Decreased food intake and body weight in pancreatic polypeptide-overexpressing mice

Ueno, Naohiko; Inui, Akio; Iwamoto, Masako; Kaga, Toshihiro; Asakawa, Akihiro; Okita, Misako; Fujimiya, Mineko; Nakajima, Yasunori; Ohmoto, Yasukazu; Ohnaka, Masaharu; Nakaya, Yutaka; Miyazaki, Jun‐ichi; Kasuga, Masato

doi:10.1016/s0016-5085(99)70293-3

Cited by 179 publications

(74 citation statements)

References 17 publications

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“…These effects may be the result of long-term elevations in plasma PP levels seen specifically in male Y2 Ϫ/Ϫ mice. This result is supported by findings that PP-overexpressing transgenic mice exhibit reductions in body weight, food intake, and fat mass (34). Furthermore, human obesity syndromes, as well as genetically obese ob͞ob mice, demonstrate reduced plasma levels of PP, whereas aspects of these obese phenotypes, including hyperphagia, are attenuated by exogenous PP administration (35)(36)(37).…”

Section: Discussionmentioning

confidence: 67%

“…Further evidence for a role of Y2 receptors in energy homeostasis comes from the finding that release of the catabolic alpha melanocyte-stimulating hormone (␣-MSH), and the expression of its precursor, proopiomelanocortin (POMC) mRNA within neurons of the Arc are strongly down-regulated by NPY (14,15). These effects are mimicked by NPY but not by the Y1͞Y5 agonist [L 31 ,P 34 ]NPY (14,15). The lack of a full complement of selective pharmacological tools for NPY receptors has made it difficult to determine which Y receptors are responsible for the effect of NPY on energy homeostasis.…”

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confidence: 99%

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Important role of hypothalamic Y2 receptors in body weight regulation revealed in conditional knockout mice

Sainsbury

Schwarzer

Couzens

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

225

204

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Neuropeptide Y is implicated in energy homeostasis, and contributes to obesity when hypothalamic levels remain chronically elevated. To investigate the specific role of hypothalamic Y2 receptors in this process, we used a conditional Y2 knockout model, using the Cre-lox system and adenoviral delivery of Cre-recombinase. Hypothalamus-specific Y2-deleted mice showed a significant decrease in body weight and a significant increase in food intake that was associated with increased mRNA levels for the orexigenic NPY and AgRP, as well as the anorexic proopiomelanocortin (POMC) and cocaine-and amphetamine-regulated transcript (CART) in the arcuate nucleus. These hypothalamic changes persisted until at least 34 days after Y2 deletion, yet the effect on body weight and food intake subsided within this time. Plasma concentrations of pancreatic polypeptide and corticosterone were 3-to 5-fold increased in hypothalamus-specific Y2 knockout mice. Germ-line Y2 receptor knockout also produced a significant increase in plasma levels of pancreatic polypeptide. However, these mice differed from conditional knockout mice in that they showed a sustained reduction in body weight and adiposity associated with increased NPY and AgRP but decreased POMC and CART mRNA levels in the arcuate nucleus. The transience of the observed effects on food intake and body weight in the hypothalamus-specific Y2 knockout mice, and the difference of this model from germ-line Y2 knockout mice, underline the importance of conditional models of gene deletion, because developmental, secondary, or extrahypothalamic mechanisms may mask such effects in germ-line knockouts.neuropeptide Y ͉ pancreatic polypeptide ͉ cre-lox ͉ arcuate nucleus N europeptide Y (NPY) in the hypothalamus is known to be a strong stimulus for food intake (1, 2), and induces many neuroendocrine and metabolic changes that favor energy storage. Such changes include decreased thermogenesis in brown adipose tissue, hyperinsulinemia, hypercorticosteronemia, and insulin hyperresponsiveness in white adipose tissue (3, 4). All of these neuroendocrine and metabolic effects of central NPY administration persist even when NPY-induced hyperphagia is prevented by pair-feeding (3, 4), demonstrating that hyperphagia is not the only mechanism by which central NPY increases adiposity.Although numerous other hormones and peptides act within the hypothalamus to regulate energy homeostasis, many exert an important component of their effects via actions on the hypothalamic NPY-ergic system (5-7), demonstrating the pivotal role of NPY in coordinating energy homeostasis. However, it is not clear which of the 5 cloned Y-receptors (Y1, Y2, Y4, Y5, and y6) are responsible for these effects (8).There is increasing evidence that Y2 receptors are involved in energy homeostasis. Over 80% of NPY-containing neurons in the arcuate nucleus (Arc) coexpress Y2 receptor mRNA (9). This presynaptic Y2 receptor has therefore been proposed to regulate the release of NPY (10, 11) and other colocalized neurotransmitters involved ...

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Section: Discussionmentioning

confidence: 67%

mentioning

confidence: 99%

Important role of hypothalamic Y2 receptors in body weight regulation revealed in conditional knockout mice

Sainsbury

Schwarzer

Couzens

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

225

204

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“…Importantly, PYY and PP levels are known to increase in response to food intake and they can act as satiety factors on specific Y-receptors in the brain 13,16,17,54,55 . A local increase in PYY or PP in the pancreatic islet would therefore also be very timely to counter-regulate the increase of insulin secretion postprandial.…”

Section: Discussionmentioning

confidence: 99%

Y1 receptor deficiency in β-cells leads to increased adiposity and impaired glucose metabolism

Loh

Shi

Bensellam

et al. 2018

Sci Rep

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Insulin secretion from pancreatic β-cells is critical for maintaining glucose homeostasis and deregulation of circulating insulin levels is associated with the development of metabolic diseases. While many factors have been implicated in the stimulation of insulin secretion, the mechanisms that subsequently reduce insulin secretion remain largely unexplored. Here we demonstrate that mice with β-cell specific ablation of the Y1 receptor exhibit significantly upregulated serum insulin levels associated with increased body weight and adiposity. Interestingly, when challenged with a high fat diet these β-cell specific Y1-deficient mice also develop hyperglycaemia and impaired glucose tolerance. This is most likely due to enhanced hepatic lipid synthesis, resulting in an increase of lipid accumulation in the liver. Together, our study demonstrates that Y1 receptor signaling negatively regulates insulin release, and pharmacological inhibition of Y1 receptor signalling for the treatment of non-insulin dependent diabetes should be taken into careful consideration.

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“…The mechanism by which peripheral administration of PP reduces food intake has been subject of research, but has not to been definitively determined [104]. Transgenic PP-overexpressing mice showed lower weight gain, with reduced food intake and fat mass than controls, which was more evident in male than in female mice [105].…”

Section: General Features Of Y 2 and Y 4 Receptorsmentioning

confidence: 99%

NPY Y2 and Y4 Receptors Selective Ligands: Promising Anti-Obesity Drugs?

Kamiji

Inui²

2007

CTMC

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Neuropeptide Y (NPY), a potent orexigen peptide widely produced and distributed in arcuate neurons in the hypothalamus, is a promising candidate for the control of appetitive ingestive behavior. In mammals, the signaling is mediated via at least five different cell surface receptors, denoted as Y(1), Y(2), Y(4), Y(5) and Y(6). Obesity is an important public health problem in the world, particularly in developed societies, and has taken on pandemic proportions. The therapeutics of obesity, including appetite suppressants, has increased 453% over the past decade, although issues concerning safety, efficacy, and little knowledge of the pharmacological activity result in the still modest effects of the anti-obesity drugs presently used. Ligands for Y receptors may be of benefit for the treatment of obesity, and recent findings have indicated a promising role of Y(2) and Y(4) in protecting against diet-induced obesity. This review highlights the supporting evidence therapeutic potential of Y(2) and Y(4) receptors antagonists as additional intervention to treat human obesity.

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Decreased food intake and body weight in pancreatic polypeptide-overexpressing mice

Cited by 179 publications

References 17 publications

Important role of hypothalamic Y2 receptors in body weight regulation revealed in conditional knockout mice

Important role of hypothalamic Y2 receptors in body weight regulation revealed in conditional knockout mice

Y1 receptor deficiency in β-cells leads to increased adiposity and impaired glucose metabolism

NPY Y2 and Y4 Receptors Selective Ligands: Promising Anti-Obesity Drugs?

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