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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 TH and UCP-1 protein levels and decreases lipid droplet content in BAT in DIO mice. After 12 weeks of high-fat feeding, mice were treated for 5 days with i.c.v. exendin-4 (n = 10) or vehicle (control n = 6, pair-fed n = 9). After treatment, mice were killed and BAT and WAT were collected and stained for TH and UCP-1. Staining with H&E was performed for lipid droplet content. Representative pictures and quantification of TH (a, b), UCP-1 (c, d) and lipid droplet content (e, f) 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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Fig4: Central GLP-1R activation increases TH and UCP-1 protein levels and decreases lipid droplet content in BAT in DIO mice. After 12 weeks of high-fat feeding, mice were treated for 5 days with i.c.v. exendin-4 (n = 10) or vehicle (control n = 6, pair-fed n = 9). After treatment, mice were killed and BAT and WAT were collected and stained for TH and UCP-1. Staining with H&E was performed for lipid droplet content. Representative pictures and quantification of TH (a, b), UCP-1 (c, d) and lipid droplet content (e, f) 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: Under high-fat-fed conditions, i.c.v. exendin-4 treatment still increased SNS output towards BAT compared with controls, reflected by increased TH content (sBAT +59%, p < 0.05 [not shown]; iBAT +107%, p < 0.01, Fig. 4a, b) and increased UCP-1 protein content (sBAT +62% [not shown], p < 0.001; iBAT +93%, p < 0.01, Fig. 4c, d), indicative of more active BAT. As a consequence, lipid droplet content was decreased in the exendin-4-treated animals compared with controls (sBAT −49%, p < 0.05 [not shown]; iBAT −41%, p < 0.01, Fig. 4e, f). Pair feeding did not affect TH expression in BAT (Fig. 4a, b), slightly increased UCP-1 protein content (Fig. 4c, d) and slightly decreased lipid content (Fig. 4e, f) compared with controls. In contrast to the lean mice, infusion of exendin-4 in DIO mice did not induce browning of WAT as evidenced by unaffected TH expression, UCP-1 protein and lipid content.Fig. 4


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 TH and UCP-1 protein levels and decreases lipid droplet content in BAT in DIO mice. After 12 weeks of high-fat feeding, mice were treated for 5 days with i.c.v. exendin-4 (n = 10) or vehicle (control n = 6, pair-fed n = 9). After treatment, mice were killed and BAT and WAT were collected and stained for TH and UCP-1. Staining with H&E was performed for lipid droplet content. Representative pictures and quantification of TH (a, b), UCP-1 (c, d) and lipid droplet content (e, f) 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

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Fig4: Central GLP-1R activation increases TH and UCP-1 protein levels and decreases lipid droplet content in BAT in DIO mice. After 12 weeks of high-fat feeding, mice were treated for 5 days with i.c.v. exendin-4 (n = 10) or vehicle (control n = 6, pair-fed n = 9). After treatment, mice were killed and BAT and WAT were collected and stained for TH and UCP-1. Staining with H&E was performed for lipid droplet content. Representative pictures and quantification of TH (a, b), UCP-1 (c, d) and lipid droplet content (e, f) 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: Under high-fat-fed conditions, i.c.v. exendin-4 treatment still increased SNS output towards BAT compared with controls, reflected by increased TH content (sBAT +59%, p < 0.05 [not shown]; iBAT +107%, p < 0.01, Fig. 4a, b) and increased UCP-1 protein content (sBAT +62% [not shown], p < 0.001; iBAT +93%, p < 0.01, Fig. 4c, d), indicative of more active BAT. As a consequence, lipid droplet content was decreased in the exendin-4-treated animals compared with controls (sBAT −49%, p < 0.05 [not shown]; iBAT −41%, p < 0.01, Fig. 4e, f). Pair feeding did not affect TH expression in BAT (Fig. 4a, b), slightly increased UCP-1 protein content (Fig. 4c, d) and slightly decreased lipid content (Fig. 4e, f) compared with controls. In contrast to the lean mice, infusion of exendin-4 in DIO mice did not induce browning of WAT as evidenced by unaffected TH expression, UCP-1 protein and lipid content.Fig. 4

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