No abstract

Apelin, the endogenous ligand of the APJ receptor, has been identified in a variety of tissues, including stomach, heart, skeletal muscle, and white adipose tissue. We sought to clarify the effects of apelin on body adiposity and the expression of uncoupling proteins (UCPs) in C57BL/6 mice. Treatment with ip apelin at a dose of 0.1 mumol/kg.d for 14 d decreased the weight of white adipose tissue and serum levels of insulin and triglycerides, compared with controls, without influencing food intake. Apelin treatment also decreased body adiposity and serum levels of insulin and triglycerides in obese mice fed a high-fat diet. Apelin increased the serum adiponectin level and decreased that of leptin. Additionally, apelin treatment increased mRNA expression of UCP1, a marker of peripheral energy expenditure, in brown adipose tissue (BAT) and of UCP3, a regulator of fatty acid export, in skeletal muscle. In addition, immunoblot bands and relative densities of UCP1 content in BAT were also higher in the apelin group than controls. Furthermore, apelin treatment increased body temperature and O(2) consumption and decreased the respiratory quotient. In conclusion, apelin appears to regulate adiposity and lipid metabolism in both lean and obese mice. In addition, apelin regulates insulin resistance by influencing the circulating adiponectin level, the expression of BAT UCP1, and energy expenditure in mice.

Histamine H 1 receptors (H 1 -Rs) are found in peripheral tissues and in regions of the hypothalamus that are concerned with regulating body composition. In the present study, we investigated the detailed mechanisms of histamine H 1 -Rs in the development of obesity. Histamine H 1 -R knockout (H1KO) mice gradually developed mature-onset obesity, which was accompanied by hyperphagia and decreased expression of uncoupling protein-1 (UCP-1) mRNA. Both younger nonobese (12-week-old) and older obese (48-week-old) H1KO mice exhibited impairment of the responsiveness to the leptin. In addition, disruption of the diurnal rhythm of feeding occurred before the onset of obesity in H1KO mice. Correction of these abnormal feeding rhythms by means of scheduled feeding caused a reduction in obesity and associated metabolic disorders in H1KO mice. Furthermore, central administration of a histamine H 1 -R agonist affected feeding behavior, body weight, and c-fos-like immunoreactivity in the hypothalamus. Taken together, these findings suggest that histamine H 1 -Rs are crucial for the regulation of feeding rhythm and in mediating the effects of leptin. Early disruption of H 1 -R-mediated functions in H1KO mice may lead to hyperphagia and decreased expression of UCP-1 mRNA, which may contribute to the development of obesity in these animals. In addition, centrally acting histamine H 1 -R may be a novel therapeutic target for the treatment of obesity and related metabolic disorders.

Histamine neurons are widely distributed in the brain and suppress food intake through the histamine H 1 receptor (H 1 -R) in the hypothalamus. To examine the role of neuronal histamine in leptin signaling pathways, we investigated the effects of H 1 -R knockout (H1KO) mice on both food intake and mRNA expressions of uncoupling proteins (UCPs) as regulated by leptin, and concomitantly on basal changes in both expression of hypothalamic neuropeptides and diet-induced fat deposition in adipose tissues. H1KO mice showed no change in daily food intake, growth curve, body weight, or adiposity. Reflecting no specificity in these parameters, H1KO mice induced no basal changes in mRNA expression of hypothalamic neuropeptides, ob gene, or peripheral UCPs. Loading H1KO mice with a high-fat diet accelerated fat deposition and ob gene expression compared with the controls. Leptin-induced feeding suppression was partially attenuated in H1KO mice, indicating involvement of histamine neurons in feeding regulation as a downstream signal of leptin. Upregulation of fat UCP mRNA and reduction of body fat induced by central infusion of leptin were attenuated in the H1KO mice. These results show that H1KO mice are a novel leptin-resistant model and that H 1 -R is a key receptor for downstream signaling of leptin in the brain that contributes to regulation of feeding, fat deposition, and UCP mRNA expression. Diabetes 50:385-391, 2001 H istamine neurons originating from the tuberomammillary nucleus of the posterior hypothalamus project diffusely in the brain to regulate energy homeostasis (1,2). Neuronal histamine has been shown to suppress food intake through histamine H 1 -receptors (H 1 -Rs) in the ventromedial hypothalamus (VMH) and the paraventricular nucleus (PVN) (3,4). It also alters thermoregulation (5). Energy deficiency in the brain, i.e., neural glucoprivation, activates histamine neurons in the hypothalamus (6) and augments glycogenolysis in the brain (7). Histamine neurons stimulate the sympathetic nervous system to increase lipolysis in the adipose tissue (8,9).Leptin, an ob gene product (10), has been recently demonstrated to promote histamine turnover by affecting the posttranscriptional process of histidine decarboxylase formation or histamine release per se (11). In addition, concentration or turnover rate of hypothalamic histamine was lowered in leptin-deficient ob/ob and leptin receptor-mutated db/db mice, but it was increased in diet-induced obese animals (11). Leptin regulates metabolic efficiency and exerts anorectic action (12-14) through its hypothalamic long-form receptors, in the VMH, the dorsomedial hypothalamus, the arcuate nucleus, and the ventral premammillary nucleus (15-17). The VMH, the PVN, and the arcuate nucleus are known as controlling centers of appetite and receive projections from histamine neurons (3,4,18,19).From the viewpoint of energy metabolism, the uncoupling protein (UCP) family plays an essential role in energy homeostasis (20)(21)(22). Gene expression of these proteins is regulated by...