Minibrain/Dyrk1a regulates food intake through the Sir2-FOXO-sNPF/NPY pathway in Drosophila and mammals

Aging Research Centre, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
PLoS Genetics (Impact Factor: 7.53). 08/2012; 8(8):e1002857. DOI: 10.1371/journal.pgen.1002857
Source: PubMed


Author Summary
Feeding behavior is one of the most essential activities in animals. Abnormal feeding behaviors cause metabolic syndromes including obesity and diabetes. Neuropeptides regulate feeding behavior in animals from nematode to human. Here, we presented molecular genetic evidences of how neuropeptides regulate food intake using fruit fly and mouse model systems. Drosophila short neuropetide F (sNPF) and the mammalian functional homolog neuropeptide Y (NPY) are produced from neurons in the brain of fruit fly and mouse, respectively. These neuropeptides turned on the minibrain, in mammals also called Dyrk1a, a target gene through the PKA-CREB pathway. Then, this Mnb/Dyrk1a enzyme activated Sir2/Sirt1 enzyme, which activated FOXO transcriptional factor, turning on the expression of a sNPF/NPY target gene. The increased sNPF/NPY increased food intake in fruit flies and mice. On the contrary, increased food intake induced insulin and activated insulin signaling. When insulin signaling is activated, FOXO transcriptional factor inhibited expression of a sNPF/NPY target gene. The inhibited sNPF/NPY reduced food intake. These findings indicate that FOXO transcription factor acts as a gatekeeper for fasting–feeding transition by regulating sNPF/NPY expression in Drosophila and mammals.

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Available from: Woo-Joo Song, Oct 06, 2015
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    • "Short neuropeptide F (sNPF) has been shown to modulate feeding behavior in a wide variety of insect species. While this peptide stimulates feeding and food-searching behavior in Drosophila melanogaster (Hong et al. 2012) and Apis mellifera (Hummon et al. 2006), an opposite effect has recently been demonstrated in the desert locust, Schistocerca gregaria (Dillen et al. 2014) and P. americana (Mikani et al. 2012). "
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    ABSTRACT: Immunohistochemical reactivities against short neuropeptide F (sNPF-ir) and crustacean cardioactive peptide (CCAP-ir) were detected in both the brain-subesophageal ganglion (Br-SOG) and midgut epithelial cells of the male American cockroach, Periplaneta americana. Four weeks of starvation increased the number of sNPF-ir cells and decreased the CCAP-ir cells in the Br-SOG, whereas refeeding reversed these effects. The contents of sNPF in the Br-SOG, midgut and hemolymph titer decreased in response to an injection of CCAP into the hemocoel of normally fed male cockroaches, while CCAP titers/contents decreased in response to an injection of sNPF. The results of a double-labeling experiment demonstrated that sNPF-ir co-existed in CCAP-ir cells in the pars intercerebralis (PI), dorsolateral region of protocerebrum (DL), deutocerebrum (De) and SOG. sNPF-ir and CCAP-ir were also colocalized in the midgut. sNPF and CCAP are neuropeptides and midgut factors that interact with each other. Since the two peptides are known to be secreted by identical cells that affect each other, this constitutes autocrine negative feedback regulation for a quick response to food accessibility/inaccessibility. These peptides not only constitute the switch in the digestive mechanism but also couple digestive adaptation with behavior. A CCAP injection suppressed locomotor activity when cockroaches were starved, whereas sNPF activated it when they were fed.
    Cell and Tissue Research 07/2015; DOI:10.1007/s00441-015-2242-4 · 3.57 Impact Factor
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    • "Sir2 knock-down resulted in a slight elevation of food consumption. In contrast, other studies reported that effects of Sirt1/Sir2 or downstream signalling events in the brain on food intake reduce food intake in mammals and Drosophila (Dietrich et al. 2010; Hong et al. 2012). The apparent discord could be a species-specific effect or related to the fact that the background diet we used was the one that supported maximum lifespan, but this is an observation that is currently difficult to reconcile with these other findings without further investigation. "
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    ABSTRACT: Dietary essential amino acids have an important influence on the lifespan and fitness of animals. The expression of the NAD+-dependent histone deacetylase, Sir2, can be influenced by diet, but its role in the extension of lifespan has recently been challenged. Here, we used the honeybee to test how the dietary balance of carbohydrates and essential amino acids and/or Sir2 affected lifespan. Using liquid diets varying in their ratio of essential amino acids to carbohydrate (EAA:C), we found that adult worker bees fed diets high in essential amino acids (≥1:10) had shorter lifespans than bees fed diets containing low levels of dietary amino acids. Bees fed a 1:500 EAA:C diet lived longer and, in contrast to bees fed any of the other diets, expressed Sir2 at levels tenfold higher or more than bees fed a 1:5 EAA:C diet. When bees were fed the 1:500 diet, small interfering RNA (siRNA)-mediated knock-down of Sir2 expression shortened lifespan but did not reduce survival to the same extent as the 1:5 diet, indicating that Sir2 contributes to mechanisms that determine lifespan in response to differences in macronutrient intake but is not the sole determinant. These data show that the ratio of dietary amino acids to carbohydrate influences Sir2 expression and clearly demonstrate that Sir2 is one of the factors that can determine honeybee lifespan. We propose that effects of dietary amino acids and Sir2 on lifespan may depend on the simultaneous activation of multiple nutrient sensors that respond to relative levels of essential amino acids and carbohydrates. Electronic supplementary material The online version of this article (doi:10.1007/s11357-014-9649-9) contains supplementary material, which is available to authorized users.
    Age 04/2014; 36(3). DOI:10.1007/s11357-014-9649-9 · 3.45 Impact Factor
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    • "The mechanism for how SIRT1 regulates the feeding response to caloric restriction is attributed to the deacetylation of FOXO and may also affect mTOR/S6K signaling (Cakir et al., 2009). SIRT1 also modulates the response to NPY, a neurotransmitter that increases food intake, by activating FOXO in response to phosphorylation by minibrain/Dyrk1a kinase (Hong et al., 2012). SIRT1 is also a critical mediator of the response to ghrelin, a peptide hormone that stimulates food intake. "
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    ABSTRACT: Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent deacylases that have traditionally been linked with calorie restriction and aging in mammals. These proteins also play an important role in maintaining neuronal health during aging. During neuronal development, the SIR2 ortholog SIRT1 is structurally important, promoting axonal elongation, neurite outgrowth, and dendritic branching. This sirtuin also plays a role in memory formation by modulating synaptic plasticity. Hypothalamic functions that affect feeding behavior, endocrine function, and circadian rhythmicity are all regulated by SIRT1. Finally, SIRT1 plays protective roles in several neurodegenerative diseases including Alzheimer's, Parkinson's, and motor neuron diseases, which may relate to its functions in metabolism, stress resistance, and genomic stability. Drugs that activate SIRT1 may offer a promising approach to treat these disorders.
    Neuron 02/2014; 81(3):471-483. DOI:10.1016/j.neuron.2014.01.028 · 15.05 Impact Factor
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