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Dietary sugar promotes systemic TOR activation in Drosophila through AKH-dependent selective secretion of Dilp3.

Kim J, Neufeld TP - Nat Commun (2015)

Bottom Line: Here we show that regulation of insulin secretion in Drosophila larvae has been segregated into distinct branches-whereas amino acids promote the secretion of Drosophila insulin-like peptide 2 (Dilp2), circulating sugars promote the selective release of Dilp3.Dilp3 is uniquely required for the sugar-mediated activation of TOR signalling and suppression of autophagy in the larval fat body.Sugar levels are not sensed directly by the IPCs, but rather by the adipokinetic hormone (AKH)-producing cells of the corpora cardiaca, and we demonstrate that AKH signalling is required in the IPCs for sugar-dependent Dilp3 release.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, 6-160 Jackson Hall, 321 Church St SE, Minneapolis, Minnesota 55455, USA.

ABSTRACT
Secreted ligands of the insulin family promote cell growth and maintain sugar homeostasis. Insulin release is tightly regulated in response to dietary conditions, but how insulin-producing cells (IPCs) coordinate their responses to distinct nutrient signals is unclear. Here we show that regulation of insulin secretion in Drosophila larvae has been segregated into distinct branches-whereas amino acids promote the secretion of Drosophila insulin-like peptide 2 (Dilp2), circulating sugars promote the selective release of Dilp3. Dilp3 is uniquely required for the sugar-mediated activation of TOR signalling and suppression of autophagy in the larval fat body. Sugar levels are not sensed directly by the IPCs, but rather by the adipokinetic hormone (AKH)-producing cells of the corpora cardiaca, and we demonstrate that AKH signalling is required in the IPCs for sugar-dependent Dilp3 release. Thus, IPCs integrate multiple cues to regulate the secretion of distinct insulin subtypes under varying nutrient conditions.

No MeSH data available.


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Activation of TOR by trehalose requires AKH signaling(a, b) Trehalose-mediated ex vivo activation of fb-TOR is disrupted by ablation of the CC (AKH-GAL4 / UAS-reaper) or depletion of AKH from the CC (AKH-GAL4 / UAS-AKHRNAi) and by  mutation of the AKH receptor (AKHR1/AKHR1). (c) Overexpression of AKH (Cg-GAL4 / UAS-Akh) increases fb-TOR signaling in the presence and absence of trehalose ex vivo. Data represent mean±s.e.m. of three (a, b) or four (c) independent experiments. *p<0.05, **p<0.01, ***p<0.001, NS p>0.05; Student’s t-test. Full-size immunoblots are presented in Supplementary Figure 5.
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Figure 5: Activation of TOR by trehalose requires AKH signaling(a, b) Trehalose-mediated ex vivo activation of fb-TOR is disrupted by ablation of the CC (AKH-GAL4 / UAS-reaper) or depletion of AKH from the CC (AKH-GAL4 / UAS-AKHRNAi) and by mutation of the AKH receptor (AKHR1/AKHR1). (c) Overexpression of AKH (Cg-GAL4 / UAS-Akh) increases fb-TOR signaling in the presence and absence of trehalose ex vivo. Data represent mean±s.e.m. of three (a, b) or four (c) independent experiments. *p<0.05, **p<0.01, ***p<0.001, NS p>0.05; Student’s t-test. Full-size immunoblots are presented in Supplementary Figure 5.

Mentions: In mammals, ATP-sensitive potassium channels in the pancreatic beta cells play a critical role in sensing glucose levels and regulating insulin secretion. Interestingly, Drosophila homologs of these channel subunits are absent from larval IPCs, but instead are specifically expressed in the corpora cardiaca (CC) cells of the ring gland7. These cells express the glucagon-like hormone AKH, and they make contact with processes from the IPCs. We found that RNAi-mediated depletion of AKH in the CC, or ablation of the CC itself, inhibited fat body TOR activation in response to trehalose (Fig. 5a; see Supplementary Fig. 3a for depletion and ablation controls). Null mutation of the AKH receptor AKHR showed a similar block in TOR activation (Fig. 5b). Conversely, overexpression of AKH increased TOR activity in both the presence and absence of trehalose (Fig. 5c).


Dietary sugar promotes systemic TOR activation in Drosophila through AKH-dependent selective secretion of Dilp3.

Kim J, Neufeld TP - Nat Commun (2015)

Activation of TOR by trehalose requires AKH signaling(a, b) Trehalose-mediated ex vivo activation of fb-TOR is disrupted by ablation of the CC (AKH-GAL4 / UAS-reaper) or depletion of AKH from the CC (AKH-GAL4 / UAS-AKHRNAi) and by  mutation of the AKH receptor (AKHR1/AKHR1). (c) Overexpression of AKH (Cg-GAL4 / UAS-Akh) increases fb-TOR signaling in the presence and absence of trehalose ex vivo. Data represent mean±s.e.m. of three (a, b) or four (c) independent experiments. *p<0.05, **p<0.01, ***p<0.001, NS p>0.05; Student’s t-test. Full-size immunoblots are presented in Supplementary Figure 5.
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Figure 5: Activation of TOR by trehalose requires AKH signaling(a, b) Trehalose-mediated ex vivo activation of fb-TOR is disrupted by ablation of the CC (AKH-GAL4 / UAS-reaper) or depletion of AKH from the CC (AKH-GAL4 / UAS-AKHRNAi) and by mutation of the AKH receptor (AKHR1/AKHR1). (c) Overexpression of AKH (Cg-GAL4 / UAS-Akh) increases fb-TOR signaling in the presence and absence of trehalose ex vivo. Data represent mean±s.e.m. of three (a, b) or four (c) independent experiments. *p<0.05, **p<0.01, ***p<0.001, NS p>0.05; Student’s t-test. Full-size immunoblots are presented in Supplementary Figure 5.
Mentions: In mammals, ATP-sensitive potassium channels in the pancreatic beta cells play a critical role in sensing glucose levels and regulating insulin secretion. Interestingly, Drosophila homologs of these channel subunits are absent from larval IPCs, but instead are specifically expressed in the corpora cardiaca (CC) cells of the ring gland7. These cells express the glucagon-like hormone AKH, and they make contact with processes from the IPCs. We found that RNAi-mediated depletion of AKH in the CC, or ablation of the CC itself, inhibited fat body TOR activation in response to trehalose (Fig. 5a; see Supplementary Fig. 3a for depletion and ablation controls). Null mutation of the AKH receptor AKHR showed a similar block in TOR activation (Fig. 5b). Conversely, overexpression of AKH increased TOR activity in both the presence and absence of trehalose (Fig. 5c).

Bottom Line: Here we show that regulation of insulin secretion in Drosophila larvae has been segregated into distinct branches-whereas amino acids promote the secretion of Drosophila insulin-like peptide 2 (Dilp2), circulating sugars promote the selective release of Dilp3.Dilp3 is uniquely required for the sugar-mediated activation of TOR signalling and suppression of autophagy in the larval fat body.Sugar levels are not sensed directly by the IPCs, but rather by the adipokinetic hormone (AKH)-producing cells of the corpora cardiaca, and we demonstrate that AKH signalling is required in the IPCs for sugar-dependent Dilp3 release.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, 6-160 Jackson Hall, 321 Church St SE, Minneapolis, Minnesota 55455, USA.

ABSTRACT
Secreted ligands of the insulin family promote cell growth and maintain sugar homeostasis. Insulin release is tightly regulated in response to dietary conditions, but how insulin-producing cells (IPCs) coordinate their responses to distinct nutrient signals is unclear. Here we show that regulation of insulin secretion in Drosophila larvae has been segregated into distinct branches-whereas amino acids promote the secretion of Drosophila insulin-like peptide 2 (Dilp2), circulating sugars promote the selective release of Dilp3. Dilp3 is uniquely required for the sugar-mediated activation of TOR signalling and suppression of autophagy in the larval fat body. Sugar levels are not sensed directly by the IPCs, but rather by the adipokinetic hormone (AKH)-producing cells of the corpora cardiaca, and we demonstrate that AKH signalling is required in the IPCs for sugar-dependent Dilp3 release. Thus, IPCs integrate multiple cues to regulate the secretion of distinct insulin subtypes under varying nutrient conditions.

No MeSH data available.


Related in: MedlinePlus