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Interplay between glucose and leptin signalling determines the strength of GABAergic synapses at POMC neurons.

Lee DK, Jeong JH, Chun SK, Chua S, Jo YH - Nat Commun (2015)

Bottom Line: Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose.High-fat feeding blunts AMPK-dependent presynaptic inhibition, whereas PLC-mediated GABAergic feedback inhibition remains responsive to leptin.Our data indicate that the interplay between glucose and leptin signalling in glutamatergic POMC neurons is critical for determining the strength of inhibitory tone towards POMC neurons.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, New York 10461, USA.

ABSTRACT
Regulation of GABAergic inhibitory inputs and alterations in POMC neuron activity by nutrients and adiposity signals regulate energy and glucose homeostasis. Thus, understanding how POMC neurons integrate these two signal molecules at the synaptic level is important. Here we show that leptin's action on GABA release to POMC neurons is influenced by glucose levels. Leptin stimulates the JAK2-PI3K pathway in both presynaptic GABAergic terminals and postsynaptic POMC neurons. Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose. However, postsynaptic TRPC channel opening by the PI3K-PLC signalling pathway in POMC neurons enhances spontaneous GABA release via activation of presynaptic MC3/4 and mGlu receptors at 2.5 mM glucose. High-fat feeding blunts AMPK-dependent presynaptic inhibition, whereas PLC-mediated GABAergic feedback inhibition remains responsive to leptin. Our data indicate that the interplay between glucose and leptin signalling in glutamatergic POMC neurons is critical for determining the strength of inhibitory tone towards POMC neurons.

No MeSH data available.


Related in: MedlinePlus

High-fat feeding upregulates JAK2-PI3K signalingA and B) Body weight and calorie intake of animals fed NCD (control, n = 15 animals) and HFD (n = 18 animals) after 3 weeks. There was no difference between control (NCD) and HFD animals. NCD: normal chow diet, HFD: high-fat dietC) Ratio of fat tissue to lean mass for control (n = 10 animals) and HFD (n = 14 animals) groups. High-fat feeding significantly increased the ratio of fat tissue to lean mass.D, E and F) Plasma glucose, leptin and insulin levels after 3 weeks on HFD. Plasma glucose and leptin levels were significantly elevated in animals fed HFD (glucose, n = 8 animals; leptin, n = 14 animals) compared with control (glucose, n = 7 animals; n = 16 animals). However, insulin levels were similar in both groups.G and H) Images of fluorescence microscopy showing the co-expression of pS6 (red) and POMC neurons (green) in the ARC of animal injected with leptin (G). Summary plot (H) showing the percent of pS6-positive POMC neurons in animals fed a NCD (n = 9 animals) and a HFD (n = 8 animals). There was a significant increase in the number of pS6-positive POMC neurons in animals fed HFD. Scale bar: 50 µm. S: saline, L: leptinI and J) PI3K p110α (I) and p110β (J) mRNA expression in POMC neurons. The dietary intervention significantly increased the expression of p110β, but not p110α, mRNAs in POMC neurons (p110α, NCD, n = 6 neurons, HFD, n = 5 neurons; p110β, NCD, n = 6 neurons, HFD, n = 9 neurons).K) Calorie intake for control and HFD groups after micro-injection of leptin into the MBH. High-fat feeding significantly diminished leptin's anorexigenic effects (NCD, n = 14 animals, HFD, n = 18 animals).*p < 0.05, **p < 0.01, ***p < 0.001 vs. control (unpaired t-test); ap < 0.05 vs. NCD + leptin (unpaired t test). All data are shown as mean ± SEM.
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Figure 7: High-fat feeding upregulates JAK2-PI3K signalingA and B) Body weight and calorie intake of animals fed NCD (control, n = 15 animals) and HFD (n = 18 animals) after 3 weeks. There was no difference between control (NCD) and HFD animals. NCD: normal chow diet, HFD: high-fat dietC) Ratio of fat tissue to lean mass for control (n = 10 animals) and HFD (n = 14 animals) groups. High-fat feeding significantly increased the ratio of fat tissue to lean mass.D, E and F) Plasma glucose, leptin and insulin levels after 3 weeks on HFD. Plasma glucose and leptin levels were significantly elevated in animals fed HFD (glucose, n = 8 animals; leptin, n = 14 animals) compared with control (glucose, n = 7 animals; n = 16 animals). However, insulin levels were similar in both groups.G and H) Images of fluorescence microscopy showing the co-expression of pS6 (red) and POMC neurons (green) in the ARC of animal injected with leptin (G). Summary plot (H) showing the percent of pS6-positive POMC neurons in animals fed a NCD (n = 9 animals) and a HFD (n = 8 animals). There was a significant increase in the number of pS6-positive POMC neurons in animals fed HFD. Scale bar: 50 µm. S: saline, L: leptinI and J) PI3K p110α (I) and p110β (J) mRNA expression in POMC neurons. The dietary intervention significantly increased the expression of p110β, but not p110α, mRNAs in POMC neurons (p110α, NCD, n = 6 neurons, HFD, n = 5 neurons; p110β, NCD, n = 6 neurons, HFD, n = 9 neurons).K) Calorie intake for control and HFD groups after micro-injection of leptin into the MBH. High-fat feeding significantly diminished leptin's anorexigenic effects (NCD, n = 14 animals, HFD, n = 18 animals).*p < 0.05, **p < 0.01, ***p < 0.001 vs. control (unpaired t-test); ap < 0.05 vs. NCD + leptin (unpaired t test). All data are shown as mean ± SEM.

Mentions: We expanded our findings to determine the physiological consequences of these synaptic alterations in POMC neurons at the whole body level. We measured body weight, calorie intake, plasma glucose, leptin, and insulin levels after 3 weeks on a HFD. Body weight and calorie intake in animals fed a HFD were no different from the control (body weight, NCD 19.9 ± 0.6 g, HFD 19.8 ± 0.5 g; calorie intake, NCD, 13.5 ± 0.5 kcal/g, HFD, 12.6 ± 0.3 kcal/g; Fig. 7A and B). However, the ratio of fat tissue to lean mass was significantly higher in animals fed a HFD than in animals on NCD (0.3 ± 0.02 vs. 0.4 ± 0.02; Fig. 7C). This was associated with elevated blood glucose and leptin levels (Fig. 7D and E).


Interplay between glucose and leptin signalling determines the strength of GABAergic synapses at POMC neurons.

Lee DK, Jeong JH, Chun SK, Chua S, Jo YH - Nat Commun (2015)

High-fat feeding upregulates JAK2-PI3K signalingA and B) Body weight and calorie intake of animals fed NCD (control, n = 15 animals) and HFD (n = 18 animals) after 3 weeks. There was no difference between control (NCD) and HFD animals. NCD: normal chow diet, HFD: high-fat dietC) Ratio of fat tissue to lean mass for control (n = 10 animals) and HFD (n = 14 animals) groups. High-fat feeding significantly increased the ratio of fat tissue to lean mass.D, E and F) Plasma glucose, leptin and insulin levels after 3 weeks on HFD. Plasma glucose and leptin levels were significantly elevated in animals fed HFD (glucose, n = 8 animals; leptin, n = 14 animals) compared with control (glucose, n = 7 animals; n = 16 animals). However, insulin levels were similar in both groups.G and H) Images of fluorescence microscopy showing the co-expression of pS6 (red) and POMC neurons (green) in the ARC of animal injected with leptin (G). Summary plot (H) showing the percent of pS6-positive POMC neurons in animals fed a NCD (n = 9 animals) and a HFD (n = 8 animals). There was a significant increase in the number of pS6-positive POMC neurons in animals fed HFD. Scale bar: 50 µm. S: saline, L: leptinI and J) PI3K p110α (I) and p110β (J) mRNA expression in POMC neurons. The dietary intervention significantly increased the expression of p110β, but not p110α, mRNAs in POMC neurons (p110α, NCD, n = 6 neurons, HFD, n = 5 neurons; p110β, NCD, n = 6 neurons, HFD, n = 9 neurons).K) Calorie intake for control and HFD groups after micro-injection of leptin into the MBH. High-fat feeding significantly diminished leptin's anorexigenic effects (NCD, n = 14 animals, HFD, n = 18 animals).*p < 0.05, **p < 0.01, ***p < 0.001 vs. control (unpaired t-test); ap < 0.05 vs. NCD + leptin (unpaired t test). All data are shown as mean ± SEM.
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Figure 7: High-fat feeding upregulates JAK2-PI3K signalingA and B) Body weight and calorie intake of animals fed NCD (control, n = 15 animals) and HFD (n = 18 animals) after 3 weeks. There was no difference between control (NCD) and HFD animals. NCD: normal chow diet, HFD: high-fat dietC) Ratio of fat tissue to lean mass for control (n = 10 animals) and HFD (n = 14 animals) groups. High-fat feeding significantly increased the ratio of fat tissue to lean mass.D, E and F) Plasma glucose, leptin and insulin levels after 3 weeks on HFD. Plasma glucose and leptin levels were significantly elevated in animals fed HFD (glucose, n = 8 animals; leptin, n = 14 animals) compared with control (glucose, n = 7 animals; n = 16 animals). However, insulin levels were similar in both groups.G and H) Images of fluorescence microscopy showing the co-expression of pS6 (red) and POMC neurons (green) in the ARC of animal injected with leptin (G). Summary plot (H) showing the percent of pS6-positive POMC neurons in animals fed a NCD (n = 9 animals) and a HFD (n = 8 animals). There was a significant increase in the number of pS6-positive POMC neurons in animals fed HFD. Scale bar: 50 µm. S: saline, L: leptinI and J) PI3K p110α (I) and p110β (J) mRNA expression in POMC neurons. The dietary intervention significantly increased the expression of p110β, but not p110α, mRNAs in POMC neurons (p110α, NCD, n = 6 neurons, HFD, n = 5 neurons; p110β, NCD, n = 6 neurons, HFD, n = 9 neurons).K) Calorie intake for control and HFD groups after micro-injection of leptin into the MBH. High-fat feeding significantly diminished leptin's anorexigenic effects (NCD, n = 14 animals, HFD, n = 18 animals).*p < 0.05, **p < 0.01, ***p < 0.001 vs. control (unpaired t-test); ap < 0.05 vs. NCD + leptin (unpaired t test). All data are shown as mean ± SEM.
Mentions: We expanded our findings to determine the physiological consequences of these synaptic alterations in POMC neurons at the whole body level. We measured body weight, calorie intake, plasma glucose, leptin, and insulin levels after 3 weeks on a HFD. Body weight and calorie intake in animals fed a HFD were no different from the control (body weight, NCD 19.9 ± 0.6 g, HFD 19.8 ± 0.5 g; calorie intake, NCD, 13.5 ± 0.5 kcal/g, HFD, 12.6 ± 0.3 kcal/g; Fig. 7A and B). However, the ratio of fat tissue to lean mass was significantly higher in animals fed a HFD than in animals on NCD (0.3 ± 0.02 vs. 0.4 ± 0.02; Fig. 7C). This was associated with elevated blood glucose and leptin levels (Fig. 7D and E).

Bottom Line: Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose.High-fat feeding blunts AMPK-dependent presynaptic inhibition, whereas PLC-mediated GABAergic feedback inhibition remains responsive to leptin.Our data indicate that the interplay between glucose and leptin signalling in glutamatergic POMC neurons is critical for determining the strength of inhibitory tone towards POMC neurons.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, New York 10461, USA.

ABSTRACT
Regulation of GABAergic inhibitory inputs and alterations in POMC neuron activity by nutrients and adiposity signals regulate energy and glucose homeostasis. Thus, understanding how POMC neurons integrate these two signal molecules at the synaptic level is important. Here we show that leptin's action on GABA release to POMC neurons is influenced by glucose levels. Leptin stimulates the JAK2-PI3K pathway in both presynaptic GABAergic terminals and postsynaptic POMC neurons. Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose. However, postsynaptic TRPC channel opening by the PI3K-PLC signalling pathway in POMC neurons enhances spontaneous GABA release via activation of presynaptic MC3/4 and mGlu receptors at 2.5 mM glucose. High-fat feeding blunts AMPK-dependent presynaptic inhibition, whereas PLC-mediated GABAergic feedback inhibition remains responsive to leptin. Our data indicate that the interplay between glucose and leptin signalling in glutamatergic POMC neurons is critical for determining the strength of inhibitory tone towards POMC neurons.

No MeSH data available.


Related in: MedlinePlus