Abstract
AimsLiraglutide is a long-acting glucagon-like peptide 1 (GLP-1) receptor agonist used as an anti-hyperglycemic agent in type 2 diabetes treatment and recently approved for obesity management. Weight loss is attributed to appetite suppression, but therapy may also increase energy expenditure. To further investigate the effect of GLP-1 signaling in thermogenic fat, we assessed adipose tissue oxygen consumption and type 2 deiodinase (D2) activity in mice treated with liraglutide, both basally and after β3-adrenergic treatment.MethodsMale C57BL/6J mice were randomly assigned to receive liraglutide (400 μg/kg, n=12) or vehicle (n=12). After 16 days, mice in each group were co-treated with the selective β3-adrenergic agonist CL316,243 (1 mg/kg, n=6) or vehicle (n=6) for 5 days. Adipose tissue depots were assessed for gene and protein expression, oxygen consumption, and D2 activity.ResultsLiraglutide increased interscapular brown adipose tissue (iBAT) oxygen consumption and enhanced β3-adrenergic-induced oxygen consumption in iBAT and inguinal white adipose tissue (ingWAT). These effects were accompanied by upregulation of UCP-1 protein levels in iBAT and ingWAT. Notably, liraglutide increased D2 activity without significantly upregulating its mRNA levels in iBAT and exhibited additive effects to β3-adrenergic stimulation in inducing D2 activity in ingWAT.ConclusionsLiraglutide exhibits additive effects to those of β3-adrenergic stimulation in thermogenic fat and increases D2 activity in BAT, implying that it may activate this adipose tissue depot by increasing intracellular thyroid activation, adding to the currently known mechanisms of GLP-1A-induced weight loss.
Highlights
Glucagon-like peptide 1 (GLP-1) is an incretin hormone with pleiotropic physiological effects, many of which occur at key sites of energy balance control and favorably affect metabolic homeostasis
Weight loss induced by GLP-1A treatment is largely attributed to reduced appetite and energy intake through GLP1 signaling in the hypothalamus
In the latter study it was shown that increased peripheral levels of iNKT cells and FGF-21 were observed in humans treated with liraglutide and were positively correlated with the degree of weight loss induced by therapy [9]
Summary
Glucagon-like peptide 1 (GLP-1) is an incretin hormone with pleiotropic physiological effects, many of which occur at key sites of energy balance control and favorably affect metabolic homeostasis. There is evidence that GLP-1A may affect energy expenditure by activating brown adipose tissue (BAT) and recruiting beige/brite adipocytes in white adipose tissue (WAT), a process so-called browning of WAT, through several mechanisms. Peripheral administration of exenatide induced browning of epididymal WAT in mice by upregulating sirtuin 1 expression in adipocytes [8], and peripheral administration of liraglutide activated invariant natural killer (iNKT) cells resident in WAT to increase fibroblast growth factor 21 (FGF21) production, leading to browning of inguinal white fat in mice. In the latter study it was shown that increased peripheral levels of iNKT cells and FGF-21 were observed in humans treated with liraglutide and were positively correlated with the degree of weight loss induced by therapy [9]
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