Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y

Erickson, Jay C.; Clegg, Kathy E.; Palmiter, Richard D.

doi:10.1038/381415a0

Cited by 957 publications

(516 citation statements)

References 26 publications

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“…This was a surprising finding as it has previously been reported, and corroborated, although not significantly in both sexes in this particular study cohort, that DYNΔ mice actually display an antiobesity effect through decreased visceral and subcutaneous adiposity levels (Sainsbury et al, 2007). Moreover, NPY knockout mice have previously been shown to exhibit either unchanged food intake (Erickson et al, 1996a andHill andLevine, 2003), as well as unaltered body weight and/or adiposity levels (Erickson et al, 1996a andZengin et al, 2013), or in some circumstances, including leptin deficiency (Erickson et al, 1996b), reductions in fat mass (Baldock et al, 2009 andZengin et al, 2013). Indeed, in our current cohort of NPY knockout mice we observed no significant change from wildtype with respect to body weight or adiposity.…”

Section: Discussionsupporting

confidence: 89%

Double deletion of orexigenic neuropeptide Y and dynorphin results in paradoxical obesity in mice

et al. 2014

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ObjectiveOrexigenic neuropeptide Y (NPY) and dynorphin (DYN) regulate energy homeostasis. Single NPY or dynorphin deletion reduces food intake or increases fat loss. Future developments of obesity therapeutics involve targeting multiple pathways. We hypothesised that NPY and dynorphin regulate energy homeostasis independently, thus double NPY and dynorphin ablation would result in greater weight and/or fat loss than the absence of NPY or dynorphin alone. Design and methodsWe generated single and double NPY and dynorphin knockout mice (NPYΔ, DYNΔ, NPYDYNΔ) and compared body weight, adiposity, feeding behaviour, glucose homeostasis and brown adipose tissue uncoupling protein-1 (UCP-1) expression to wildtype counterparts. Results Body weight and adiposity were significantly increased in NPYDYNΔ, but not in NPYΔ or DYNΔ. This was not due to increased food intake or altered UCP-1 expression, which were not significantly altered in double knockouts. NPYDYNΔ mice demonstrated increased body weight loss after a 24-h fast, with no effect on serum glucose levels after glucose injection. Conclusions Contrary to the predicted phenotype delineated from single knockouts, double NPY and dynorphin deletion resulted in heavier mice, with increased adiposity, despite no significant changes in food intake or UCP-1 activity. This indicates that combining long-term opioid antagonism with blockade of NPY-ergic systems may not produce anti-obesity effects.

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Section: Discussionsupporting

confidence: 89%

Double deletion of orexigenic neuropeptide Y and dynorphin results in paradoxical obesity in mice

et al. 2014

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“…Y2 receptors mediate the inhibitory effects of NPY on, amongst others, ion excretion in the rat small intestine, adrenaline release in the mesenteric arteries and bronchial contraction in guinea pig. One of the most important activities of the neurohormone -as shown with NPY knock-out mice is the control of neural excitability, because it suppresses glutamate release from neurons in the hippocampus [6]. Furthermore, elevation of memory retention of rats and modulation of other neurotransmitters have been reported (for recent reviews, see [4,7,8]).…”

Section: Introductionmentioning

confidence: 99%

Modified, cyclic dodecapeptide analog of neuropeptide Y is the smallest full agonist at the human Y₂ receptor

et al. 1996

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In order to stabilize the C-terminal dodecapeptide of neuropeptide Y (NPY) we replaced Leu 2s and Thr 32 by Lys and Glu, respectively, and subsequently linked these residues by lactamization. This peptide analog of NPY shows a more than 100-fold increase in affinity compared to the C-terminal linear dodecapeptide in receptor binding studies performed at human neuroblastoma cells SMS-KAN, which exclusively express the Y2 receptor subtype.2+ Signal transduction was investigated" by measuring Ca current inhibition in human SH-SY5Y cells and cyclic [Lys2S-Glu3Z] NPY Ac-25-36 and NPY were shown to be equipotent in this assay. Thus, this molecule is the smallest Y2 receptor selective full agonist of NPY. Using 2D-NMR experiments and molecular modelling techniques, the structures of the linear and cyclic peptides have been investigated and significant differences have been found, which may explain the improvement in biological activity. Thus, a model of the bioactive conformation of NPY at the human Yz receptor is suggested.

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“…For example, NPY À/À and Y1-R À/À mice are not hypophagic, [157][158][159][160] although this may be dependent on the background strain of the mouse studied. Nevertheless, other lines of evidence indicate that such discrepancies do not diminish the potential therapeutic efficacy of NPYergic agents.…”

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confidence: 99%

Body weight is regulated by the brain: a link between feeding and emotion

2005

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Regulated energy homeostasis is fundamental for maintaining life. Unfortunately, this critical process is affected in a high number of mentally ill patients. Eating disorders such as anorexia nervosa are prevalent in modern societies. Impaired appetite and weight loss are common in patients with depression. In addition, the use of neuroleptics frequently produces obesity and diabetes mellitus. However, the neural mechanisms underlying the pathophysiology of these behavioral and metabolic conditions are largely unknown. In this review, we first concentrate on the established brain machinery of food intake and body weight, especially on the melanocortin and neuropeptide Y (NPY) systems as illustration. These systems play a critical role in receiving and processing critical peripheral metabolic cues such as leptin and ghrelin. It is also notable that both systems modulate emotion and motivated behavior as well. Secondly, we discuss the significance and potential promise of multidisciplinary molecular and neuroanatomic techniques that will likely increase the understanding of brain circuitries coordinating energy homeostasis and emotion. Finally, we introduce several lines of evidence suggesting a link between the melanocortin/NPY systems and several neurotransmitter systems on which many of the psychotropic agents exert their influence. Maintaining energy homeostasis is fundamental for survival. However, obesity due to over-nutrition is an increasing worldwide public health problem. 1 In psychiatric practice, on the other hand, impaired appetite is one of the crucial issues. Anorexia and weight loss are common, for example, in patients suffering from depression. Eating disorders are medically intractable and life threatening. In addition, the so-called 'atypical' antipsychotic agents, currently and widely used to treat psychoses, often induce hyperphagia, obesity, and diabetes mellitus. [2][3][4] In the past decade, fortunately, there has been remarkable progress in understanding the molecular mechanisms of food intake and body weight. This is due in large part to increased research activity towards combating the rising incidences of obesity and associated metabolic disorders. As a result, it is now established that the central nervous system (CNS) senses and processes peripheral metabolic cues including leptin 5 and ghrelin, 6,7 resulting in coordinated energy homeostasis. However, the pathophysiology of the disequilibrium between energy intake and expenditure in psychiatric disorders remains largely unknown. Nevertheless, evidence suggests that several CNS systems regulating energy balance may be dysregulated in patients with mental illnesses, for example, eating disorders, and drug addiction. [8][9][10][11][12][13][14] In the current review, we will illustrate the neuroanatomic and molecular genetic aspects of the melanocortin and neuropeptide Y (NPY) systems residing in the CNS downstream of leptin and ghrelin, to discuss the neural bases of feeding, metabolism, and emotion. Additionally, we point the reader to...

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Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y

Cited by 957 publications

References 26 publications

Double deletion of orexigenic neuropeptide Y and dynorphin results in paradoxical obesity in mice

Double deletion of orexigenic neuropeptide Y and dynorphin results in paradoxical obesity in mice

Modified, cyclic dodecapeptide analog of neuropeptide Y is the smallest full agonist at the human Y₂ receptor

Body weight is regulated by the brain: a link between feeding and emotion

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Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y

Cited by 957 publications

References 26 publications

Double deletion of orexigenic neuropeptide Y and dynorphin results in paradoxical obesity in mice

Double deletion of orexigenic neuropeptide Y and dynorphin results in paradoxical obesity in mice

Modified, cyclic dodecapeptide analog of neuropeptide Y is the smallest full agonist at the human Y2 receptor

Body weight is regulated by the brain: a link between feeding and emotion

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Modified, cyclic dodecapeptide analog of neuropeptide Y is the smallest full agonist at the human Y₂ receptor