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Pregnancy Timeline by SemestersDevelopmental TimelineFertilizationFirst TrimesterSecond TrimesterThird TrimesterFirst Thin Layer of Skin AppearsEnd of Embryonic PeriodEnd of Embryonic PeriodFemale Reproductive SystemBeginning Cerebral HemispheresA Four Chambered HeartFirst Detectable Brain WavesThe Appearance of SomitesBasic Brain Structure in PlaceHeartbeat can be detectedHeartbeat can be detectedFinger and toe prints appearFinger and toe prints appearFetal sexual organs visibleBrown fat surrounds lymphatic systemBone marrow starts making blood cellsBone marrow starts making blood cellsInner Ear Bones HardenSensory brain waves begin to activateSensory brain waves begin to activateFetal liver is producing blood cellsBrain convolutions beginBrain convolutions beginImmune system beginningWhite fat begins to be madeHead may position into pelvisWhite fat begins to be madePeriod of rapid brain growthFull TermHead may position into pelvisImmune system beginningLungs begin to produce surfactant
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Stop eating! You are full!

Research has identified in flies, a molecule sent by fat cells to the fly brain to say the fly has eaten enough and to stop feeding. Because fruit flies replicate many of our human feeding-related mechanisms, as well as genes, they are a good model in finding out about our own bodies.

Fat is our primary energy storing molecule. Controlling the level of fat in our bodies is critical to our survival as it is to all animals. When we experience a loss of fat, the hormone leptin induces us to eat to make up for that loss. But so far, no signal has ever been identified in any animal that inhibits eating in response to fat gain. Until now.

This latest study began by focusing on short non-coding RNAs — or microRNAs — because microRNAs are well-known for inhibiting genes in producing proteins. Researchers first looked for microRNAs that appear abundant in fat bodies (small white structures in the body of an animal, especially an insect, that store fats) especially those that affect feeding behavior. Secondly, they looked for the genes targeted by these microRNAs.

Researchers found a microRNA called miR-iab-4, which increases feeding by more than 27%. Its target gene is called purple. Reducing purple expression increased a fly's feeding desire, suggesting purple normally inhibits that desire.

Purple is known to affect one of two insect fat-body enzymes in building a molecule called PTP. Also in the fly brain, a third enzyme converts PTP into the enzyme tetrahydrobiopterin (BH4) essential to neurons and in the production of NPF, a neuropeptide that regulates food intake. Interestingly, if BH4 deficiency occurs in humans, serious metabolic disorders occur.

The research showed that loss of the gene purple, or reduction of BH4 in neurons, led to increased release of NPF and increased feeding habits in fruit flies. On the other hand, increasing BH4 in neurons reduced NPF release and decreased feeding behavior. Feeding flies a low-calorie diet led to a reduced expression of fat body enzymes that control BH4 production, and subsequently led to increased feeding behaviors in flies as well.

Study results suggest BH4 plays a key role in suppressing appetite in flies. Also, that PTP released from fat bodies delivers a signal to the brain that energy stores are sufficient and feeding can stop.

The work is published in the March 28 open access journal PLOS Biology, by Walton Jones and colleagues at the Korea Advanced Institute of Science and Technology in Daejeon, South Korea. While these results apply only to flies, identifying this appetite-suppression mechanism will hopefully encourage research into related human pathways.

"Our study indicates fat tissue sends a molecular signal to the fly brain to regulate feeding behavior. Further studies will be needed to determine if a similar system acts in mammals, and if so, whether it can be safely manipulated to help achieve weight loss, or gain, in people."

Walton D. Jones PhD, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea.

Here, we show that the enzymatic cofactor tetrahydrobiopterin (BH4) inhibits feeding in Drosophila. BH4 biosynthesis requires the sequential action of the conserved enzymes Punch, Purple, and Sepiapterin Reductase (Sptr). Although we observe increased feeding upon loss of Punch and Purple in the adult fat body, loss of Sptr must occur in the brain. We found Sptr expression is required in four adult neurons that express neuropeptide F (NPF), the fly homologue of the vertebrate appetite regulator neuropeptide Y (NPY). As expected, feeding flies BH4 rescues the loss of Punch and Purple in the fat body and the loss of Sptr in NPF neurons. Mechanistically, we found BH4 deficiency reduces NPF staining, likely by promoting its release, while excess BH4 increases NPF accumulation without altering its expression. We thus show that, because of its physically distributed biosynthesis, BH4 acts as a fat-derived signal that induces satiety by inhibiting the activity of the NPF neurons.

Author summary
As the primary site of energy storage, adipose tissue must somehow monitor energy reserves and communicate this information to the brain. The brain must then modulate feeding behavior to maintain energy balance; however, the mechanisms underlying this communication between fat cells and the brain remain poorly understood. Here, we perform a targeted genetic screen in Drosophila melanogaster and identify a role for the enzymatic cofactor tetrahydrobiopterin (BH4) in regulating ad libitum feeding behavior in fruit flies. We show that three highly conserved enzymes—Punch, Purple, and Sepiapterin Reductase (Sptr)—are required for the biosynthesis of BH4. Fat body-specific knock-down of either Punch or Purple increases feeding, and this increase can be rescued by BH4. We find that rather than also being required in the fat body, Sptr is required in brain neurons that express neuropeptide F (NPF), the fly homologue of the vertebrate appetite regulator neuropeptide Y (NPY). BH4 also rescues the increase in feeding caused by NPF neuron-specific knock-down of Sptr. Although the exact mechanism remains unclear, our results suggest that BH4 inhibits signaling through NPF neurons by blocking their release of NPF. Based on its novel function in feeding and its physically distributed biosynthesis, BH4 may, therefore, represent one of the elusive signals that communicates energy status from the adipose tissue to the brain.

Citation: Kim D-H, Shin M, Jung S-H, Kim Y-J, Jones WD (2017) A fat-derived metabolite regulates a peptidergic feeding circuit in Drosophila. PLoS Biol 15(3): e2000532. doi:10.1371/journal.pbio.2000532

Funding: KAIST High-Risk High-Return Project http://www.kaist.edu (grant number N10150061). Received by WDJ. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Research Foundation of the Republic of Korea http://www.nrf.re.kr (grant number 2013R1A1A2011339). Received by WDJ. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Research Foundation of the Republic of Korea http://www.nrf.re.kr (grant number 2010-0006217). Received by WDJ. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.
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Mar 30, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   

Have you ever seen a fat fly?
Image Credit: Hannes Tkadletz (graphic department of the IMP)


Phospholid by Wikipedia