Direct Sensing of Nutrients via a LAT1-like Transporter in Drosophila Insulin-Producing Cells

Manière, Gérard; Ziegler, Anna; Geillon, Flore; Featherstone, David E.; Grosjean, Yaël

doi:10.1016/j.celrep.2016.08.093

Cited by 52 publications

(72 citation statements)

References 58 publications

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“…IPCs project long axons onto the gut, heart and APCs to deliver their cargo, and receive input from a number of other cells in addition to their primary input of increased circulating nutrient concentration. As is the case for insulin secreted by pancreatic β-cells, feeding promotes Ilp expression and secretion from brain IPCs, although larval IPCs respond to elevated concentrations of protein (in particular the amino acid leucine) rather than sugar (Géminard et al, 2009;Ikeya et al, 2002;Maniere et al, 2016). Early genetic ablation studies targeting IPCs by expression of cell death effectors did not reveal major effects on obesity (Broughton et al, 2005;Rulifson et al, 2002).…”

Section: Neurosecretory Cellsmentioning

confidence: 99%

Drosophilaas a model to study obesity and metabolic disease

Musselman

Kühnlein

2018

Journal of Experimental Biology

179

130

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Excess adipose fat accumulation, or obesity, is a growing problem worldwide in terms of both the rate of incidence and the severity of obesity-associated metabolic disease. Adipose tissue evolved in animals as a specialized dynamic lipid storage depot: adipose cells synthesize fat (a process called lipogenesis) when energy is plentiful and mobilize stored fat (a process called lipolysis) when energy is needed. When a disruption of lipid homeostasis favors increased fat synthesis and storage with little turnover owing to genetic predisposition, overnutrition or sedentary living, complications such as diabetes and cardiovascular disease are more likely to arise. The vinegar fly Drosophila melanogaster (Diptera: Drosophilidae) is used as a model to better understand the mechanisms governing fat metabolism and distribution. Flies offer a wealth of paradigms with which to study the regulation and physiological effects of fat accumulation. Obese flies accumulate triacylglycerols in the fat body, an organ similar to mammalian adipose tissue, which specializes in lipid storage and catabolism. Discoveries in Drosophila have ranged from endocrine hormones that control obesity to subcellular mechanisms that regulate lipogenesis and lipolysis, many of which are evolutionarily conserved. Furthermore, obese flies exhibit pathophysiological complications, including hyperglycemia, reduced longevity and cardiovascular functionsimilar to those observed in obese humans. Here, we review some of the salient features of the fly that enable researchers to study the contributions of feeding, absorption, distribution and the metabolism of lipids to systemic physiology.

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Section: Neurosecretory Cellsmentioning

confidence: 99%

Drosophilaas a model to study obesity and metabolic disease

Musselman

Kühnlein

2018

Journal of Experimental Biology

179

130

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“…The identification of LHLK neurons as being active under starvation conditions and suppressed by glucose provide a system to investigate feeding-state dependent changes in neural activity. A number of neurons in the fly brain are acutely regulated by feeding state including the starvation-active Taotie neurons that inhibit insulin producing cells (IPCs) of the pars intercerebralis to regulate insulin-like peptide release under nutrient deprivation conditions [70–72]. Conversely the IPCs, which are cell autonomous nutrient sensors themselves, are activated by glucose through the inhibition of K ATP channels, supporting the notion that ingested nutrients are directly sensed by neurons [73].…”

Section: Discussionmentioning

confidence: 99%

A single pair of leucokinin neurons are modulated by feeding state and regulate sleep-metabolism interactions

Yurgel

Kakad

Zandawala

et al. 2018

Preprint

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1Dysregulation of sleep and feeding has widespread health consequences. Despite 2 extensive epidemiological evidence for interactions between sleep and metabolic 3 function, little is known about the neural or molecular basis underlying the integration of 4 these processes. Drosophila melanogaster potently suppress sleep in response to 5 starvation, and powerful genetic tools allow for mechanistic investigation of sleep-6 metabolism interactions. We have previously identified neurons expressing the 7 neuropeptide leucokinin (Lk) as being required for starvation-mediated changes in sleep. 8Here, we demonstrate an essential role for Lk neuropeptide in metabolic regulation of 9 sleep. Further, we find that the activity of Lk neurons is modulated by feeding state and 10 circulating nutrients, with reduced activity in response to glucose and increased activity 11 under starvation conditions. Both genetic silencing and laser-mediated microablation 12 localize Lk-mediated sleep regulation to a single pair of Lk neurons within the lateral 13 horn (LHLK) that project near primary sleep and metabolic centers of the brain. A 14 targeted screen identified a critical role for AMP-activated protein kinase (AMPK) in 15 starvation-modulated changes in sleep. Disruption of AMPK function in Lk neurons 16 suppresses sleep and increases LHLK activity in fed flies, phenocopying the starvation 17 state. Taken together, these findings localize feeding state-dependent regulation of 18 sleep to a single pair of neurons within the fruit fly brain and provide a system for 19 investigating the cellular basis of sleep-metabolism interactions. 20 21 Introduction 1 Dysregulation of sleep and feeding has widespread health consequences and reciprocal 2 interactions between these processes underlie a number of pathologies [1-4]. Sleep loss 3 correlates with increased appetite and insulin insensitivity, while short-sleeping 4 individuals are more likely to develop obesity, metabolic syndrome, type II diabetes, and 5 cardiovascular disease [1,3,4]. Although the neural basis for sleep regulation has been 6 studied in detail, little is known about how feeding state and changes in metabolic 7 function modulate sleep [5,6]. Understanding how sleep and feeding states are 8 integrated may provide novel insights into the co-morbidity of disorders linked to sleep 9 and metabolic regulation.10 Animals balance nutritional state and energy expenditure in order to achieve metabolic 11 homeostasis [7,8]. In both flies and mammals, diet potently affects sleep regulation, 12 strengthening the idea that sleep and metabolic state interact [5,6,9]. Starvation leads to 13 sleep loss, or disrupted sleep architecture, presumably to induce foraging behavior, 14 while high-calorie diets have complex effects on sleep depending on macronutrient 15 content [10-13]. Behavioral and physiological responses to changes in feeding state are 16 modulated both by cell autonomous nutrient centers in the brain that sense changes in 17 circulating nutrients and through communication b...

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“…Conversely, shortly after feeding on protein-rich diet, the insulin-producing cells (IPCs) in the fly brain are activated and exert robust suppressive effect on protein feeding (Liu et al, 2015; Wu et al, 2005). The activation of IPCs after protein intake is directly mediated by circulating L-Leucine (L-Leu) via a leucine transporter minidiscs (MND) and glutamate dehydrogenase (GDH) (Manière et al, 2016), and indirectly mediated by a fat body derived satiety hormone named female-specific independent of transformer (FIT) (Sun et al, 2017). In addition, flies rapidly detect and reject food sources lacking one or more essential amino acids (essential amino acid deficiency, EAAD), which is regulated by a different set of dopaminergic neurons (Bjordal et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

An internal sensor detects dietary amino acids and promotes food consumption in Drosophila

Yang

Huang

et al. 2017

Preprint

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Adequate protein intake is crucial for animals. Despite the recent progress in understanding protein hunger and satiety in the fruit fly Drosophila melanogaster, how fruit flies assess prospective dietary protein sources and ensure protein consumption remains elusive. We show here that three specific amino acids, L-glutamate (L-Glu), L-alanine (L-Ala), and L-aspartate (L-Asp), rapidly promote food consumption in fruit flies when present in food. The effect of dietary amino acids to promote food consumption is independent of mating experience and internal nutritional status. Genetic analysis identifies six brain neurons expressing diuretic hormone 44 (DH44) as a sensor of dietary amino acids. DH44 + neurons can be directly activated by these three amino acids, and are both necessary and sufficient for dietary amino acids to promote food consumption. By conducting single cell RNAseq analysis, we also identify an amino acid transporter, CG13248, which is highly expressed in DH44 + neurons and is required for dietary amino acids to promote food consumption. Therefore, these data suggest that dietary amino acids may enter DH44 + neurons via CG13248 and modulate their activity and hence food consumption.Taken together, these data identify an internal amino acid sensor in the fly brain that evaluate food sources post-ingestively and facilitates adequate protein intake.

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Direct Sensing of Nutrients via a LAT1-like Transporter in Drosophila Insulin-Producing Cells

Cited by 52 publications

References 58 publications

Drosophilaas a model to study obesity and metabolic disease

Drosophilaas a model to study obesity and metabolic disease

A single pair of leucokinin neurons are modulated by feeding state and regulate sleep-metabolism interactions

An internal sensor detects dietary amino acids and promotes food consumption in Drosophila

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