Central administration of metformin into the third ventricle of C57BL/6 mice decreases meal size and number and activates hypothalamic S6 kinase.

Administration of metformin is known to reduce both body weight and food intake. Although the hypothalamus is recognized as a critical regulator of energy balance and body weight, there is currently no evidence for an effect of metformin in the hypothalamus. Therefore, we sought to determine the central action of metformin on energy balance and body weight, as well as its potential involvement with key hypothalamic energy sensors, including adenosine monophosphate-activated protein kinase (AMPK) and S6 kinase (S6K). We used meal pattern analysis and a conditioned taste aversion (CTA) test and measured energy expenditure in C56BL/6 mice administered metformin (0, 7.5, 15, or 30 µg) into the third ventricle (I3V). Furthermore, we I3V-administered either control or metformin (30 µg) and compared the phosphorylation of AMPK and S6K in the mouse mediobasal hypothalamus. Compared with the control, I3V administration of metformin decreased body weight and food intake in a dose-dependent manner and did not result in CTA. Furthermore, the reduction in food intake induced by I3V administration of metformin was accomplished by decreases in both nocturnal meal size and number. Compared with the control, I3V administration of metformin significantly increased phosphorylation of S6K at Thr(389) and AMPK at Ser(485/491) in the mediobasal hypothalamus, while AMPK phosphorylation at Thr(172) was not significantly altered. Moreover, I3V rapamycin pretreatment restored the metformin-induced anorexia and weight loss. These results suggest that the reduction in food intake induced by the central administration of metformin in the mice may be mediated by activation of S6K pathway.

High fat diet altered the mechanism of energy homeostasis induced by nicotine and withdrawal in C57BL/6 mice.

Nicotine treatment has known to produce an inverse relationship between body weight and food intake in rodents. Present study determined the effect of repeated treatment with nicotine and withdrawal in control and obese mice, on: (1) body weight, caloric intake and energy expenditure; (2) hypothalamic neuropeptides mRNA expression; and (3) serum leptin. 21-week-old C57BL/6 mice (n = 65) received nicotine (3.0 mg/kg/day; 2 weeks) and saline (1 ml/kg/day; 2 weeks) subcutaneously. Animals were given either a normal-fat (10% kcal from fat, NF) or a high-fat diet (45% kcal from fat, HF) from the 12th week to 25th week. While, nicotine treatment for 14 days induced an increase in hypothalamic agouti-related protein, cocaine- and amphetamine- regulated transcript, pro-opiomelanocortin mRNA expressions, nicotine also produced a reducing effect in body weight gain and leptin concentration in NF mice. High-fat diet induced obese mice showed a blunted hypothalamic and leptin response to nicotine. Remarkable weight loss in obese mice was mediated not just by decreasing caloric intake, but also by increasing total energy expenditure (EE). During nicotine withdrawal period, weight gain occurred in NF and HF groups, which was ascribed to a decrease in EE rather than changes in caloric intake. Hypothalamic AgRP might play a role for maintaining energy balance under the nicotine-induced negative energy status.

Proteomic analysis of lithium-induced gene expression in the rat hypothalamus.

The hypothalamic proteomes were analyzed 1 and 6 hr after an intraperitoneal injection of lithium chloride or sodium chloride (0.15 M, 12 ml/kg). Results showed that expression of 14 and 32 proteomes was increased consistently by 1 hr and 6 hr of lithium treatment, respectively. Among them, tentative implications of glial fibrillary acidic protein, receptor-type protein tyrosine phosphatase, spectrin, and glutamate dehydrogenase in the lithium-induced activation of the hypothalamic-pituitary-adrenal axis, and conditioned taste aversion have been discussed. The proteomes listed in this study will provide, at least, a new insight to understand the molecular mechanism of lithium's action in the brain.

Effect of colloidal silver against the cytotoxicity of hydrogen peroxide and naphthazarin on primary cultured cortical astrocytes.

One major pathogenesis in degenerative disorders of the central nervous system (CNS), including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and ischemia, is the oxidative stress induced by reactive oxygen species (ROS). The present study investigated the protective effect of colloidal silver, which is widely marketed as a dietary supplement for diseases like diabetes, AIDS, cancer, and various infections, upon the oxidative brain damage induced by H(2)O(2) or naphthazarin treatment. LDH release from primary cultured astrocytes was enhanced by naphthazarin treatment, and this elevation of the LDH concentration in medium was blocked by colloidal silver treatment. However, hydrogen peroxide was little affected by the colloidal silver. Fluorescence of DCF (peroxides) increased in astrocytes incubated with hydrogen peroxide or naphthazarin compared to the control. When exposed to naphthazarin-induced cells, ROS formation appeared to be reduced by colloidal silver. However, intracellular ROS formation in hydrogen peroxide-treated cells slightly reduced by colloidal silver. These results suggest that colloidal silver has a protective activity against the oxidative stress induced by naphthazarin, but not by hydrogen peroxide.