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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 decreases body weight and food intake and induces activation of BAT in lean mice. Mice were treated for 5 days with i.c.v. exendin-4 (n = 8) or vehicle (control n = 9, pair-fed n = 6). On a daily basis, body weight (a, b) and food intake (c) were monitored. Samples of BAT and WAT were collected and stained for TH and UCP-1. Representative pictures and quantification of TH (d, e), UCP-1 (f, g) and lipid droplet content with H&E staining (h, i) are shown. Values are mean ± SD. *p < 0.05, **p < 0.01 and ***p < 0.001 compared with control; †p < 0.01 compared with pair-fed control. White bars, control; black bars, exendin-4; grey bars, pair-fed control
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Fig1: Central GLP-1R activation decreases body weight and food intake and induces activation of BAT in lean mice. Mice were treated for 5 days with i.c.v. exendin-4 (n = 8) or vehicle (control n = 9, pair-fed n = 6). On a daily basis, body weight (a, b) and food intake (c) were monitored. Samples of BAT and WAT were collected and stained for TH and UCP-1. Representative pictures and quantification of TH (d, e), UCP-1 (f, g) and lipid droplet content with H&E staining (h, i) are shown. Values are mean ± SD. *p < 0.05, **p < 0.01 and ***p < 0.001 compared with control; †p < 0.01 compared with pair-fed control. White bars, control; black bars, exendin-4; grey bars, pair-fed control

Mentions: Intracerebroventricular infusion of exendin-4 in lean C57Bl/6J mice decreased body weight compared with controls (Fig. 1a, b), and this was accompanied by a reduced food intake (Fig. 1c), both of which are well-known effects of activation of the central GLP-1R system [3, 17]. Reduction of food intake per se, as shown by the control mice that were pair fed with the exendin-4-treated mice (Fig. 1c), resulted in a reduction in body weight compared with controls that was delayed compared with that evoked by exendin-4 (Fig. 1a).Fig. 1


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 decreases body weight and food intake and induces activation of BAT in lean mice. Mice were treated for 5 days with i.c.v. exendin-4 (n = 8) or vehicle (control n = 9, pair-fed n = 6). On a daily basis, body weight (a, b) and food intake (c) were monitored. Samples of BAT and WAT were collected and stained for TH and UCP-1. Representative pictures and quantification of TH (d, e), UCP-1 (f, g) and lipid droplet content with H&E staining (h, i) are shown. Values are mean ± SD. *p < 0.05, **p < 0.01 and ***p < 0.001 compared with control; †p < 0.01 compared with pair-fed control. White bars, control; black bars, exendin-4; grey bars, pair-fed control
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4589565&req=5

Fig1: Central GLP-1R activation decreases body weight and food intake and induces activation of BAT in lean mice. Mice were treated for 5 days with i.c.v. exendin-4 (n = 8) or vehicle (control n = 9, pair-fed n = 6). On a daily basis, body weight (a, b) and food intake (c) were monitored. Samples of BAT and WAT were collected and stained for TH and UCP-1. Representative pictures and quantification of TH (d, e), UCP-1 (f, g) and lipid droplet content with H&E staining (h, i) are shown. Values are mean ± SD. *p < 0.05, **p < 0.01 and ***p < 0.001 compared with control; †p < 0.01 compared with pair-fed control. White bars, control; black bars, exendin-4; grey bars, pair-fed control
Mentions: Intracerebroventricular infusion of exendin-4 in lean C57Bl/6J mice decreased body weight compared with controls (Fig. 1a, b), and this was accompanied by a reduced food intake (Fig. 1c), both of which are well-known effects of activation of the central GLP-1R system [3, 17]. Reduction of food intake per se, as shown by the control mice that were pair fed with the exendin-4-treated mice (Fig. 1c), resulted in a reduction in body weight compared with controls that was delayed compared with that evoked by exendin-4 (Fig. 1a).Fig. 1

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