Tachykinin-1 in the central nervous system regulates adiposity in rodents.

Ghrelin is a circulating hormone that targets the central nervous system to regulate feeding and adiposity. The best-characterized neural system that mediates the effects of ghrelin on energy balance involves the activation of neuropeptide Y/agouti-related peptide neurons, expressed exclusively in the arcuate nucleus of the hypothalamus. However, ghrelin receptors are expressed in other neuronal populations involved in the control of energy balance. We combined laser capture microdissection of several nuclei of the central nervous system expressing the ghrelin receptor (GH secretagoge receptor) with microarray gene expression analysis to identify additional neuronal systems involved in the control of central nervous system-ghrelin action. We identified tachykinin-1 (Tac1) as a gene negatively regulated by ghrelin in the hypothalamus. Furthermore, we identified neuropeptide k as the TAC1-derived peptide with more prominent activity, inducing negative energy balance when delivered directly into the brain. Conversely, loss of Tac1 expression enhances the effectiveness of ghrelin promoting fat mass gain both in male and in female mice and increases the susceptibility to diet-induced obesity in ovariectomized mice. Taken together, our data demonstrate a role TAC1 in the control energy balance by regulating the levels of adiposity in response to ghrelin administration and to changes in the status of the gonadal function.

DFT study of Fe-Ni core-shell nanoparticles: stability, catalytic activity, and interaction with carbon atom for single-walled carbon nanotube growth.

Metal catalysts play an important role in the nucleation and growth of single-walled carbon nanotubes (SWCNTs). It is essential for probing the nucleation and growth mechanism of SWCNTs to fundamentally understand the properties of the metal catalysts and their interaction with carbon species. In this study, we systematically studied the stability of 13- and 55-atom Fe and Fe-Ni core-shell particles as well as these particles interaction with the carbon atoms using the density functional theory calculations. Icosahedral 13- and 55-atom Fe-Ni core-shell bimetallic particles have higher stability than the corresponding monometallic Fe and Ni particles. Opposite charge transfer (or distribution) in these particles leads to the Fe surface-shell displays a positive charge, while the Ni surface-shell exhibits a negative charge. The opposite charge transfer would induce different chemical activities. Compared with the monometallic Fe and Ni particles, the core-shell bimetallic particles have weaker interaction with C atoms. More importantly, C atoms only prefer staying on the surface of the bimetallic particles. In contrast, C atoms prefer locating into the subsurface of the monometallic particles, which is more likely to form stable metal carbides. The difference of the mono- and bimetallic particles on this issue may result in different nucleation and growth mechanism of SWCNTs. Our findings provide useful insights for the design of bimetallic catalysts and a better understanding nucleation and growth mechanism of SWCNTs.

Theoretical investigation on carbon nucleation on nickel carbides at initial stages of single-walled carbon nanotube formation.

It is a long-standing controversy whether metal carbide clusters do exist during the nucleation and growth process of single-walled carbon nanotubes (SWCNTs). In the current work, we are trying to elucidate the carbon nucleation on nickel carbides during the initial stages based on density functional theory calculated formation energy and chemical potential for a series of Ni55Cn carbides (n is the number of carbon atoms dissolved in the Ni55 cluster). It is found that the formation energies of the Ni55Cn carbides decrease gradually with an increase of dissolved carbon atomic numbers, meaning the Ni55Cn carbides are thermodynamically stable. Meanwhile, the calculated chemical potentials indicate that not only nickel carbides are preferentially formed during the initial stage of the SWCNT nucleation, but also saturated nickel carbides may be able to exist during the nucleation and growth process of SWCNTs. In addition, the nickel carbides have a high selectivity for the formation of the carbon pentagon and carbon structures with pentagon-incorporated end-edge according to the adsorption energies. All of these findings provide opportunities in controlling the growth of the SWCNTs.

Central leptin and ghrelin signalling: comparing and contrasting their mechanisms of action in the brain.

In the past two decades, two major discoveries have greatly contributed to our current knowledge on the central control of food intake and body-weight; the discovery of the anorexigenic adipocyte derived hormone leptin in 1994 and the orexigenic gut derived hormone ghrelin in 1999. Both hormones act as crucial signals to indicate nutritional status as well as to modulate feeding behaviour through a variety of distinct pathways. They target overlapping CNS regions in order to mediate their obvious opposing effects on energy balance. Here we depict the integral picture of leptin and ghrelin on central regulation of food intake by reviewing their actions across the CNS, in regions of the hypothalamus, brainstem, mesolimbic reward pathway and other higher brain areas.

The anti-atherogenic aspect of metformin treatment in insulin resistant women with the polycystic ovary syndrome: role of the newly established pro-inflammatory adipokine Acute-phase Serum Amyloid A; evidence of an adipose tissue-monocyte axis.

OBJECTIVE: Acute-phase Serum Amyloid A (ASAA) is a novel pro-inflammatory adipokine, increased in obese, insulin resistant subjects. Polycystic ovary syndrome (PCOS) is associated with inflammation and atherosclerosis. We assessed sera, adipose tissue (AT) mRNA and protein levels of ASAA of PCOS women and matched controls. Ex vivo regulation of AT ASAA by d-glucose, effects of metformin treatment on circulating ASAA in PCOS subjects and effects of sera from normal and PCOS subjects (before and after metformin) on ASAA production (THP-1 macrophages) were also studied. METHODS AND RESULTS: Circulating ASAA (ELISA), subcutaneous and omental AT ASAA mRNA (RT-PCR) and protein (western blotting) were significantly higher in PCOS women (P<0.05). In AT explants, glucose significantly increased ASAA production and secretion (P<0.05, P<0.01). Furthermore, ASAA production (THP-1 macrophages) was significantly greater by sera from PCOS women compared to controls (P<0.01). ASAA protein production was significantly decreased by sera from PCOS women following 6 months of metformin treatment (P<0.05). After 6 months of metformin treatment, there was a significant decrease in circulating ASAA (P<0.05). Importantly, changes in intima media thickness were predictive of changes in circulating ASAA (P=0.034). CONCLUSION: Serum and AT ASAA are increased in PCOS women and are elevated by glucose. Metformin treatment decreases serum ASAA in these women. An adipose tissue-monocyte axis may be pivotal in the pathogenesis of inflammation and atherosclerosis. ASAA may be a valuable diagnostic marker in the management of dysmetabolic states including PCOS.

Hypothalamic-specific manipulation of Fto, the ortholog of the human obesity gene FTO, affects food intake in rats.

Sequence variants in the first intron of FTO are strongly associated with human obesity and human carriers of the risk alleles show evidence for increased appetite and food intake. Mice globally lacking Fto display a complex phenotype characterised by both increased energy expenditure and increased food intake. The site of action of FTO on energy balance is unclear. Fasting reduces levels of Fto mRNA in the arcuate nucleus (ARC) of the hypothalamus, a site where Fto expression is particularly high. In this study, we have extended this nutritional link by demonstrating that consumption of a high fat diet (45%) results in a 2.5 fold increase in Arc Fto expression. We have further explored the role of hypothalamic Fto in the control of food intake by using stereotactic injections coupled with AAV technology to bi-directionally modulate Fto expression. An over expression of Fto protein by 2.5-fold in the ARC results in a 14% decrease in average daily food intake in the first week. In contrast, knocking down Arc Fto expression by 40% increases food intake by 16%. mRNA levels of Agrp, Pomc and Npy, ARC-expressed genes classically associated with the control of food intake, were not affected by the manipulation of Fto expression. However, over expression of Fto resulted in a 4-fold increase in the mRNA levels of Stat3, a signalling molecule critical for leptin receptor signalling, suggesting a possible candidate for the mediation of Fto's actions. These data provide further support for the notion that FTO itself can influence key components of energy balance, and is therefore a strong candidate for the mediation of the robust association between FTO intronic variants and adiposity. Importantly, this provide the first indication that selective alteration of FTO levels in the hypothalamus can influence food intake, a finding consistent with the reported effects of FTO alleles on appetite and food intake in man.

Ex vivo and in vivo regulation of lipocalin-2, a novel adipokine, by insulin.

OBJECTIVE: Lipocalin-2, a novel adipokine, has been shown to be elevated in obese, insulin-resistant, and diabetic subjects. We therefore sought to study the ex vivo and in vivo effects of insulin on lipocalin-2 levels in humans. RESEARCH DESIGN AND METHODS: We investigated the in vivo effects of insulin (hyperinsulinemia) on circulating lipocalin-2 levels by enzyme-linked immunosorbent assay via a prolonged insulin-glucose infusion. The ex vivo effect of insulin on adipose tissue lipocalin-2 protein production and secretion into conditioned media was assessed by Western blotting and enzyme-linked immunosorbent assay, respectively. RESULTS: Hyperinsulinemic induction in human subjects significantly increased circulating lipocalin-2 levels (P < 0.01). Also, in omental adipose tissue explants, insulin caused a significant dose-dependent increase in lipocalin-2 protein production and secretion into conditioned media (P < 0.05, P < 0.01, respectively); these effects were negated by both phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase inhibitors. CONCLUSIONS: Lipocalin-2 is upregulated by insulin via phosphatidylinositol 3-kinase and mitogen-activated protein kinase signaling pathways.