Liraglutide Activates Type 2 Deiodinase and Enhances β3-Adrenergic-Induced Thermogenesis in Mouse Adipose Tissue

Fernanda C B Oliveira, Eduarda J Bauer, Carolina M Ribeiro, Sidney A Pereira, Bruna T S Beserra, Simone M Wajner, Ana L Maia, Francisco A R Neves, Michella S Coelho, Angelica A Amato, Fernanda C B Oliveira, Eduarda J Bauer, Carolina M Ribeiro, Sidney A Pereira, Bruna T S Beserra, Simone M Wajner, Ana L Maia, Francisco A R Neves, Michella S Coelho, Angelica A Amato

Abstract

Aims: Liraglutide 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.

Methods: Male 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.

Results: Liraglutide 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.

Conclusions: Liraglutide 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.

Keywords: GLP-1 receptor agonist; adipose tissue; liraglutide; type 2 deiodinase; β3-adrenergic stimulation.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Oliveira, Bauer, Ribeiro, Pereira, Beserra, Wajner, Maia, Neves, Coelho and Amato.

Figures

Figure 1
Figure 1
Effect of liraglutide and β3-AR stimulation on fasting blood glucose, body weight, fat mass, and food intake. (A) Study design: male C57BL/6J received liraglutide (400 μg/kg/d) or control for 21 days, ± the β3-adrenergic agonist CL 316,243 (CL) during the last 5 days of treatment. (B) Fasting blood glucose levels after liraglutide and CL treatment, (C) body weight before and during liraglutide and CL treatment, (D) body weight change after liraglutide and CL treatment, (E) energy intake before and during liraglutide and CL treatment, (F) mean daily energy intake during liraglutide and CL treatment, (G) caloric efficiency, and (H) iBAT, (I) ingWAT, and (J) epiWAT mass. #p < 0.05 liraglutide-treated mice (Lira and Lira + CL) vs vehicle by Two-way ANOVA followed by Tukey’s multiple comparison test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 vs control or indicated group, by One-way ANOVA followed by Tukey’s multiple comparison test. Data presented as mean ± SEM, n=5-6 for each experimental group. CL, CL316,243; epiWAT, epidydimal white adipose tissue; iBAT, interscapular brown adipose tissue; ingWAT, inguinal white adipose tissue; Lira, liraglutide.
Figure 2
Figure 2
Additive effects of liraglutide and β3-AR stimulation in activating iBAT. (A) iBAT immunostaining for UCP-1 (magnification: X10; scale bar: 100 μm), (B) iBAT UCP-1 mRNA levels, (C) iBAT oxygen consumption. *p < 0.05, ***p < 0.001, ****p < 0.0001 vs control or indicated group, by One-way ANOVA followed by Tukey’s multiple comparison test. Data presented as mean ± SEM, n=5-6 for each experimental group. CL, CL316,243; iBAT, interscapular brown adipose tissue; Lira, liraglutide.
Figure 3
Figure 3
Additive effects of liraglutide and β3-AR stimulation in inducing browning of ingWAT. (A) ingWAT immunostaining for UCP-1 (magnification: X10; scale bar: 200 μm), (B) adipocyte diameter, (C) ingWAT UCP-1 mRNA levels, (D) ingWAT oxygen consumption. *p < 0.05, **p < 0.001, ***p < 0.001, vs control or indicated group, by One-way ANOVA followed by Tukey’s multiple comparison test. Data presented as mean ± SEM, n=5-6 for each experimental group. CL, CL316,243; ingWAT, inguinal white adipose tissue; Lira, liraglutide.
Figure 4
Figure 4
Effect of liraglutide treatment on D2 activity in adipose tissue. (A) D2 activity in iBAT, (B) mRNA levels of D2, thyroid hormone transporters and thyroid hormone receptors in iBAT, (C) D2 activity in ingWAT, (D) mRNA levels of D2, thyroid hormone transporters and thyroid hormone receptors in ingWAT. *p < 0.05, **p < 0.01 vs control by One-way ANOVA followed by Tukey’s multiple comparison test. Data presented as mean ± SEM, n=5-6 for each experimental group. CL, CL316,243; iBAT, interscapular brown adipose tissue; ingWAT, inguinal white adipose tissue; Lira, liraglutide.

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