Unlike during development, blood vessels in the adult are generally thought not to require VEGF for normal function. However, VEGF is a survival factor for many tumor vessels, and there are clues that some normal blood vessels may also depend on VEGF. In this study, we sought to identify which, if any, vascular beds in adult mice depend on VEGF for survival. Mice were treated with a small-molecule VEGF receptor (VEGFR) tyrosine kinase inhibitor or soluble VEGFRs for 1-3 wk. Blood vessels were assessed using immunohistochemistry or scanning or transmission electron microscopy. In a study of 17 normal organs after VEGF inhibition, we found significant capillary regression in pancreatic islets, thyroid, adrenal cortex, pituitary, choroid plexus, small-intestinal villi, and epididymal adipose tissue. The amount of regression was dose dependent and varied from organ to organ, with a maximum of 68% in thyroid, but was less in normal organs than in tumors in RIP-Tag2-transgenic mice or in Lewis lung carcinoma. VEGF-dependent capillaries were fenestrated, expressed high levels of both VEGFR-2 and VEGFR-3, and had normal pericyte coverage. Surviving capillaries in affected organs had fewer fenestrations and less VEGFR expression. All mice appeared healthy, but distinct physiological changes, including more efficient blood glucose handling, accompanied some regimens of VEGF inhibition. Strikingly, most capillaries in the thyroid grew back within 2 wk after cessation of treatment for 1 wk. Our findings of VEGF dependency of normal fenestrated capillaries and rapid regrowth after regression demonstrate the plasticity of the adult microvasculature.

Huntington disease (HD) is characterized by the loss of striatal projection neurons, which constitute the vast majority of striatal neurons. To determine whether there is differential loss among different populations of striatal projection neurons, the integrity of the axon terminal plexuses arising from the different populations of substance P-containing and enkephalin-containing striatal projection neurons was studied in striatal target areas by immunohistochemistry. Analysis of 17 HD specimens indicated that in early and middle stages of HD, enkephalin-containing neurons projecting to the external segment of the globus pallidus were much more affected than substance P-containing neurons projecting to the internal pallidal segment. Furthermore, substance P-containing neurons projecting to the substantia nigra pars reticulata were more affected than those projecting to the substantia nigra pars compacta. At the most advanced stages of the disease, projections to all striatal target areas were depleted, with the exception of some apparent sparing of the striatal projection to the substantia nigra pars compacta. These findings may explain some of the clinical manifestations and pharmacology of HD. They also may aid in identifying the neural defect underlying HD and provide additional data with which to evaluate current models of HD pathogenesis.Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by choreiform movements, cognitive decline, and personality disturbance (1). The underlying genetic defect in HD is unknown, but the gene has been localized to the short arm of chromosome 4 (2). The histopathology of HD reveals cell loss and astrogliosis in several brain areas, with the most prominent alterations occurring in the striatum (3-5). Although the pathogenetic mechanism of this process is unknown, endogenous "excitotoxins" have been proposed as the mechanism of cell death (6-8). Recent findings indicate that striatal neurons are not uniformly affected in HD and that somatostatin-neuropeptide Y-containing interneurons and cholinergic interneurons are relatively spared (8, 9). Striatal interneurons, however, constitute only a small fraction of the total number of striatal neurons, and it has not been possible to correlate the preservation of interneuron populations with the clinical features of HD.The great majority of striatal neurons are projection neurons, which are heterogeneous in terms of their projection targets and in terms of the neuropeptides they contain (10, 11). These neurons show the earliest evidence of abnormality and are progressively depleted in HD (4, 12). Previous studies, however, have not resolved whether all populations of striatal projection neurons are equally affected in HD. The identification ofthe putative populations of striatal projection neurons that are earliest and most severely affected in HD, however, could provide valuable clues regarding the basis of striatal cell death in HD. To determine whether some populations of striatal proje...

Ghrelin is a recently identified growth hormone (GH) secretogogue whose administration not only induces GH release but also stimulates food intake, increases adiposity, and reduces fat utilization in mice. The effect on food intake appears to be independent of GH release and instead due to direct activation of orexigenic neurons in the arcuate nucleus of the hypothalamus. The effects of ghrelin administration on food intake have led to the suggestion that inhibitors of endogenous ghrelin could be useful in curbing appetite and combating obesity. To further study the role of endogenous ghrelin in appetite and body weight regulation, we generated ghrelin-deficient (ghrl ؊/؊ ) mice, in which the ghrelin gene was precisely replaced with a lacZ reporter gene. ghrl ؊/؊ mice were viable and exhibited normal growth rates as well as normal spontaneous food intake patterns, normal basal levels of hypothalamic orexigenic and anorexigenic neuropeptides, and no impairment of reflexive hyperphagia after fasting. These results indicate that endogenous ghrelin is not an essential regulator of food intake and has, at most, a redundant role in the regulation of appetite. However, analyses of ghrl ؊/؊ mice demonstrate that endogenous ghrelin plays a prominent role in determining the type of metabolic substrate (i.e., fat vs. carbohydrate) that is used for maintenance of energy balance, particularly under conditions of high fat intake.G hrelin is a 28-aa peptide produced predominantly in the stomach (1, 2) that has recently been identified as a ligand of the growth hormone (GH) secretogogue (GHS) receptor (GHS-R). Like other GHSs, activation of the receptor stimulates GH secretion from the pituitary gland (1). In addition to inducing GH release, administration of exogenous ghrelin also stimulates food intake and body weight gain (3-7), increases gastric motility and acid secretion (8, 9), and decreases lipid metabolism in mice and rats (3, 4). The effects of centrally administered ghrelin on food intake are independent of its ability to induce GH release and thought to result from its direct actions on the arcuate nucleus of the hypothalamus. Furthermore, recent studies have demonstrated that plasma ghrelin levels increase preceding meals and during fasting (10, 11). Thus, it has been suggested that ghrelin stimulates appetite and that inhibitors of endogenous ghrelin, therefore, could prove useful in reducing food intake and combating obesity (11).Supporting the possibility that ghrelin acts as a key regulator of appetite and food intake by actions on the hypothalamus, GHS-R is colocalized with neuropeptide Y (NPY)͞agouti-related protein (AgRP) neurons (12) in the arcuate nucleus, a region that is responsive to circulating peripheral nutrients and hormones and critically involved in the regulation of food intake (13). Indeed, ghrelin stimulates the spontaneous activity of these neurons (14), and central ghrelin administration increases NPY and AgRP gene expression (15). Moreover, ghrelin-immunoreactivity has been reported in the h...

Ciliary Neurotrophic Factor (CNTF) was first characterized as a trophic factor for motor neurons in the ciliary ganglion and spinal cord, leading to its evaluation in humans suffering from motor neuron disease. In these trials, CNTF caused unexpected and substantial weight loss, raising concerns that it might produce cachectic-like effects. Countering this possibility was the suggestion that CNTF was working via a leptin-like mechanism to cause weight loss, based on the findings that CNTF acts via receptors that are not only related to leptin receptors, but also similarly distributed within hypothalamic nuclei involved in feeding. However, although CNTF mimics the ability of leptin to cause fat loss in mice that are obese because of genetic deficiency of leptin (ob͞ob mice), CNTF is also effective in diet-induced obesity models that are more representative of human obesity, and which are resistant to leptin. This discordance again raised the possibility that CNTF might be acting via nonleptin pathways, perhaps more analogous to those activated by cachectic cytokines. Arguing strongly against this possibility, we now show that CNTF can activate hypothalamic leptin-like pathways in diet-induced obesity models unresponsive to leptin, that CNTF improves prediabetic parameters in these models, and that CNTF acts very differently than the prototypical cachectic cytokine, IL-1. Further analyses of hypothalamic signaling reveals that CNTF can suppress food intake without triggering hunger signals or associated stress responses that are otherwise associated with food deprivation; thus, unlike forced dieting, cessation of CNTF treatment does not result in binge overeating and immediate rebound weight gain.

We have reported previously that striatal projection neurons are differentially affected in the course of Huntington's disease, and in a prior patient report we noted that differential loss of striatal projection neurons occurs also in patients with presymptomatic Huntington's disease. Striatal neurons projecting to the external segment of the globus pallidus or the substantia nigra show evident loss, whereas those projecting to the internal segment of the globus pallidus appear relatively spared at presymptomatic and early stages of symptomatic Huntington's disease. We now report similar findings in a second apparently presymptomatic Huntington's disease allele carrier.