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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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Related in: MedlinePlus

Vagotomy suppresses sympathetic nerve-mediated lipolysis.(a),Ad-CRE-luc activities in adipose tissue visualized using IVIS Imaging System after 20 h of fasting. *P<0.05 versus sham group (by Student’s t-test) (n=6). (b) Left, protein expressions assessed by western blot analysis using specific antibodies for Ser 563 phospho-HSL (p-HSL) and ATGL in epididymal adipose tissue of sham and HVx mice after 0 and 20 h of fasting. Right, quantification of the blot (ratio of p-HSL to total HSL) (n=5 pooled). (c) mRNA expressions in epididymal fat of 24 h fasting animals, examined by real-time quantitative PCR (RT–qPCR). *P<0.05 versus sham group (by Tukey’s post-hoc test) (n=7). (d) Circulating non-esterified fatty acid (NEFA), glycerol, β-hydroxybutyrate, glucose and insulin levels after 20 h of fasting. *P<0.05 versus sham group (by Student’s t-test) (n=4–9). (e,f) Respiratory quotient (RQ), fat utilization and energy consumption measured using a calorimetric system. *P<0.05 versus sham group (by Student’s t-test) (n=15–18). (g) Weight of remnant epididymal fat tissue in sham or HVx mice with or without guanethidine (GD) treatment after 24 h fasting. *P<0.05 versus sham group (by Tukey’s post-hoc test) (n=6–10). NS, not significant. Error bars, s.e.m.
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f2: Vagotomy suppresses sympathetic nerve-mediated lipolysis.(a),Ad-CRE-luc activities in adipose tissue visualized using IVIS Imaging System after 20 h of fasting. *P<0.05 versus sham group (by Student’s t-test) (n=6). (b) Left, protein expressions assessed by western blot analysis using specific antibodies for Ser 563 phospho-HSL (p-HSL) and ATGL in epididymal adipose tissue of sham and HVx mice after 0 and 20 h of fasting. Right, quantification of the blot (ratio of p-HSL to total HSL) (n=5 pooled). (c) mRNA expressions in epididymal fat of 24 h fasting animals, examined by real-time quantitative PCR (RT–qPCR). *P<0.05 versus sham group (by Tukey’s post-hoc test) (n=7). (d) Circulating non-esterified fatty acid (NEFA), glycerol, β-hydroxybutyrate, glucose and insulin levels after 20 h of fasting. *P<0.05 versus sham group (by Student’s t-test) (n=4–9). (e,f) Respiratory quotient (RQ), fat utilization and energy consumption measured using a calorimetric system. *P<0.05 versus sham group (by Student’s t-test) (n=15–18). (g) Weight of remnant epididymal fat tissue in sham or HVx mice with or without guanethidine (GD) treatment after 24 h fasting. *P<0.05 versus sham group (by Tukey’s post-hoc test) (n=6–10). NS, not significant. Error bars, s.e.m.

Mentions: Next, we examined the metabolic changes in adipose tissue caused by HVx. When cAMP signalling, which is the second messenger mediating the lipolytic signal, was visualized using adenovirally delivered luciferase reporter driven by the cAMP response element (CRE-luc) using an in vivo imaging system, cAMP signalling in the epididymal fat was reduced by HVx (Fig. 2a). Accordingly, the activated form of hormone-sensitive lipase (HSL), phosphorylated at Ser 563, tended to be reduced by hepatic vagus nerve interference (Fig. 2b; Supplementary Fig. S4a). The mRNA levels of HSL and adipose triglyceride lipase (ATGL) as well as pyruvate dehydrogenase kinase 4, a key enzyme regulating glyceroneogenesis that is induced by fasting or epinephrine treatment3, were also downregulated (Fig. 2c). There were no differences between HVx and capsaicin-treated groups, indicating that afferent signal is of key importance. These changes in lipolytic activities resulted in lower levels of plasma non-esterified fatty acids and glycerol in the HVx groups (Fig. 2d), leading to higher respiratory quotient and lower fat utilization per body despite the equal energy consumption (Fig. 2e,f). These differences were cancelled by guanethidine administration, which reduces the release of catecholamines from sympathetic nerves (Fig. 2g, Supplementary Fig. S5a,b)4. The plasma glucose, insulin, glucagon, catecholamines and FGF21 concentrations during fasting were not significantly different between the HVx and sham groups (Fig. 2d, Supplementary Figs S6 and S7a,b). These data demonstrate that the hepatic vagal signals control the lipolytic activities in adipose tissues through the sympathetic nervous system.


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)

Vagotomy suppresses sympathetic nerve-mediated lipolysis.(a),Ad-CRE-luc activities in adipose tissue visualized using IVIS Imaging System after 20 h of fasting. *P<0.05 versus sham group (by Student’s t-test) (n=6). (b) Left, protein expressions assessed by western blot analysis using specific antibodies for Ser 563 phospho-HSL (p-HSL) and ATGL in epididymal adipose tissue of sham and HVx mice after 0 and 20 h of fasting. Right, quantification of the blot (ratio of p-HSL to total HSL) (n=5 pooled). (c) mRNA expressions in epididymal fat of 24 h fasting animals, examined by real-time quantitative PCR (RT–qPCR). *P<0.05 versus sham group (by Tukey’s post-hoc test) (n=7). (d) Circulating non-esterified fatty acid (NEFA), glycerol, β-hydroxybutyrate, glucose and insulin levels after 20 h of fasting. *P<0.05 versus sham group (by Student’s t-test) (n=4–9). (e,f) Respiratory quotient (RQ), fat utilization and energy consumption measured using a calorimetric system. *P<0.05 versus sham group (by Student’s t-test) (n=15–18). (g) Weight of remnant epididymal fat tissue in sham or HVx mice with or without guanethidine (GD) treatment after 24 h fasting. *P<0.05 versus sham group (by Tukey’s post-hoc test) (n=6–10). NS, not significant. Error bars, s.e.m.
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f2: Vagotomy suppresses sympathetic nerve-mediated lipolysis.(a),Ad-CRE-luc activities in adipose tissue visualized using IVIS Imaging System after 20 h of fasting. *P<0.05 versus sham group (by Student’s t-test) (n=6). (b) Left, protein expressions assessed by western blot analysis using specific antibodies for Ser 563 phospho-HSL (p-HSL) and ATGL in epididymal adipose tissue of sham and HVx mice after 0 and 20 h of fasting. Right, quantification of the blot (ratio of p-HSL to total HSL) (n=5 pooled). (c) mRNA expressions in epididymal fat of 24 h fasting animals, examined by real-time quantitative PCR (RT–qPCR). *P<0.05 versus sham group (by Tukey’s post-hoc test) (n=7). (d) Circulating non-esterified fatty acid (NEFA), glycerol, β-hydroxybutyrate, glucose and insulin levels after 20 h of fasting. *P<0.05 versus sham group (by Student’s t-test) (n=4–9). (e,f) Respiratory quotient (RQ), fat utilization and energy consumption measured using a calorimetric system. *P<0.05 versus sham group (by Student’s t-test) (n=15–18). (g) Weight of remnant epididymal fat tissue in sham or HVx mice with or without guanethidine (GD) treatment after 24 h fasting. *P<0.05 versus sham group (by Tukey’s post-hoc test) (n=6–10). NS, not significant. Error bars, s.e.m.
Mentions: Next, we examined the metabolic changes in adipose tissue caused by HVx. When cAMP signalling, which is the second messenger mediating the lipolytic signal, was visualized using adenovirally delivered luciferase reporter driven by the cAMP response element (CRE-luc) using an in vivo imaging system, cAMP signalling in the epididymal fat was reduced by HVx (Fig. 2a). Accordingly, the activated form of hormone-sensitive lipase (HSL), phosphorylated at Ser 563, tended to be reduced by hepatic vagus nerve interference (Fig. 2b; Supplementary Fig. S4a). The mRNA levels of HSL and adipose triglyceride lipase (ATGL) as well as pyruvate dehydrogenase kinase 4, a key enzyme regulating glyceroneogenesis that is induced by fasting or epinephrine treatment3, were also downregulated (Fig. 2c). There were no differences between HVx and capsaicin-treated groups, indicating that afferent signal is of key importance. These changes in lipolytic activities resulted in lower levels of plasma non-esterified fatty acids and glycerol in the HVx groups (Fig. 2d), leading to higher respiratory quotient and lower fat utilization per body despite the equal energy consumption (Fig. 2e,f). These differences were cancelled by guanethidine administration, which reduces the release of catecholamines from sympathetic nerves (Fig. 2g, Supplementary Fig. S5a,b)4. The plasma glucose, insulin, glucagon, catecholamines and FGF21 concentrations during fasting were not significantly different between the HVx and sham groups (Fig. 2d, Supplementary Figs S6 and S7a,b). These data demonstrate that the hepatic vagal signals control the lipolytic activities in adipose tissues through the sympathetic nervous system.

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