Orally administered levodopa remains the most effective symptomatic treatment for Parkinson's disease (PD). The introduction of levodopa therapy is often delayed, however, because of the fear that it might be toxic for the remaining dopaminergic neurons and, thus, accelerate the deterioration of patients. However, in vivo evidence of levodopa toxicity is scarce. We have evaluated the effects of a 6-month oral levodopa treatment on several dopaminergic markers, in rats with moderate or severe 6-hydroxydopamine-induced lesions of mesencephalic dopamine neurons and sham-lesioned animals. Counts of tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra and ventral tegmental area showed no significant difference between levodopa-treated and vehicle-treated rats. In addition, for rats of the sham-lesioned and severely lesioned groups, immunoradiolabeling for TH, the dopamine transporter (DAT), and the vesicular monoamine transporter (VMAT2) at the striatal level was not significantly different between rats treated with levodopa or vehicle. It was unexpected that quantification of immunoautoradiograms showed a partial recovery of all three dopaminergic markers (TH, DAT, and VMAT2) in the denervated territories of the striatum of moderately lesioned rats receiving levodopa. Furthermore, the density of TH-positive fibers observed in moderately lesioned rats was higher in those treated chronically with levodopa than in those receiving vehicle. Last, that chronic levodopa administration reversed the up-regulation of D2 dopamine receptors seen in severely lesioned rats provided evidence that levodopa reached a biologically active concentration at the basal ganglia. Our results demonstrate that a pharmacologically effective 6-month oral levodopa treatment is not toxic for remaining dopamine neurons in a rat model of PD but instead promotes the recovery of striatal innervation in rats with partial lesions.

Interleukin-1 (IL-1) is a major mediator of inflammation that exerts its biological activities through the IL-1 type I receptor (IL-1RI). The body weights of IL-1RI؊/؊ mice of both sexes started to deviate from those of wild-type mice at 5-6 months of age and were 20% higher at 9 months of age. Visceral and subcutaneous fat mass, measured by dual-energy X-ray absorptiometry and magnetic resonance imaging, was markedly (1.5-to 2.5-fold) increased. Lean body mass and crown-rump length were also slightly (11 and 5%, respectively) increased, as was serum IGF-I. Obese IL-1RI؊/؊ mice were insulin resistant, as evidenced by hyperinsulinemia, decreased glucose tolerance, and insulin sensitivity. To elucidate the mechanisms for the development of obesity, young preobese IL-1RI ؊/؊ mice were investigated. They showed decreased suppression of body weight and food intake in response to systemic leptin treatment. The decreased leptin responsiveness was even more pronounced in older obese animals. Moreover, spontaneous locomotor activity and fat utilization, as measured by respiratory quotient, were decreased in preobese IL-1RI ؊/؊ mice. In conclusion, lack of IL-1RI-mediated biological activity causes mature-onset obesity. This obese phenotype is preceded by decreased leptin sensitivity, fat utilization, and locomotor activity. Diabetes 55: [1205][1206][1207][1208][1209][1210][1211][1212][1213] 2006 T he prevalence of obesity is growing rapidly in many parts of the world and reaching epidemic proportions in several developed countries (1). Overweight and obesity are associated with increased risk of metabolic disorders, such as type 2 diabetes and hyperlipidemia, and thereby increased risk of cardiovascular mortality. Although the regulation of body weight and body composition involves input from lifestyle and environment, compelling scientific evidence indicates that propensity to develop obesity is in large part attributable to genetic factors. Over the last decade, the study of different transgenic and knockout mouse models has contributed to the identification of new factors involved in the complex mechanisms regulating energy balance and to the clarification of the contribution of genetics to obesity (2,3). Moreover, a number of human genes have been identified in which major missense or nonsense mutations as well as genetic variations are associated with obesityrelated phenotypes. Many of these genetic variants have occurred in molecules identical or similar to those identified as a cause of obesity in rodents, supporting their involvement in the regulation of body weight homeostasis also in humans (4).Interleukin-1 (IL-1) is a major mediator of inflammation and exerts effects on the neuro-immuno-endocrine system (5). Infection, injury, and inflammation are associated with negative energy balance, characterized by reduced food intake, weight loss, increased thermogenesis, and fever. IL-1 could be of importance for these effects, as peripheral or central injection of IL-1 induces a marked rise in body temperature (f...

Aim/hypothesis: Perinatal overfeeding predisposes humans and rats to obesity and diabetes in later life. One classical model for studying the effect of early feeding is manipulation of the size of rat litters. Rats growing up in small litters gain more weight than rats growing up in normal-sized litters. Interestingly, these obese rats maintain this phenotype in adulthood. Conversely, rats raised in large litters show a delay in growth and a decrease in body weight. The aim of this work was to assess the hypothalamic control mechanisms of food intake regulated by perinatal feeding. Methods: Leptin levels were analysed using RIA. Leptin receptor mRNA levels were analysed using RT-PCR. Neuropeptide mRNA levels were analysed using in situ hybridisation. Results: Perinatally overfed neonatal male rats exhibited hyperleptinaemia and a decrease in hypothalamic mRNA levels of the long isoform of the leptin receptor (OB-Rb), explaining their leptin resistance. Moreover, this obese model showed an increase in the mRNA expression of cocaine-and amphetamine-regulated transcript, neuropeptide Y and agouti-related protein in the hypothalamic arcuate nucleus (ARC). In contrast, perinatally underfed neonatal male rats with hypoleptinaemia showed an increase in hypothalamic mRNA of the short isoforms of the leptin receptor. Furthermore, they exhibited an increase in expression of neuropeptide Y and agoutirelated protein in the ARC. Conclusions/interpretation: Rats overfed during early postnatal life show a leptinresistant state mediated by down-regulation of the hypothalamic OB-Rb. These data, together with the increased expression of neuropeptide Y and agouti-related protein in specific neurons in the ARC, might indicate the existence of regulated programming in this nucleus and may provide a new aetiopathogenic concept in susceptibility to obesity.

Ghrelin, the endogenous ligand of GH secretagogue receptor type 1a, has emerged as a pleiotropic modulator of diverse biological functions, including energy homeostasis and, lately reproduction. Here, we review recent reports evaluating the reproductive effects and sites of action of ghrelin, with particular emphasis regarding its role as a molecule integrating reproductive function and energy status. Data gleaned from rodent studies clearly show that besides having direct gonadal effects, ghrelin may participate in the regulation of gonadotropin secretion and it may influence the timing of puberty. In addition, experimental data showing that ghrelin and/or its receptor are expressed in normal human ovary and testis as well as in human ovarian and testicular tumors raise the possibility that the ghrelin system may be involved in the control of cell proliferation in these tumors. We propose that ghrelin either acting as an endocrine and/or paracrine signal may play a major role in the endocrine network that integrates energy balance and reproduction.

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