Diabetes mellitus is a chronic disease that leads to complications including heart disease, stroke, kidney failure, blindness and nerve damage. Type 2 diabetes, characterized by target-tissue resistance to insulin, is epidemic in industrialized societies and is strongly associated with obesity; however, the mechanism by which increased adiposity causes insulin resistance is unclear. Here we show that adipocytes secrete a unique signalling molecule, which we have named resistin (for resistance to insulin). Circulating resistin levels are decreased by the anti-diabetic drug rosiglitazone, and increased in diet-induced and genetic forms of obesity. Administration of anti-resistin antibody improves blood sugar and insulin action in mice with diet-induced obesity. Moreover, treatment of normal mice with recombinant resistin impairs glucose tolerance and insulin action. Insulin-stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment. Resistin is thus a hormone that potentially links obesity to diabetes.

Adiponectin (ADP) is an adipocyte hormone involved in glucose and lipid metabolism. We detected a rise in ADP in cerebrospinal fluid after intravenous (i.v.) injection, consistent with brain transport. In contrast to leptin, intracerebroventricular (i.c.v.) administration of ADP decreased body weight mainly by stimulating energy expenditure. Full-length ADP, mutant ADP with Cys39 replaced with serine, and globular ADP were effective, whereas the collagenous tail fragment was not. Lep(ob/ob) mice were especially sensitive to i.c.v. and systemic ADP, which resulted in increased thermogenesis, weight loss and reduction in serum glucose and lipid levels. ADP also potentiated the effect of leptin on thermogenesis and lipid levels. While both hormones increased expression of hypothalamic corticotropin-releasing hormone (CRH), ADP had no substantial effect on other neuropeptide targets of leptin. In addition, ADP induced distinct Fos immunoreactivity. Agouti (A(y)/a) mice did not respond to ADP or leptin, indicating the melanocortin pathway may be a common target. These results show that ADP has unique central effects on energy homeostasis.

Neuropeptide Y (NPY) stimulates feeding and weight gain, but deletion of the NPY gene does not affect food intake and body weight in mice bred on a mixed genetic background. We reasoned that the orexigenic action of NPY would be evident in C57Bl/6J mice susceptible to obesity. NPY deficiency has no significant effect in mice fed a normal rodent diet. However, energy expenditure is elevated during fasting, and hyperphagia and weight gain are blunted during refeeding. Expression of agouti-related peptide (AGRP) in the hypothalamus is increased in NPY knockout (NPYko) than wild-type mice, but unlike wild type there is no further increase in AGRP when NPYko mice are fasted. Moreover, NPYko mice have higher oxygen consumption and uncoupling protein-1 expression in brown adipose tissue during fasting. The failure of an increase in orexigenic peptides and higher thermogenesis may contribute to attenuation of weight gain when NPYko mice are refed. C57Bl/6J mice lacking NPY are also less susceptible to diet-induced obesity (DIO) as a result of reduced feeding and increased energy expenditure. The resistance to DIO in NPYko mice is associated with a reduction in nocturnal feeding and increased expression of anorexigenic hypothalamic peptides. Insulin, leptin, and triglyceride levels increase with adiposity in both wild-type and NPYko mice. Diabetes 55:3091-3098, 2006 E nergy balance involves a complex interaction between hormones, such as leptin, insulin, and glucocorticoids, and key neurons in the hypothalamus, brainstem, and other areas of the central nervous system (1). Neuropeptide Y (NPY) is expressed in the hypothalamus, stimulates food intake, decreases energy expenditure, and increases body weight when administered in the brain (1). Consistent with its role as an orexigenic peptide, hypothalamic NPY expression is increased during fasting and hypoglycemia and suppressed by feeding, leptin, and insulin (1). Despite the strong pharmacological evidence supporting its role in energy balance, genetic disruption of NPY did not affect feeding or body weight in mice bred on a mixed 129J-C57Bl/6J background (2). Paradoxically, deletion of NPY or the Y1 and Y5 receptors that mediate effects of NPY on energy balance resulted in mild obesity (3-6). Nonetheless, loss of NPY attenuated hyperphagia and obesity in Lep ob/ob mice (7). Others have also shown that NPY deficiency decreases hyperphagia after fasting and hypoglycemia (8 -10). Furthermore, deletion of NPY Y2/Y4 receptors prevents diet-induced obesity (DIO) (11).We reasoned that the controversies surrounding the actions of NPY in these genetic models are partly due to the use of the 129 mouse strain, which is resistant to obesity (12). The seemingly normal phenotype of NPYdeficient mice could also result from compensatory developmental changes. For example, ablation of hypothalamic neurons expressing NPY/AGRP did not alter feeding in neonatal mice, whereas ablation in adults caused starvation (13,14). AGRP is coexpressed with NPY in the arcuate nucleus, and both peptides ...

The rise in obesity and its complications has generated enormous interest in the regulation of feeding and body weight. We show that a spermine metabolite of cholesterol (MSI-1436) decreases body weight, specifically fat, by suppressing feeding and preventing the reduction in energy expenditure, hormonal changes, and patterns of neuropeptide expression normally associated with weight loss. MSI-1436 enters the brain after peripheral injection and is more potent when injected into the cerebral ventricle (

Three sentences in this article appeared incorrectly. On p. 524, in the second paragraph after the abstract, the fifth sentence should read "ADP circulates in serum as low-molecular-weight dimers of trimers and high-molecular weight complexes 5 ." On p. 525, in the first paragraph in the right column, the second sentence should read "We also injected ADP (2 µg/g) or PBS i.v. and measured serum and CSF ADP." In the second paragraph in the same column, several words were repeated in the second and third sentences; the second sentence should read "ADP (0.1 µg/g, i.c.v.) induced Fos-positive cells in the paraventricular nucleus (PVN; Fig. 2d)."We regret the errors.