Chronic administration of neuropeptide Y into the lateral ventricle of C57BL/6J male mice produces an obesity syndrome including hyperphagia, hyperleptinemia, insulin resistance, and hypogonadism

Raposinho, Paula; Pierroz, D. D.; Broqua, Pierre; White, Richard; Pedrazzini, Thierry; Aubert, Michel L.

doi:10.1016/s0303-7207(01)00620-7

Cited by 135 publications

(81 citation statements)

References 40 publications

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“…Increased central NPY-ergic tone elicits robust hyperphagia and induces a series of obesogenic changes that lead to gain of body weight and fat. [1][2][3][4][5][6] These obesefying changes include decreases in body temperature and thermogenetic capacity in brown adipose tissue 5,[7][8][9][10] Findicative of decreased energy expenditure, glucose partitioning towards storage rather than utilization, 2,11 increased lipogenic activity in white adipose tissue and liver, 7,8,12 and increased respiratory exchange ratio (RER) [13][14][15] Findicative of a higher preference for carbohydrate versus lipid as a fuel source. Importantly, when NPY-induced hyperphagia is prevented by pair feeding, central administration of NPY for 5-7 days in rodents still leads to significant fat gain without changes in body weight, 2,12 showing an important function of NPY in increasing adiposity independent of changes in food intake and body weight.…”

Section: Introductionmentioning

confidence: 99%

Peripheral neuropeptide Y Y1 receptors regulate lipid oxidation and fat accretion

et al. 2009

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Objective: Neuropeptide Y and its Y receptors are important players in the regulation of energy homeostasis. However, while their functions in feeding regulation are well recognized, functions in other critical aspects of energy homeostasis are largely unknown. To investigate the function of Y1 receptors in the regulation of energy homeostasis, we examined energy expenditure, physical activity, body composition, oxidative fuel selection and mitochondrial oxidative capacity in germline Y1 À/À mice as well as in a conditional Y1-receptor-knockdown model in which Y1 receptors were knocked down in peripheral tissues of adult mice. Results: Germline Y1À/À mice of both genders not only exhibit a decreased respiratory exchange ratio, indicative of increased lipid oxidation, but interestingly also develop late-onset obesity. However, the increased lipid oxidation is a primary effect of Y1 deletion rather than secondary to increased adiposity, as young Y1 À/À mice are lean and show the same effect. The mechanism behind this is likely because of increased liver and muscle protein levels of carnitine palmitoyltransferase-1 (CPT-1) and maximal activity of key enzymes involved in b-oxidation; b-hydroxyacyl CoA dehydrogenase (bHAD) and medium-chain acyl-CoA dehydrogenase (MCAD), leading to increased mitochondrial capacity for fatty acid transport and oxidation. These effects are controlled by peripheral Y1-receptor signalling, as adult-onset conditional Y1 knockdown in peripheral tissues also leads to increased lipid oxidation, liver CPT-1 levels and bHAD activity. Importantly, these mice are resistant to diet-induced obesity. Conclusions: This work shows the primary function of peripheral Y1 receptors in the regulation of oxidative fuel selection and adiposity, opening up new avenues for anti-obesity treatments by targeting energy utilization in peripheral tissues rather than suppressing appetite by central effects.

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Section: Introductionmentioning

confidence: 99%

Peripheral neuropeptide Y Y1 receptors regulate lipid oxidation and fat accretion

et al. 2009

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“…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. ob/ob mice deficient in NPY have increased body length and hepatic IGFI mRNA compared to NPY-expressing ob/obs, which exhibit increased Arc NPY mRNA expression.…”

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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“…ICV infusion of a melanocortin antagonist (SHU9119) does not affect the ability of hyperinsulinemia to inhibit EGP, which suggests that the POMC pathway is not involved in the acute effects of insulin on hepatic fuel flux (3). In regard to the other major insulinsensitive neural route, it was reported that subchronic ICV infusion of NPY in Sprague-Dawley rats and mice induces hyperinsulinemia, hyperglycemia, and dyslipidemia (6,7). These findings led us to hypothesize that downregulation of central (hypothalamic) NPY neuronal activities by insulin is critical for its ability to control EGP and lipid production.…”

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confidence: 99%

Intracerebroventricular Neuropeptide Y Infusion Precludes Inhibition of Glucose and VLDL Production by Insulin

et al. 2004

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Recent evidence demonstrates that hypothalamic insulin signaling is required for inhibition of endogenous glucose production. The downstream mechanisms that are responsible for the effects of hypothalamic insulin receptor activation on hepatic fuel flux remain to be determined. To establish whether downregulation of neuropeptide Y (NPY) release by insulin is mandatory for its capacity to suppress glucose production, we examined the effects of a continuous intracerebroventricular (ICV) infusion of NPY (10 g/h for 3-5 h) on glucose flux during a hyperinsulinemic-euglycemic clamp in mice. We also evaluated the effects of ICV NPY administration on free fatty acid and glycerol flux and VLDL production in this experimental context. In basal conditions, none of the metabolic parameters was affected by NPY infusion. In hyperinsulinemic conditions, peripheral glucose disposal was not different between vehicle-and NPY-infused animals. In contrast, hyperinsulinemia suppressed endogenous glucose production by ϳ8% vs. 30% in NPY-vs. vehicle-infused mice, respectively (P < 0.05). Also, VLDL production was significantly higher during hyperinsulinemia in NPYcompared with vehicle-infused mice (97.5 ؎ 18.0 vs. 54.7 ؎ 14.9 mol ⅐ kg ؊1 ⅐ h ؊1 ; P < 0.01). These data suggest that the neurophysiological action of insulin to downregulate hypothalamic NPY release is a prerequisite for its ability to suppress hepatic fuel production, whereas it is not mandatory for its capacity to modulate glucose disposal or lipolysis. Diabetes 53:2529 -2534, 2004 I nsulin resistance is an important characteristic of obesity and type 2 diabetes (1,2). It hampers proper suppression of endogenous glucose and VLDL production in response to food intake. Accordingly, the metabolic features of obesity and type 2 diabetes include hyperglycemia and hypertriglyceridemia.It was shown recently that hypothalamic insulin signaling is required for inhibition of endogenous glucose production (EGP) (3). Indeed, intracerebroventricular (ICV) infusion of insulin can suppress glucose production (by 40%) in the presence of basal circulating insulin concentrations, whereas antagonism of insulin signaling or downregulation of insulin receptor expression in hypothalamic nuclei considerably impairs the ability of circulating insulin to inhibit EGP (3,4).The downstream mechanisms that are responsible for the apparent impact of hypothalamic insulin receptor activation on hepatic fuel flux remain to be established. The arcuate nucleus of the hypothalamus is a major target of insulin in the brain. This nucleus contains two insulinsensitive populations of neurons that exert powerful, opposing effects on fuel flux: pro-opiomelanocortin (POMC) neurons (stimulated by insulin), guiding a catabolic adaptive response to environmental cues, and NPY neurons (inhibited by insulin) that primarily promote anabolic adaptations (5). ICV infusion of a melanocortin antagonist (SHU9119) does not affect the ability of hyperinsulinemia to inhibit EGP, which suggests that the POMC pathway is not inv...

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Chronic administration of neuropeptide Y into the lateral ventricle of C57BL/6J male mice produces an obesity syndrome including hyperphagia, hyperleptinemia, insulin resistance, and hypogonadism

Cited by 135 publications

References 40 publications

Peripheral neuropeptide Y Y1 receptors regulate lipid oxidation and fat accretion

Peripheral neuropeptide Y Y1 receptors regulate lipid oxidation and fat accretion

Abnormalities of the somatotrophic axis in the obese agouti mouse

Intracerebroventricular Neuropeptide Y Infusion Precludes Inhibition of Glucose and VLDL Production by Insulin

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