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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 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 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 the 3H activity (b) and 14C activity (d) 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, control; black bars, exendin-4; grey bars, pair-fed control
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Fig5: Central GLP-1R activation increases uptake of plasma TG-derived fatty acids and glucose by 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 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 the 3H activity (b) and 14C activity (d) 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, control; black bars, exendin-4; grey bars, pair-fed control

Mentions: Similar to lean mice, chronic i.c.v. infusion of exendin-4 in DIO mice accelerated the plasma clearance of [3H]TO (Fig. 5a) and [14C]DG (Fig. 5c). This was accompanied by a selectively increased uptake of [3H]TO-derived activity and [14C]DG by iBAT (+291%, p < 0.001 and +482%, p < 0.001, respectively) and sBAT (+217%, p < 0.01 and +247%, p < 0.001, respectively) (Fig. 5b, d). Despite the lack of evidence for browning of WAT, exendin-4 enhanced the uptake of both [3H]TO-derived activity and [14C]DG by both sWAT (+146%, p < 0.05 and +93%, p < 0.05) and gWAT (+69%, p < 0.01 and +82%, p < 0.01). To some extent, the pair-fed animals showed similar results on [3H]TO and [14C]DG kinetics as the exendin-4 treated mice. Plasma clearance was increased (Fig. 5a, c), associated with a marked increase in uptake of [3H]TO-derived activity and [14C]DG by iBAT (+170%, p < 0.01 and +482%, p < 0.001, respectively) and sBAT (+188%, p < 0.001 and +247%, p < 0.001, respectively) compared with control-infused animals (Fig. 5b, d). Interestingly, the uptake of [3H]TO-derived activity by iBAT and the uptake of [14C]DG by iBAT and sBAT were significantly lower compared with the exendin-4-treated mice (−31%, p < 0.05, −63%, p < 0.01 and −43%, p < 0.01, respectively), indicating that exendin-4 exerts its effects partly independent of lowering food intake.Fig. 5


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 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 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 the 3H activity (b) and 14C activity (d) 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, control; black bars, exendin-4; grey bars, pair-fed control
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig5: Central GLP-1R activation increases uptake of plasma TG-derived fatty acids and glucose by 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 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 the 3H activity (b) and 14C activity (d) 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, control; black bars, exendin-4; grey bars, pair-fed control
Mentions: Similar to lean mice, chronic i.c.v. infusion of exendin-4 in DIO mice accelerated the plasma clearance of [3H]TO (Fig. 5a) and [14C]DG (Fig. 5c). This was accompanied by a selectively increased uptake of [3H]TO-derived activity and [14C]DG by iBAT (+291%, p < 0.001 and +482%, p < 0.001, respectively) and sBAT (+217%, p < 0.01 and +247%, p < 0.001, respectively) (Fig. 5b, d). Despite the lack of evidence for browning of WAT, exendin-4 enhanced the uptake of both [3H]TO-derived activity and [14C]DG by both sWAT (+146%, p < 0.05 and +93%, p < 0.05) and gWAT (+69%, p < 0.01 and +82%, p < 0.01). To some extent, the pair-fed animals showed similar results on [3H]TO and [14C]DG kinetics as the exendin-4 treated mice. Plasma clearance was increased (Fig. 5a, c), associated with a marked increase in uptake of [3H]TO-derived activity and [14C]DG by iBAT (+170%, p < 0.01 and +482%, p < 0.001, respectively) and sBAT (+188%, p < 0.001 and +247%, p < 0.001, respectively) compared with control-infused animals (Fig. 5b, d). Interestingly, the uptake of [3H]TO-derived activity by iBAT and the uptake of [14C]DG by iBAT and sBAT were significantly lower compared with the exendin-4-treated mice (−31%, p < 0.05, −63%, p < 0.01 and −43%, p < 0.01, respectively), indicating that exendin-4 exerts its effects partly independent of lowering food intake.Fig. 5

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