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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Feeding is influenced by hypothalamic neuropeptides that promote (orexigenic peptides) or inhibit feeding. Of these, neuropeptide Y (NPY) in the arcuate nucleus and melanin-concentrating hormone (MCH) and orexins/hypocretins in the lateral hypothalamus have received attention because their expression is increased during fasting and because they promote feeding when administered centrally. Surprisingly, absence of the orexigenic neuropeptide NPY fails to alter feeding or body weight in normal mice. As deficiency of a single component of the pathway that limits food intake (such as leptin or receptors for melanocortin-4) causes obesity, it has been suggested that orexigenic signals are more redundant than those limiting food intake. To define further the physiological role of MCH and to test the redundancy of orexigenic signals, we generated mice carrying a targeted deletion of the MCH gene. MCH-deficient mice have reduced body weight and leanness due to hypophagia (reduced feeding) and an inappropriately increased metabolic rate, despite their reduced amounts of both leptin and arcuate nucleus pro-opiomelanocortin messenger RNA. Our results show that MCH is a critical regulator of feeding and energy balance which acts downstream of leptin and the melanocortin system, and that deletion of a gene encoding a single orexigenic peptide can result in leanness.
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PMID:Mice lacking melanin-concentrating hormone are hypophagic and lean. 987 14

Mutations reducing the functional activity of leptin, the leptin receptor, alpha-melanocyte stimulating hormones (alpha-MSH) and the melanocortin-4 receptor (Mc4r) all lead to obesity in mammals. Moreover, mutant mice that ectopically express either agouti (Ay/a mice) or agouti-related protein (Agrp), antagonists of melanocortin signalling, become obese. These data suggest that alpha-MSH signalling transduced by Mc4r tonically inhibits feeding; however, it is not known to what extent this pathway mediates leptin signalling. We show here that Mc4r-deficient (Mc4r-/-) mice do not respond to the anorectic actions of MTII, an MSH-like agonist, suggesting that alpha-MSH inhibits feeding primarily by activating Mc4r. Obese Mc4r-/-mice do not respond significantly to the inhibitory effects of leptin on feeding, whereas non-obese Mc4r-/- mice do. These data demonstrate that melanocortin signalling transduced by Mc4r is not an exclusive target of leptin action and that factors resulting from obesity contribute to leptin resistance. Leptin resistance of obese Mc4r-/- mice does not prevent their response to the anorectic actions of ciliary neurotrophic factor (CNTF), corticotropin releasing factor (CRF), or urocortin; or the orexigenic actions of neuropeptide Y (NPY) or peptide YY (PYY), indicating that these neuromodulators act independently or downstream of Mc4r signalling.
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PMID:Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. 991 4

Cocaine and amphetamine regulated transcript peptide (CART), is a recently discovered hypothalamic peptide with a potent appetite suppressing activity. In the rat the CART gene encodes a peptide of either 129 or 116 amino acid residues whereas only the short form exists in humans. The predicted signal sequence is 27 amino acid residues resulting in a prohormone of 102 or 89 residues. The C-terminal end of CART, consisting of 48 amino acid residues and 3 disulphide bonds, is thought to constitute a biologically active part of the molecule. In the central nervous system CART is highly expressed in many hypothalamic nuclei, some of which are involved in regulating feeding behaviour. The CART mRNA is regulated by leptin, and the expressed CART is a potent inhibitor of feeding that even overrides the feeding response induced by neuropeptide Y. The putative CART receptor is therefore a potential therapeutic target for an anti-obesity drug.
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PMID:CART, a new anorectic peptide. 992 97

Agouti-related protein (AGRP) is a homologue of the agouti gene product and, when overexpressed, promotes obesity. Like neuropeptide Y (NPY) messenger RNA (mRNA), AGRP mRNA is produced in the hypothalamic arcuate nucleus and is elevated in leptin-deficient ob/ob and leptin-resistant db/db mice. These data suggest that AGRP mRNA might be affected by leptin and nutritional status in parallel with NPY mRNA. To test this hypothesis, we examined if AGRP mRNA would be, like NPY mRNA, inhibited by leptin injections and stimulated by fasting. AGRP mRNA was elevated in ob/ob mice about 5-fold compared with wild-type controls and was significantly inhibited by leptin treatment, as assessed by Northern blot analysis. In wild-type mice, AGRP mRNA was increased at least 13-fold by a 2-day fast, as assessed both by Northern blot analysis and in situ hybridization. In ad lib fed db/db mice, AGRP mRNA was elevated about 8-fold compared with ad lib fed wild-type controls, and was further increased by fasting in db/db mice. These data suggest that AGRP mRNA and NPY mRNA respond similarly to leptin and fasting.
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PMID:Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. 992 10

Abnormalities of plasma high density lipoprotein (HDL) levels commonly reflect altered metabolism of the major HDL apolipoproteins, apoA-I and apoA-II, but the regulation of apolipoprotein metabolism is poorly understood. Two mouse models of obesity, ob/ob and db/db, have markedly increased plasma HDL cholesterol levels. The purpose of this study was to evaluate mechanisms responsible for increased HDL in ob/ob mice and to assess potential reversibility by leptin administration. ob/ob mice were found to have increased HDL cholesterol (2-fold), apoA-I (1.3-fold), and apoA-II (4-fold). ApoA-I mRNA was markedly decreased (to 25% of wild-type) and apoA-II mRNA was unchanged, suggesting a defect in HDL catabolism. HDL apoprotein turnover studies using nondegradable radiolabels confirmed a decrease in catabolism of apoA-I and apoA-II and a 4-fold decrease in hepatic uptake in ob/ob mice compared with wild-type, but similar renal uptake. Low dose leptin treatment markedly lowered HDL cholesterol and apoA-II levels in both ob/ob mice and in lean wild-type mice, and it restored apoA-I mRNA to normal levels in ob/ob mice. These changes occurred without significant alteration in body weight. Moreover, ob/ob neuropeptide Y-/- mice, despite marked attenuation of diabetes and obesity phenotypes, showed no change in HDL cholesterol levels relative to ob/ob mice. Thus, increased HDL levels in ob/ob mice reflect a marked hepatic catabolic defect for apoA-I and apoA-II. In the case of apoA-I, this is offset by decreased apoA-I mRNA, resulting in apoA-II-rich HDL particles. The studies reveal a specific HDL particle catabolic pathway that is down-regulated in ob/ob mice and suggest that HDL apolipoprotein turnover may be regulated by obesity and/or leptin signaling.
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PMID:Increased high density lipoprotein (HDL), defective hepatic catabolism of ApoA-I and ApoA-II, and decreased ApoA-I mRNA in ob/ob mice. Possible role of leptin in stimulation of HDL turnover. 993 8

The neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus regulate and are regulated by short-term changes in energy homeostasis. Both outbred and inbred strains of rats that develop diet-induced obesity (DIO) or are diet resistant (DR) when fed a diet relatively high in energy, fat, and sucrose content (HE diet) were used to study arcuate NPY mRNA expression during long-term changes in energy balance. Outbred, chow-fed obesity-prone rats had 59% higher NPY levels than obesity-resistant rats. After 14 wk on HE diet, DIO rats had 17% lower NPY levels than DR rats made comparably obese on a highly palatable diet. When switched to chow, obese DR rats spontaneously reduced their intake and their body weights fell to control levels in association with a 10% decrease in NPY levels. DIO rats lost weight only with energy restriction associated with a 21% increase in their NPY levels. When again fed ad libitum, the weight and NPY levels in the rats returned to those of unrestricted DIO rats. Chow-fed, inbred DIO rats weigh more and are fatter than age-matched inbred DR rats. As with outbred DIO rats fed the HE diet, inbred DIO rats had 20% lower NPY levels than DR rats. Thus preobese, outbred DIO rats have high levels of NPY message that are not susceptible to metabolic regulation. When obesity develops in both inbred and outbred rats, the levels of NPY mRNA fall but become responsive to alterations in energy availability.
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PMID:Arcuate NPY neurons and energy homeostasis in diet-induced obese and resistant rats. 995 Sep 15

Leptin inhibits feeding and decreases body weight. It may act partly by inhibiting hypothalamic neurons that express neuropeptide Y, a powerful inducer of feeding and obesity. These neuropeptide Y neurons express the Ob-Rb leptin receptor and are overactive in the fatty (fa/fa) Zucker rat. The fa mutation affects the extracellular domain of the leptin receptor, but its impact on leptin action and neuropeptide Y neuronal activity is not fully known. We compared the effects of three doses of leptin given intracerebroventricularly and three doses of leptin injected intraperitoneally on food intake and hypothalamic neuropeptide Y mRNA, in lean and fatty Zucker rats. In lean rats, 4-h food intake was reduced in a dose-related fashion (P<0.01) by all intracerebroventricular leptin doses and by intraperitoneal doses of 300 and 600 microg/kg. Neuropeptide Y mRNA levels were reduced by 28% and 21% after the highest intracerebroventricular and intraperitoneal doses respectively (P<0. 01 for both). In fatty rats, only the highest intracerebroventricular leptin dose reduced food intake (by 22%; P<0. 01). Neuropeptide Y mRNA levels were 100% higher in fatty rats than in lean animals, and were reduced by 18% (P<0.01) after the highest intracerebroventricular leptin dose. Intraperitoneal injection had no effect on food intake and neuropeptide Y mRNA. The fa/fa Zucker rat is therefore less sensitive to leptin given intracerebroventricularly and particularly intraperitoneally, suggesting that the fa mutation interferes both with leptin's direct effects on neurons and its transport into the central nervous system. Obesity in the fa/fa Zucker rat may be partly due to the inability of leptin to inhibit hypothalamic neuropeptide Y neurons.
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PMID:Divergent effects of intracerebroventricular and peripheral leptin administration on feeding and hypothalamic neuropeptide Y in lean and obese (fa/fa) Zucker rats. 1002 67

The aim of this paper is to review the present knowledge of interactions between the neuropeptide Y (NPY) system and the hypothalamic-pituitary-adrenal (HPA) axis. On the basis of in vitro and in vivo studies of various animal species, we review the effects of NPY on all levels of HPA axis activity. We also describe the effects of glucocorticosteroids on the NPY system in the hypothalamus, including interactions between glucocorticosteroids and insulin. On the basis of available literature, we discuss the role of these interactions in the control of food intake and in the pathogenesis of obesity.
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PMID:Interactions between the neuropeptide Y system and the hypothalamic-pituitary-adrenal axis. 1006 55

The recent cloning of the ob gene (leptin) has revolutionized our understanding of obesity and the underlying factors that govern weight homeostasis. There is growing evidence that long term food intake regulation is controlled by the central nervous system by a number of peptide hormones in response to changes in leptin levels. Studies of these hormones, using both genetic and pharmacological approaches, have provided a foundation for decoding the molecular logic of the neuronal circuits which regulate food intake control and energy balance. A review of the current progress in the melanocortin-4 receptor pathway, with particular emphasis on its relation to leptin, neuropeptide Y and other obesity hormones known to modulate weight homeostasis, is presented.
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PMID:Melanocortin and leptin signaling systems: central regulation of catabolic energy balance. 1007 59

Maintenance of appropriate stores of metabolic fuels depends on carefully matching caloric intake to caloric expenditure. Achieving such 'energy balance' is a product of complex interactions of peripheral hormones with effector systems in the central nervous system (CNS) that regulate food intake and energy expenditure. Leptin is a hormone that is made in the adipocytes, circulates in the blood and interacts with receptors in the CNS. These receptors can be found in two different types of systems. One effector system is termed 'anabolic' and is activated by low levels of leptin during negative energy balance. This system (exemplified by the hypothalamic neuropeptide Y system) increases food intake and decreases energy expenditure to facilitate the regaining of lost energy stores. The other effector system is termed 'catabolic' and is activated by high levels of leptin during positive energy balance. This system (exemplified by the hypothalamic melanocortin and corticotrophin-releasing hormone systems) decreases food intake and increases energy expenditure to facilitate the loss of excess energy stores. Further understanding of these systems is necessary to develop adequate treatments for disorders of energy balance, such as obesity and wasting.
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PMID:Neuroendocrine regulation of food intake. 1010 53


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