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Central GLP-1 receptor signalling accelerates plasma clearance of triacylglycerol and glucose by activating brown adipose tissue in mice.

Kooijman S, Wang Y, Parlevliet ET, Boon MR, Edelschaap D, Snaterse G, Pijl H, Romijn JA, Rensen PC - Diabetologia (2015)

Bottom Line: Central administration of exendin-4 in lean mice increased sympathetic outflow towards BAT and white adipose tissue (WAT), resulting in increased thermogenesis as evidenced by increased uncoupling protein 1 (UCP-1) protein levels and decreased lipid content, while the uptake of TG-derived fatty acids was increased in both BAT and WAT.These effects were accompanied by increased fat oxidation, lower plasma TG and glucose concentrations, and reduced body weight.Collectively, our results suggest that BAT activation may be a major contributor to the glucose- and TG-lowering effects of GLP-1R agonism.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Room C7-Q44, Albinusdreef 2, PO Box 9600, 2300, RC, Leiden, the Netherlands. s.kooijman@lumc.nl.

ABSTRACT

Aims/hypothesis: Glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism, used in the treatment of type 2 diabetes, has recently been shown to increase thermogenesis via the brain. As brown adipose tissue (BAT) produces heat by burning triacylglycerol (TG) and takes up glucose for de novo lipogenesis, the aim of this study was to evaluate the potential of chronic central GLP-1R activation by exendin-4 to facilitate clearance of lipids and glucose from the circulation by activating BAT.

Methods: Lean and diet-induced obese (DIO) C57Bl/6J mice were used to explore the effect of a 5 day intracerebroventricular infusion of the GLP-1 analogue exendin-4 or vehicle on lipid and glucose uptake by BAT in both insulin-sensitive and insulin-resistant conditions.

Results: Central administration of exendin-4 in lean mice increased sympathetic outflow towards BAT and white adipose tissue (WAT), resulting in increased thermogenesis as evidenced by increased uncoupling protein 1 (UCP-1) protein levels and decreased lipid content, while the uptake of TG-derived fatty acids was increased in both BAT and WAT. Interestingly, in DIO mice, the effects on WAT were blunted, while exendin-4 still increased sympathetic outflow towards BAT and increased the uptake of plasma TG-derived fatty acids and glucose by BAT. These effects were accompanied by increased fat oxidation, lower plasma TG and glucose concentrations, and reduced body weight.

Conclusions/interpretation: Collectively, our results suggest that BAT activation may be a major contributor to the glucose- and TG-lowering effects of GLP-1R agonism.

No MeSH data available.


Related in: MedlinePlus

Central GLP-1R activation increases uptake of plasma TG-derived fatty acids and glucose by BAT in lean mice. Mice were treated for 5 days via i.c.v. (a–d) or i.v. (e–f) routes with exendin-4 (n = 8) or vehicle (control n = 9, pair-fed n = 6). After treatment, mice were injected with [3H]TO-labelled particles and [14C]DG. Plasma 3H activity (a) and 14C activity (c) were plotted relative to the injected dose. At 15 min after injection, organs were isolated and uptake of 3H activity (b, e) and 14C activity (d, f) was determined. Values are mean ± SD. *p < 0.05, **p < 0.01 and ***p < 0.001 compared with control. †p < 0.05 and ††p < 0.01 compared with pair-fed control. White bars/circles, control; black bars/circles, exendin-4; grey bars/circles, pair-fed control
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Fig2: Central GLP-1R activation increases uptake of plasma TG-derived fatty acids and glucose by BAT in lean mice. Mice were treated for 5 days via i.c.v. (a–d) or i.v. (e–f) routes with exendin-4 (n = 8) or vehicle (control n = 9, pair-fed n = 6). After treatment, mice were injected with [3H]TO-labelled particles and [14C]DG. Plasma 3H activity (a) and 14C activity (c) were plotted relative to the injected dose. At 15 min after injection, organs were isolated and uptake of 3H activity (b, e) and 14C activity (d, f) was determined. Values are mean ± SD. *p < 0.05, **p < 0.01 and ***p < 0.001 compared with control. †p < 0.05 and ††p < 0.01 compared with pair-fed control. White bars/circles, control; black bars/circles, exendin-4; grey bars/circles, pair-fed control

Mentions: Subsequently, we tested our hypothesis that BAT activated during chronic GLP-1R activation is a major contributor to the plasma clearance of TG and glucose. To this end, mice were injected i.v. with [3H]TO-labelled TRL-like emulsion particles and [14C]DG. Indeed, exendin-4 accelerated the clearance of [3H]TO from plasma (Fig. 2a). This enhanced clearance was the result of a greatly increased uptake of [3H]TO-derived activity by iBAT (+276%, p < 0.001; Fig. 2b). In addition, exendin-4 enhanced the uptake of [3H]TO-derived activity by both sWAT (+111%, p < 0.01) and gonadal (g)WAT (+138%, p < 0.05) compared with the control group, corresponding to the browning observed in these WAT depots. The pair-fed animals showed similar results for [3H]TO kinetics as the exendin-4-treated group. Plasma clearance was increased (Fig. 2a), relating to a marked increase in the uptake of 3H activity by iBAT compared with control-infused animals (+314%, p < 0.001; Fig. 2b). In addition, the uptake by sWAT was increased (+194%, p < 0.05), whereas there was no significant effect on uptake by gWAT (+109%, p = 0.20) in pair-fed conditions.Fig. 2


Central GLP-1 receptor signalling accelerates plasma clearance of triacylglycerol and glucose by activating brown adipose tissue in mice.

Kooijman S, Wang Y, Parlevliet ET, Boon MR, Edelschaap D, Snaterse G, Pijl H, Romijn JA, Rensen PC - Diabetologia (2015)

Central GLP-1R activation increases uptake of plasma TG-derived fatty acids and glucose by BAT in lean mice. Mice were treated for 5 days via i.c.v. (a–d) or i.v. (e–f) routes with exendin-4 (n = 8) or vehicle (control n = 9, pair-fed n = 6). After treatment, mice were injected with [3H]TO-labelled particles and [14C]DG. Plasma 3H activity (a) and 14C activity (c) were plotted relative to the injected dose. At 15 min after injection, organs were isolated and uptake of 3H activity (b, e) and 14C activity (d, f) was determined. Values are mean ± SD. *p < 0.05, **p < 0.01 and ***p < 0.001 compared with control. †p < 0.05 and ††p < 0.01 compared with pair-fed control. White bars/circles, control; black bars/circles, exendin-4; grey bars/circles, pair-fed control
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig2: Central GLP-1R activation increases uptake of plasma TG-derived fatty acids and glucose by BAT in lean mice. Mice were treated for 5 days via i.c.v. (a–d) or i.v. (e–f) routes with exendin-4 (n = 8) or vehicle (control n = 9, pair-fed n = 6). After treatment, mice were injected with [3H]TO-labelled particles and [14C]DG. Plasma 3H activity (a) and 14C activity (c) were plotted relative to the injected dose. At 15 min after injection, organs were isolated and uptake of 3H activity (b, e) and 14C activity (d, f) was determined. Values are mean ± SD. *p < 0.05, **p < 0.01 and ***p < 0.001 compared with control. †p < 0.05 and ††p < 0.01 compared with pair-fed control. White bars/circles, control; black bars/circles, exendin-4; grey bars/circles, pair-fed control
Mentions: Subsequently, we tested our hypothesis that BAT activated during chronic GLP-1R activation is a major contributor to the plasma clearance of TG and glucose. To this end, mice were injected i.v. with [3H]TO-labelled TRL-like emulsion particles and [14C]DG. Indeed, exendin-4 accelerated the clearance of [3H]TO from plasma (Fig. 2a). This enhanced clearance was the result of a greatly increased uptake of [3H]TO-derived activity by iBAT (+276%, p < 0.001; Fig. 2b). In addition, exendin-4 enhanced the uptake of [3H]TO-derived activity by both sWAT (+111%, p < 0.01) and gonadal (g)WAT (+138%, p < 0.05) compared with the control group, corresponding to the browning observed in these WAT depots. The pair-fed animals showed similar results for [3H]TO kinetics as the exendin-4-treated group. Plasma clearance was increased (Fig. 2a), relating to a marked increase in the uptake of 3H activity by iBAT compared with control-infused animals (+314%, p < 0.001; Fig. 2b). In addition, the uptake by sWAT was increased (+194%, p < 0.05), whereas there was no significant effect on uptake by gWAT (+109%, p = 0.20) in pair-fed conditions.Fig. 2

Bottom Line: Central administration of exendin-4 in lean mice increased sympathetic outflow towards BAT and white adipose tissue (WAT), resulting in increased thermogenesis as evidenced by increased uncoupling protein 1 (UCP-1) protein levels and decreased lipid content, while the uptake of TG-derived fatty acids was increased in both BAT and WAT.These effects were accompanied by increased fat oxidation, lower plasma TG and glucose concentrations, and reduced body weight.Collectively, our results suggest that BAT activation may be a major contributor to the glucose- and TG-lowering effects of GLP-1R agonism.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Room C7-Q44, Albinusdreef 2, PO Box 9600, 2300, RC, Leiden, the Netherlands. s.kooijman@lumc.nl.

ABSTRACT

Aims/hypothesis: Glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism, used in the treatment of type 2 diabetes, has recently been shown to increase thermogenesis via the brain. As brown adipose tissue (BAT) produces heat by burning triacylglycerol (TG) and takes up glucose for de novo lipogenesis, the aim of this study was to evaluate the potential of chronic central GLP-1R activation by exendin-4 to facilitate clearance of lipids and glucose from the circulation by activating BAT.

Methods: Lean and diet-induced obese (DIO) C57Bl/6J mice were used to explore the effect of a 5 day intracerebroventricular infusion of the GLP-1 analogue exendin-4 or vehicle on lipid and glucose uptake by BAT in both insulin-sensitive and insulin-resistant conditions.

Results: Central administration of exendin-4 in lean mice increased sympathetic outflow towards BAT and white adipose tissue (WAT), resulting in increased thermogenesis as evidenced by increased uncoupling protein 1 (UCP-1) protein levels and decreased lipid content, while the uptake of TG-derived fatty acids was increased in both BAT and WAT. Interestingly, in DIO mice, the effects on WAT were blunted, while exendin-4 still increased sympathetic outflow towards BAT and increased the uptake of plasma TG-derived fatty acids and glucose by BAT. These effects were accompanied by increased fat oxidation, lower plasma TG and glucose concentrations, and reduced body weight.

Conclusions/interpretation: Collectively, our results suggest that BAT activation may be a major contributor to the glucose- and TG-lowering effects of GLP-1R agonism.

No MeSH data available.


Related in: MedlinePlus