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Glycogen shortage during fasting triggers liver-brain-adipose neurocircuitry to facilitate fat utilization.

Izumida Y, Yahagi N, Takeuchi Y, Nishi M, Shikama A, Takarada A, Masuda Y, Kubota M, Matsuzaka T, Nakagawa Y, Iizuka Y, Itaka K, Kataoka K, Shioda S, Niijima A, Yamada T, Katagiri H, Nagai R, Yamada N, Kadowaki T, Shimano H - Nat Commun (2013)

Bottom Line: However, the trigger for this switch has not yet been entirely elucidated.Here we show that a selective hepatic vagotomy slows the speed of fat consumption by attenuating sympathetic nerve-mediated lipolysis in adipose tissue.Moreover, the blockade of glycogenolysis [corrected] through the knockdown of the glycogen phosphorylase gene and the resulting elevation in the glycogen content abolished the lipolytic signal from the liver, indicating that glycogen is the key to triggering this neurocircuitry.

View Article: PubMed Central - PubMed

Affiliation: Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.

ABSTRACT
During fasting, animals maintain their energy balance by shifting their energy source from carbohydrates to triglycerides. However, the trigger for this switch has not yet been entirely elucidated. Here we show that a selective hepatic vagotomy slows the speed of fat consumption by attenuating sympathetic nerve-mediated lipolysis in adipose tissue. Hepatic glycogen pre-loading by the adenoviral overexpression of glycogen synthase or the transcription factor TFE3 abolished this liver-brain-adipose axis activation. Moreover, the blockade of glycogenolysis [corrected] through the knockdown of the glycogen phosphorylase gene and the resulting elevation in the glycogen content abolished the lipolytic signal from the liver, indicating that glycogen is the key to triggering this neurocircuitry. These results demonstrate that liver glycogen shortage activates a liver-brain-adipose neural axis that has an important role in switching the fuel source from glycogen to triglycerides under prolonged fasting conditions.

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Glycolysis blockade abolishes lipolytic signal from liver.(a,b) Weight of epididymal fat pad after fasting. Effects of short hairpin RNA expression adenovirus vector targeted for Gys2 (hatched bar, a) or Pygl (filled bar, b). (n=4–8). (c) Immunoblot analysis of glycogen synthase (GS) and glycogen phosphorylase (PYGL) expression in the livers of Ad-Gys2-i or Ad-Pygl-i injected mice. (n=3–4). (d) RT–qPCR analysis of mRNA expression of glycogen synthase (Gys2) and glycogen phosphorylase (Pygl) genes. (n=3). (e) Liver glycogen content of mice infected with adenovirus expressing short hairpin RNA targeted for LacZ, Gys2 or Pygl (Ad-LacZ-i, Ad-Gys2-i or Ad-Pygl-I, respectively) (n=3–4). (f) Immunoblot analysis of Ser485-phosphorylated AMPKα (pAMPKα), total AMPKα, Ser181-phosphorylated AMPKβ (pAMPKβ) and total AMPKβ. Whole-cell lysates from the livers of mice infected with adenovirus expressing short hairpin RNA targeted for LacZ, Gys2 or Pygl (Ad-LacZ-i, Ad-Gys2-i or Ad-Pygl-i). (g) Quantified results of the data shown in (f), shown as the ratio of pAMPKα to total AMPKα and pAMPKβ to total AMPKβ. (n=3–4). All mice are analysed on 24-h fasting condition. *P<0.05 versus Ad-LacZ-i sham group (by Tukey’s post-hoc test). NS, not significant. Error bars, s.e.m.
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f4: Glycolysis blockade abolishes lipolytic signal from liver.(a,b) Weight of epididymal fat pad after fasting. Effects of short hairpin RNA expression adenovirus vector targeted for Gys2 (hatched bar, a) or Pygl (filled bar, b). (n=4–8). (c) Immunoblot analysis of glycogen synthase (GS) and glycogen phosphorylase (PYGL) expression in the livers of Ad-Gys2-i or Ad-Pygl-i injected mice. (n=3–4). (d) RT–qPCR analysis of mRNA expression of glycogen synthase (Gys2) and glycogen phosphorylase (Pygl) genes. (n=3). (e) Liver glycogen content of mice infected with adenovirus expressing short hairpin RNA targeted for LacZ, Gys2 or Pygl (Ad-LacZ-i, Ad-Gys2-i or Ad-Pygl-I, respectively) (n=3–4). (f) Immunoblot analysis of Ser485-phosphorylated AMPKα (pAMPKα), total AMPKα, Ser181-phosphorylated AMPKβ (pAMPKβ) and total AMPKβ. Whole-cell lysates from the livers of mice infected with adenovirus expressing short hairpin RNA targeted for LacZ, Gys2 or Pygl (Ad-LacZ-i, Ad-Gys2-i or Ad-Pygl-i). (g) Quantified results of the data shown in (f), shown as the ratio of pAMPKα to total AMPKα and pAMPKβ to total AMPKβ. (n=3–4). All mice are analysed on 24-h fasting condition. *P<0.05 versus Ad-LacZ-i sham group (by Tukey’s post-hoc test). NS, not significant. Error bars, s.e.m.

Mentions: Conversely, when Gys2 expression was knocked down by adenovirally transferred short hairpin RNA (shRNA), and liver glycogen shortage was concomitantly exacerbated, the adipose tissue tended to shrink faster, and this tendency was cancelled by the HVx (Fig. 4a,c–e, Supplementary Fig. S4d, Supplementary Table S1). Next, to distinguish which of the parameters, glycogen itself or its downstream metabolites, is the key to triggering liver–brain–adipose axis activation when depleted, the glycogen phosphorylase liver type gene (Pygl) was knocked down using shRNA (Fig. 4b–e, Supplementary Fig. S4d, Supplementary Table S1); when glycolysis was suppressed by this RNA interference, the liver glycogen content was elevated and this in turn led to a decrease in lipolysis in the adipose tissue. This result demonstrates that the shortage of glycogen, but not that of the downstream metabolites, is the key to triggering the neurocircuitry. Meanwhile, AMP-activated kinases (AMPKs) were prone to be activated by the knockdown of glycogen phosphorylase (Fig. 4f,g, Supplementary Fig. S4e).


Glycogen shortage during fasting triggers liver-brain-adipose neurocircuitry to facilitate fat utilization.

Izumida Y, Yahagi N, Takeuchi Y, Nishi M, Shikama A, Takarada A, Masuda Y, Kubota M, Matsuzaka T, Nakagawa Y, Iizuka Y, Itaka K, Kataoka K, Shioda S, Niijima A, Yamada T, Katagiri H, Nagai R, Yamada N, Kadowaki T, Shimano H - Nat Commun (2013)

Glycolysis blockade abolishes lipolytic signal from liver.(a,b) Weight of epididymal fat pad after fasting. Effects of short hairpin RNA expression adenovirus vector targeted for Gys2 (hatched bar, a) or Pygl (filled bar, b). (n=4–8). (c) Immunoblot analysis of glycogen synthase (GS) and glycogen phosphorylase (PYGL) expression in the livers of Ad-Gys2-i or Ad-Pygl-i injected mice. (n=3–4). (d) RT–qPCR analysis of mRNA expression of glycogen synthase (Gys2) and glycogen phosphorylase (Pygl) genes. (n=3). (e) Liver glycogen content of mice infected with adenovirus expressing short hairpin RNA targeted for LacZ, Gys2 or Pygl (Ad-LacZ-i, Ad-Gys2-i or Ad-Pygl-I, respectively) (n=3–4). (f) Immunoblot analysis of Ser485-phosphorylated AMPKα (pAMPKα), total AMPKα, Ser181-phosphorylated AMPKβ (pAMPKβ) and total AMPKβ. Whole-cell lysates from the livers of mice infected with adenovirus expressing short hairpin RNA targeted for LacZ, Gys2 or Pygl (Ad-LacZ-i, Ad-Gys2-i or Ad-Pygl-i). (g) Quantified results of the data shown in (f), shown as the ratio of pAMPKα to total AMPKα and pAMPKβ to total AMPKβ. (n=3–4). All mice are analysed on 24-h fasting condition. *P<0.05 versus Ad-LacZ-i sham group (by Tukey’s post-hoc test). NS, not significant. Error bars, s.e.m.
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f4: Glycolysis blockade abolishes lipolytic signal from liver.(a,b) Weight of epididymal fat pad after fasting. Effects of short hairpin RNA expression adenovirus vector targeted for Gys2 (hatched bar, a) or Pygl (filled bar, b). (n=4–8). (c) Immunoblot analysis of glycogen synthase (GS) and glycogen phosphorylase (PYGL) expression in the livers of Ad-Gys2-i or Ad-Pygl-i injected mice. (n=3–4). (d) RT–qPCR analysis of mRNA expression of glycogen synthase (Gys2) and glycogen phosphorylase (Pygl) genes. (n=3). (e) Liver glycogen content of mice infected with adenovirus expressing short hairpin RNA targeted for LacZ, Gys2 or Pygl (Ad-LacZ-i, Ad-Gys2-i or Ad-Pygl-I, respectively) (n=3–4). (f) Immunoblot analysis of Ser485-phosphorylated AMPKα (pAMPKα), total AMPKα, Ser181-phosphorylated AMPKβ (pAMPKβ) and total AMPKβ. Whole-cell lysates from the livers of mice infected with adenovirus expressing short hairpin RNA targeted for LacZ, Gys2 or Pygl (Ad-LacZ-i, Ad-Gys2-i or Ad-Pygl-i). (g) Quantified results of the data shown in (f), shown as the ratio of pAMPKα to total AMPKα and pAMPKβ to total AMPKβ. (n=3–4). All mice are analysed on 24-h fasting condition. *P<0.05 versus Ad-LacZ-i sham group (by Tukey’s post-hoc test). NS, not significant. Error bars, s.e.m.
Mentions: Conversely, when Gys2 expression was knocked down by adenovirally transferred short hairpin RNA (shRNA), and liver glycogen shortage was concomitantly exacerbated, the adipose tissue tended to shrink faster, and this tendency was cancelled by the HVx (Fig. 4a,c–e, Supplementary Fig. S4d, Supplementary Table S1). Next, to distinguish which of the parameters, glycogen itself or its downstream metabolites, is the key to triggering liver–brain–adipose axis activation when depleted, the glycogen phosphorylase liver type gene (Pygl) was knocked down using shRNA (Fig. 4b–e, Supplementary Fig. S4d, Supplementary Table S1); when glycolysis was suppressed by this RNA interference, the liver glycogen content was elevated and this in turn led to a decrease in lipolysis in the adipose tissue. This result demonstrates that the shortage of glycogen, but not that of the downstream metabolites, is the key to triggering the neurocircuitry. Meanwhile, AMP-activated kinases (AMPKs) were prone to be activated by the knockdown of glycogen phosphorylase (Fig. 4f,g, Supplementary Fig. S4e).

Bottom Line: However, the trigger for this switch has not yet been entirely elucidated.Here we show that a selective hepatic vagotomy slows the speed of fat consumption by attenuating sympathetic nerve-mediated lipolysis in adipose tissue.Moreover, the blockade of glycogenolysis [corrected] through the knockdown of the glycogen phosphorylase gene and the resulting elevation in the glycogen content abolished the lipolytic signal from the liver, indicating that glycogen is the key to triggering this neurocircuitry.

View Article: PubMed Central - PubMed

Affiliation: Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.

ABSTRACT
During fasting, animals maintain their energy balance by shifting their energy source from carbohydrates to triglycerides. However, the trigger for this switch has not yet been entirely elucidated. Here we show that a selective hepatic vagotomy slows the speed of fat consumption by attenuating sympathetic nerve-mediated lipolysis in adipose tissue. Hepatic glycogen pre-loading by the adenoviral overexpression of glycogen synthase or the transcription factor TFE3 abolished this liver-brain-adipose axis activation. Moreover, the blockade of glycogenolysis [corrected] through the knockdown of the glycogen phosphorylase gene and the resulting elevation in the glycogen content abolished the lipolytic signal from the liver, indicating that glycogen is the key to triggering this neurocircuitry. These results demonstrate that liver glycogen shortage activates a liver-brain-adipose neural axis that has an important role in switching the fuel source from glycogen to triglycerides under prolonged fasting conditions.

Show MeSH
Related in: MedlinePlus