Attenuation of the Obesity Syndrome of
            <i>ob/ob</i>
            Mice by the Loss of Neuropeptide Y

Erickson, Jay C.; Hollopeter, Gunther; Palmiter, Richard D.

doi:10.1126/science.274.5293.1704

Cited by 780 publications

(468 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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“…Results from diverse molecular and genetic paradigms are consistent with the implication that NPY, in concert with co-expressed orexigenic AgrP, GABA and adrenergic transmitters, constitutes an obligatory orexigenic signaling modality that is intimately involved in propagation of the timely appetitive drive under the direction of photoperiodic and hormonal cues (7,11,(27)(28)(29)47,(49)(50)(51)54,(56)(57)(58)(59). Additional recent disclosures that the hard wiring for the timely operation of this interplay is established during postnatal development have put the notion that NPY is a physiological appetite transducer on firm footing (11,(28)(29)(30)49,64).…”

Section: Is Npy a Naturally Occurring Appetite Transducer?supporting

confidence: 56%

To subjugate NPY is to improve the quality of life and live longer

Kalra

2007

Peptides

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The interactive network of Neuropeptide Y (NPY) and cohorts is necessary for integrating the hypothalamic regulation of appetite and energy expenditure with the endocrine and neuroendocrine systems on a daily basis. Genetic and environmental factors that produce an insufficiency of leptin restraint on NPY and cognate receptors deregulate the homeostasis to engender various lifethreatening risk factors. Recent studies from our laboratory show that neurotherapy consisting of a single central administration of recombinant adeno-associated virus vector encoding the leptin gene can repress the hypothalamic NPY system for the lifetime of rodents. A major benefit of this stable tonic restraint is deceleration of pathophysiologic sequalae that shorten life span. These include suppression of weight gain, fat accumulation, circulating adipokines, amelioration of major symptoms of metabolic syndrome, improved reproduction and bone health. Thus, sustained repression of NPY signaling in the hypothalamus by leptin transgene expression can improve the quality of life and extend longevity.

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“…15,16 Leptin, a signal of body adiposity, may promote longitudinal skeletal growth, since leptin-deficient obese (ob/ob) and diabetic (db/db) mice, with disrupted leptin signalling, display reduced linear growth. 17 Leptin may achieve this effect via direct effects on cartilage and bone 18,19 and also via CNS regulation of the somatotrophic axis. Several rodent studies have shown that chronic CNS administration of the potent orexigenic signal neuropeptide Y (NPY) inhibits the growth axis, 20,21 supporting a role for NPY in mediating linear growth.…”

Section: Introductionmentioning

confidence: 99%

Abnormalities of the somatotrophic axis in the obese agouti mouse

et al. 2005

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Objective: Abnormalities of the melanocortin system produce obesity and increased linear growth. While the obesity phenotype is well characterised, the mechanism responsible for increased linear growth is unclear. The somatotrophic axis was studied in the obese agouti (A y /a) mouse as a model of a perturbed melanocortin system. Design: Adult obese A y /a mice were compared to age-and sex-matched wild-type (WT) controls. Weight and body length (nose-anus) were recorded. Plasma growth hormone (GH), insulin-like growth factor-I (IGFI), insulin and leptin were measured using radioimmunoassay. Since ghrelin is a potent GH secretagogue, plasma ghrelin, stomach ghrelin peptide and stomach ghrelin mRNA expression were studied. Hypothalamic periventricular (PeVN) somatostatin neurones and arcuate (Arc) neuropeptide Y (NPY) neurones inhibit the growth axis, whereas Arc growth hormone-releasing hormone (GHRH) neurones are stimulatory. Therefore, specific hypothalamic expression of somatostatin, NPY and GHRH was measured using quantitative in situ hybridisation. Results: Obese A y /a mice were significantly heavier and longer than WT controls. Plasma IGFI concentrations were 30% greater in obese A y /a mice. Obese A y /a mice were hyperinsulinaemic and hyperleptinaemic, yet plasma ghrelin, and stomach ghrelin peptide and mRNA were significantly reduced. In obese A y /a mice, PeVN somatostatin and Arc NPY mRNA expression were reduced by 50% compared to WT controls, whereas Arc GHRH mRNA expression was unchanged. Conclusion: Increased body length in adult obese A y /a mice may result from reduced Arc NPY and PeVN somatostatin mRNA expression, which in turn, may increase plasma IGFI concentrations and upregulate the somatotrophic axis.

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Attenuation of the Obesity Syndrome of ob/ob Mice by the Loss of Neuropeptide Y

Cited by 780 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

To subjugate NPY is to improve the quality of life and live longer

Abnormalities of the somatotrophic axis in the obese agouti mouse

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