Orexin-A represses satiety-inducing POMC neurons and contributes to obesity via stimulation of endocannabinoid signaling.

In the hypothalamic arcuate nucleus (ARC), proopiomelanocortin (POMC) neurons and the POMC-derived peptide α-melanocyte-stimulating hormone (α-MSH) promote satiety. POMC neurons receive orexin-A (OX-A)-expressing inputs and express both OX-A receptor type 1 (OX-1R) and cannabinoid receptor type 1 (CB1R) on the plasma membrane. OX-A is crucial for the control of wakefulness and energy homeostasis and promotes, in OX-1R-expressing cells, the biosynthesis of the endogenous counterpart of marijuana's psychotropic and appetite-inducing component Δ(9)-tetrahydrocannabinol, i.e., the endocannabinoid 2-arachidonoylglycerol (2-AG), which acts at CB1R. We report that OX-A/OX-1R signaling at POMC neurons promotes 2-AG biosynthesis, hyperphagia, and weight gain by blunting α-MSH production via CB1R-induced and extracellular-signal-regulated kinase 1/2 activation- and STAT3 inhibition-mediated suppression of Pomc gene transcription. Because the systemic pharmacological blockade of OX-1R by SB334867 caused anorectic effects by reducing food intake and body weight, our results unravel a previously unsuspected role for OX-A in endocannabinoid-mediated promotion of appetite by combining OX-induced alertness with food seeking. Notably, increased OX-A trafficking was found in the fibers projecting to the ARC of obese mice (ob/ob and high-fat diet fed) concurrently with elevation of OX-A release in the cerebrospinal fluid and blood of mice. Furthermore, a negative correlation between OX-A and α-MSH serum levels was found in obese mice as well as in human obese subjects (body mass index > 40), in combination with elevation of alanine aminotransferase and γ-glutamyl transferase, two markers of fatty liver disease. These alterations were counteracted by antagonism of OX-1R, thus providing the basis for a therapeutic treatment of these diseases.

Electroacupuncture enhancement of natural killer cell activity suppressed by anterior hypothalamic lesions in rats.

BACKGROUND/OBJECTIVE: Neuroendocrine hormones are derived from the hypothalamus. The central nervous system, particularly the hypothalamus, is capable of modulating the cytolytic activity of adherent natural killer (NK) cells. In addition, electroacupuncture (EA) stimulation of the Zusanli (ST36) acupoint enhances splenic NK cell and cytokine activities in rats. However, it is still unclear whether the anterior hypothalamus affects this immunomodulation. Therefore, the aim of the present study was to examine the effect of EA stimulation at the Zusanli acupoint on the NK cell activity modulated by an anterior hypothalamic area lesion. METHODS: Male Sprague-Dawley rats were used. Lesions were placed by means of a direct current through a concentric electrode. The electric acupuncture stimulation was delivered for 30 min per each experiment at the right ST36 acupoint with an electrical stimulator. The NK cell activity of the spleen was measured by a fluorescence assay. RESULTS: The NK cell activity was significantly reduced on the 2nd day after the lesion, but was restored to that of the sham group by the 7th day. However, when EA was applied for 2 days after the operation, the NK cell activity of the lesion group was restored to that of the sham group. After 7 days of EA, the NK cell activity of the lesion group was slightly higher than that of the sham group. CONCLUSION: From these results, we can suggest that EA enhances or restores the NK cell activity suppressed by an anterior hypothalamic area lesion.

Filament size influences temperature changes and brain damage following middle cerebral artery occlusion in rats.

Postischemic spontaneous hyperthermia as a complication of occlusion of the middle cerebral artery with an intraluminal filament has been observed by some authors, but many other reports do not discuss this factor. The possible reasons why some of the authors have not seen severe hyperthermia in their experiments include differences in surgical technique, the strain of animals, the type of the anesthesia, and the occluder filament. The aim of this study was to examine the changes in the core temperature of rats using different types of filaments. The middle cerebral artery was occluded for 2 h with three different types of filaments. The changes in the temperature were continuously monitored during occlusion and for the next 4 h. Groups with uncontrolled hyperthermia and with controlled normal core temperature were used. In addition, the necrotic and penumbral areas were measured 4 and 48 h after the ischemia in both groups. Spontaneous postischemic hyperthermia was detected using all types of filaments. A close correlation was found between the size of the occluder filament and the time-course and degree of hyperthermia. Moreover, the size of the filament correlated well with the size of the infarct at both 4 and 48 h after the occlusion. We suggest that filament size is a major contributor to the degree of hyperthermia and the development of brain damage in the middle cerebral artery occlusion model. Our results call attention to the need to standardize the methods used to screen for therapeutic agents for stroke.

Volumetric analysis of sexually dimorphic limbic nuclei in normal and sex-reversed whiptail lizards.

Sex differences in the size of key limbic nuclei have been found in many species. In some of these species, steroid hormones have been implicated in both the development and the maintenance of the sex difference. However, the possible role of sex-specific genes has not been examined, in part due to lack of an appropriate model system. In this study we measured the size of the ventromedial hypothalamus and preoptic area-anterior hypothalamus in normal female whiptail lizards and in genetic female whiptails that had been sex-reversed by treatment early in development with the aromatase inhibitor fadrozole. We found no difference in the size of these two nuclei between females and the sex-reversed animals. These results suggest that either the sex-reversing treatment itself interfered with the masculinization process, or that a male genome is required to produce a male-like limbic phenotype.

Gonadotropin-releasing hormone (GnRH) neurons in the hypogonadal mouse elaborate normal projections despite their biosynthetic deficiency.

This study was undertaken to determine whether gonadotropin-releasing hormone (GnRH) neurons in the mutant hypogonadal (hpg) mouse can establish axonal connections with their target despite their failure to synthesize and secrete the GnRH neuropeptide. Normal and hpg males received intraperitoneal injections of the retrograde tracer Fluoro-Gold. This tracer does not cross the blood-brain-barrier and hence is taken up only by neurons in the central nervous system whose axons terminate on fenestrated capillaries, such as the capillaries of the median eminence. The brains of the injected animals were processed for in situ hybridization to visualize GnRH transcribing cells. In 3 hpg males 64.1 +/- 5.6% of GnRH transcribing cells contained Fluoro-Gold, while 55.8 +/- 6.4% of the cells in 3 normal males had Fluoro-Gold. Thus, we have demonstrated that secretory-deficient GnRH neurons can establish axonal connections with their primary secretory target, the median eminence. We conclude that the capability of GnRH neurons to recognize and interact with their target is not dependent upon their neurosecretory function.

[The enzymatic activity of the neurosecretory nuclei of the anterior hypothalamus in exposure of the body to organophosphorus compounds]. / Aktivnost' fermentov neirosekretornykh iader perednego gipotalamusa pri vozdeistvii na organizm fosfororganicheskikh soedinenii.

Under study were activities of glycolysis enzymes: LDH, Krebs' cycle--SDH, those of electron transport system--NAD and NADP-diaphorase, and of the hydrolytic enzymes, acid and alkaline phosphatases in the hypothalamus, as were morphofunctional shifts in these enzymes' activities in poisoning with organophosphorus compounds. The experiments were carried out in 72 white male outbred rats weighing 180-200 g, that were administered PHOS antio (an organo-phosphorus compound) in a daily dose of 0.1 LD50 for 30 days. Early dates of poisoning were associated with an essential rise of the redox enzymes and a lowering of the hydrolytic enzymes levels, this being paralleled by morphologic signs of activation of the neurosecretory cells. Later high levels of neurosecretory material in the neurosecretory nuclei and reduced counts of neurosecretory cells were coupled with almost all the enzymes' activities lowering. This permits a conclusion that changed activities of the enzymic systems may be one of the pathogenetic mechanisms and possible causes of neurosecretory cell dysfunction in pesticide poisonings.

Lesions of the anterior hypothalamic area increase arterial pressure in NaCl-sensitive spontaneously hypertensive rats.

In NaCl-sensitive spontaneously hypertensive rats, diets high in NaCl increase arterial pressure and peripheral sympathetic nervous system activity and decrease the sympatho-inhibition mediated by the anterior hypothalamic area. To test the importance of the defect in anterior hypothalamic area-mediated sympatho-inhibition in the pathogenesis of NaCl-sensitive hypertension, bilateral ibotenic acid lesions of the anterior hypothalamic area were made in NaCl-sensitive spontaneous hypertensive rats, in NaCl-resistant spontaneously hypertensive rats and in normotensive, NaCl-resistant Wistar Kyoto rats. In NaCl-sensitive spontaneous hypertensive rats on a basal NaCl diet, the anterior hypothalamic area lesions caused a rapid rise in arterial pressure within the first week after surgery; by 21 days after surgery, mean systolic arterial pressure of the lesion group was 24 mmHg higher than that of the sham-operated group. In a second experiment, NaCl-sensitive spontaneous hypertensive rats were placed on an 8% NaCl diet 1 day after the lesion of the anterior hypothalamic area. 5 days after the operation, the lesion group of NaCl-sensitive spontaneous hypertensive rats on the 8% NaCl diet had a significantly higher arterial pressure than the sham-operated group, but by 1 week after the lesion, arterial pressures were not significantly different between the lesion and sham-operated NaCl-sensitive spontaneous hypertensive rats on the high NaCl diet. In Wistar Kyoto rats on a basal NaCl diet, lesions of the anterior hypothalamic area resulted in a small, transient elevation of arterial pressure, but no sustained effect. In NaCl-resistant spontaneous hypertensive rats, the anterior hypothalamic area lesions did not affect arterial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)