalectomy and this effect of adrenalectomy was reversed by dexamethasone treatment. The content of CCK-IR in the neurointermediate lobe of the pituitary gland was not changed under these conditions. These results raise the possibility that after activation of the hypothalamo-pituitary-adrenal axis cholecystokinin may be secreted from nerve terminals in the external layer of the median eminence into the hypophyseal portal blood.

Vasopressin-immunoreactive cells in the dorsomedial hypothalamic region, medial amygdaloid nucleus and locus coeruleus of the rat.

Recently, the existence of a vasopressin-immunoreactive cell group was described in the bed nucleus of the stria terminalis (van Leeuwen and Caffé 1983). In the present investigation additional nuclei containing vasopressin-immunoreactive cells were found, after colchicine pretreatment, in the dorsomedial hypothalamus, medial amygdaloid nucleus and the locus coeruleus. Vasopressin-immunoreactive cells in the dorsomedial hypothalamus and medial amygdaloid nucleus are small (8--14 micrometers and 10--14 micrometers, respectively), while those in the locus coeruleus are medium-sized (20--25 micrometers). Incubation with anti-bovine neurophysin II and anti-rat neurophysin revealed staining of the same cell group in the above-mentioned areas. None of these cell groups show stained cells after incubation with anti-oxytocin and anti-bovine neurophysin I. When sections of the homozygous Brattleboro rat, which shows a deficiency in vasopressin synthesis, are incubated with anti-vasopressin, anti-bovine neurophysin II, or anti-rat neurophysin, no immunoreactivity can be observed in these brain regions. The above-mentioned cell groups may contribute to the vasopressinergic innervation of brain sites that have been reported to persist after lesioning of the suprachiasmatic, paraventricular and bed nuclei of the stria terminalis.

Neuroimmunomodulation: neural anatomical basis for impairment and facilitation.

Rats with bilateral electrolytic lesions of specific limbic nuclei show alterations in lymphoid cell number and in lymphocyte activation induced in vitro by concanavalin A (Con A). The number of splenocytes decreases after lesioning in the anterior hypothalamus (p less than 0.001), ventromedial hypothalamus (p less than .0.2), and mamillary bodies (p less than. 0.001). The number of thymocytes decreases after lesioning of the anterior hypothalamus (p less than 0.001) and increases after hippocampal lesioning (p less than 0.001). Spleen cell responsiveness to con A decreases subsequent to lesioning of the anterior hypothalamus, whereas reactivity was enhanced after lesion placement in the mamillary bodies (p less than 0.002), hippocampus (p less than 0.001), and amygdaloid complex (p less than 0.001). Thymocyte mitogen reactivity is increased by lesions of the hippocampus (p less than 0.001) and amygdaloid complex (p less than 0.001). These effects manifest themselves maximally 4 days after lesioning, with a return to normal by day 14. These preliminary data indicated that quantitative and qualitative lymphocyte functions are altered by ablation of selected brain nuclei, thereby suggesting the presence of neural modulation of immune function.

Possible involvement of the central nervous system in graft rejection.

Electrolytic lesions were produced in the tuberal hypothalamus and amygdala of male Fischer and female BNLF1 rats, and in male Fischer and female BNLF1 rats that had received antecedent hypophysectomies. Skin grafts from Lewis rats survived less well on tuberal-lesioned male Fischer rats than similar grafts on sham-operated and amygdala-lesioned male Fischer rats. Lewis skin graft survival was also curtailed in male Fischer rats that had received hypophysectomies followed by tuberal lesions. These differences were not apparent across the male to female (H-Y) BNLF1 histocompatibility barrier. We conclude: (1) that tuberal hypothalamic lesions stimulate allograft reactivity in rats, (2)that this response is greater when the immunogenetic disparity between donor and host is greater, and (3) that the mechanism governing this response involves a direct neural pathway which bypasses the hypothalamic-hypophyseal axis.

[Role of the hypothalamus in the formation of antitumor resistance]. / O roli gipotalamusa v formirovanii protivoopukholevoi rezistentnosti

The development of Brown-Pearce tumor in rabbits is accompanied with regular changes in the functional activity of the hypothalamic zone, related close enough with the regulation of adrenal cortex functions and immunological processes. In electrostimulation of the posterior hypothalamus median zones an accelerated resorption of the tumor, inoculated subcutaneously, was noted. The destruction of the posteromedian hypothalamic structures resulted in a sharp fall of corticosteroids level in the organism and a decreased intensity of generally persistant immunity to repeat inoculations of Brown-Pearce tumor. Thus, the fact of the immunocompetent system being ready to realize protective reactions for preservation of the genetic constancy of the organism is conditioned by the hypothalamo-hypophyseal-adrenal system functional activity.