Top

Published in:

Open Access 01-11-2015 | Article

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

Authors: Sander Kooijman, Yanan Wang, Edwin T. Parlevliet, Mariëtte R. Boon, David Edelschaap, Gido Snaterse, Hanno Pijl, Johannes A. Romijn, Patrick C. N. Rensen

Published in: Diabetologia | Issue 11/2015

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.

Gallwitz B (2011) Glucagon-like peptide-1 analogues for Type 2 diabetes mellitus: current and emerging agents. Drugs 71:1675–1688CrossRefPubMed

Hwa JJ, Ghibaudi L, Williams P, Witten MB, Tedesco R, Strader CD (1998) Differential effects of intracerebroventricular glucagon-like peptide-1 on feeding and energy expenditure regulation. Peptides 19:869–875CrossRefPubMed

Turton MD, O'Shea D, Gunn I et al (1996) A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379:69–72CrossRefPubMed

Knauf C, Cani PD, Perrin C et al (2005) Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage. J Clin Invest 115:3554–3563PubMedCentralCrossRefPubMed

Sandoval DA, Bagnol D, Woods SC, D'Alessio DA, Seeley RJ (2008) Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake. Diabetes 57:2046–2054PubMedCentralCrossRefPubMed

Parlevliet ET, de Leeuw van Weenen JE, Romijn JA, Pijl H (2010) GLP-1 treatment reduces endogenous insulin resistance via activation of central GLP-1 receptors in mice fed a high-fat diet. Am J Physiol Endocrinol Metab 299:E318–E324PubMed

Boon MR, van den Berg SA, Wang Y et al (2013) BMP7 activates brown adipose tissue and reduces diet-induced obesity only at subthermoneutrality. PLoS One 8, e74083PubMedCentralCrossRefPubMed

Geerling JJ, Boon MR, van der Zon GC et al (2014) Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice. Diabetes 63:880–891CrossRefPubMed

Bartelt A, Bruns OT, Reimer R et al (2011) Brown adipose tissue activity controls triglyceride clearance. Nat Med 17:200–205CrossRefPubMed

10.

Emanuelli B, Vienberg SG, Smyth G et al (2014) Interplay between FGF21 and insulin action in the liver regulates metabolism. J Clin Invest 124:515–527PubMedCentralCrossRefPubMed

11.

Khedoe PP, Hoeke G, Kooijman S et al (2015) Brown adipose tissue takes up plasma triglycerides mostly after lipolysis. J Lipid Res 56:51–59CrossRefPubMed

12.

Lockie SH, Heppner KM, Chaudhary N et al (2012) Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling. Diabetes 61:2753–2762PubMedCentralCrossRefPubMed

13.

Beiroa D, Imbernon M, Gallego R et al (2014) GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 63:3346–3358CrossRefPubMed

14.

Coomans CP, Biermasz NR, Geerling JJ et al (2011) Stimulatory effect of insulin on glucose uptake by muscle involves the central nervous system in insulin-sensitive mice. Diabetes 60:3132–3140PubMedCentralCrossRefPubMed

15.

Rensen PC, Herijgers N, Netscher MH, Meskers SC, van Eck M, van Berkel TJ (1997) Particle size determines the specificity of apolipoprotein E-containing triglyceride-rich emulsions for the LDL receptor versus hepatic remnant receptor in vivo. J Lipid Res 38:1070–1084PubMed

16.

Van Klinken JB, van den Berg SA, Havekes LM, van Willems DK (2012) Estimation of activity related energy expenditure and resting metabolic rate in freely moving mice from indirect calorimetry data. PLoS One 7, e36162PubMedCentralCrossRefPubMed

17.

Al-Barazanji KA, Arch JR, Buckingham RE, Tadayyon M (2000) Central exendin-4 infusion reduces body weight without altering plasma leptin in (fa/fa) Zucker rats. Obes Res 8:317–323CrossRefPubMed

18.

Nogueiras R, Perez-Tilve D, Veyrat-Durebex C et al (2009) Direct control of peripheral lipid deposition by CNS GLP-1 receptor signaling is mediated by the sympathetic nervous system and blunted in diet-induced obesity. J Neurosci 29:5916–5925CrossRefPubMed

19.

Giordano A, Frontini A, Cinti S (2008) Adipose organ nerves revealed by immunohistochemistry. Methods Mol Biol 456:83–95CrossRefPubMed

20.

Challa TD, Beaton N, Arnold M, Rudofsky G, Langhans W, Wolfrum C (2012) Regulation of adipocyte formation by GLP-1/GLP-1R signaling. J Biol Chem 287:6421–6430PubMedCentralCrossRefPubMed

21.

Korsheninnikova E, van der Zon GC, Voshol PJ et al (2006) Sustained activation of the mammalian target of rapamycin nutrient sensing pathway is associated with hepatic insulin resistance, but not with steatosis, in mice. Diabetologia 49:3049–3057CrossRefPubMed

22.

Surwit RS, Kuhn CM, Cochrane C, McCubbin JA, Feinglos MN (1988) Diet-induced type II diabetes in C57BL/6J mice. Diabetes 37:1163–1167CrossRefPubMed

23.

van Baak MA (2001) The peripheral sympathetic nervous system in human obesity. Obes Rev 2:3–14CrossRefPubMed

24.

Bartness TJ, Song CK (2007) Brain-adipose tissue neural crosstalk. Physiol Behav 91:343–351PubMedCentralCrossRefPubMed

25.

Goke R, Larsen PJ, Mikkelsen JD, Sheikh SP (1995) Distribution of GLP-1 binding sites in the rat brain: evidence that exendin-4 is a ligand of brain GLP-1 binding sites. Eur J Neurosci 7:2294–2300CrossRefPubMed

26.

Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84:277–359CrossRefPubMed

27.

Parlevliet ET, Wang Y, Geerling JJ et al (2012) GLP-1 receptor activation inhibits VLDL production and reverses hepatic steatosis by decreasing hepatic lipogenesis in high-fat-fed APOE*3-Leiden mice. PLoS One 7, e49152PubMedCentralCrossRefPubMed

28.

Tachibana T, Oikawa D, Adachi N, Boswell T, Furuse M (2007) Intracerebroventricular injection of glucagon-like peptide-1 changes lipid metabolism in chicks. Comp Biochem Physiol A Mol Integr Physiol 147:1104–1108CrossRefPubMed

29.

Dickson SL, Shirazi RH, Hansson C, Bergquist F, Nissbrandt H, Skibicka KP (2012) The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: a new role for mesolimbic GLP-1 receptors. J Neurosci 32:4812–4820CrossRefPubMed

30.

Virtue S, Even P, Vidal-Puig A (2012) Below thermoneutrality, changes in activity do not drive changes in total daily energy expenditure between groups of mice. Cell Metab 16:665–671PubMedCentralCrossRefPubMed

31.

Berbee JF, Boon MR, Khedoe PP et al (2015) Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development. Nat Commun 6:6356PubMedCentralCrossRefPubMed

Title: Central GLP-1 receptor signalling accelerates plasma clearance of triacylglycerol and glucose by activating brown adipose tissue in mice
Authors: Sander Kooijman
Yanan Wang
Edwin T. Parlevliet
Mariëtte R. Boon
David Edelschaap
Gido Snaterse
Hanno Pijl
Johannes A. Romijn
Patrick C. N. Rensen
Publication date: 01-11-2015
Publisher: Springer Berlin Heidelberg
Published in: Diabetologia / Issue 11/2015
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-015-3727-0

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Please log in to get access to this content

Other articles of this Issue 11/2015

Feasibility, acceptability and uptake rates of gestational diabetes mellitus screening in primary care vs secondary care: findings from a randomised controlled mixed methods trial

The new biology of diabetes

Elevated nocturnal NEFA are an early signal for hyperinsulinaemic compensation during diet-induced insulin resistance in dogs

Caesarean section per se does not increase the risk of offspring developing type 1 diabetes: a Swedish population-based study

Ethnic differences in hepatic and systemic insulin sensitivity and their associated determinants in obese black and white South African women

Elevated HbA1c levels and the accumulation of differentiated T cells in CMV+ individuals

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials