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  • Considerable evidence links sustained GCG administration to


    Considerable evidence links sustained GCG administration to the reduction of food intake, enhancement of energy expenditure and weight loss in rodent and human studies [16], [17], [18]. Moreover, patients presenting with GCG-producing tumors frequently manifest severe weight loss, through mechanisms that are incompletely understood [19]. Despite several decades of experimentation, the precise processes and cell types contributing to GCG-mediated weight loss remain incompletely understood. Although intracerebroventricular infusion of GCG directly reduces food intake [20] and increases energy expenditure [21], other studies have demonstrated that the GCG-mediated reduction of food intake requires intact hepatic vagal nerve innervation [22] and rats with surgical BAT denervation exhibit diminished metabolic and mitochondrial responses to exogenous glucagon [23]. The clinical development of investigational GCG-containing multi-agonists, including oxyntomodulin and its derivatives [3], [24], [25], for the treatment of diabetes and obesity has rekindled interest in whether and how GCGR signaling results in BAT activation and increased energy expenditure [2], [26], [27]. Several studies invoke an indirect role for GCG on BAT and energy expenditure, acting through enhanced blood flow [28], the sympathetic nervous system (SNS) [29], [30], or fibroblast growth factor (FGF)21 [31], [32]. However, other studies support a direct role for GCG as an activator of oxygen consumption in BAT [14], [33]. Interestingly, GCG infusion in healthy humans subjected to cold exposure increased energy expenditure without evidence for BAT activation as assessed by positron emission tomography scanning [15]. Here we examined the importance of the BAT GCGR for GCG-stimulated energy expenditure in mice and characterized the metabolic phenotype of mice with genetic TAE684 of the Gcgr in BAT using myogenic factor 5 (Myf5)-Cre. Using BAT cells and explants ex vivo, as well as WT and knockout mice, we demonstrate that GCG acts both directly and indirectly to enhance whole body and BAT oxygen consumption. Nevertheless, the BAT Gcgr is physiologically dispensable for GCG-stimulated increase in energy expenditure, and the adaptive metabolic responses to HFD feeding or prolonged cold exposure.
    Materials and methods
    Discussion Considerable experimentation links acute GCG administration to increased core body temperature [39], BAT blood flow [28], BAT mass, and thermogenic activity [17], [23], as well as enhanced energy expenditure in rodents TAE684 and humans [13], [40]. Moreover, several studies have demonstrated direct actions of GCG on BAT [11], [41], raising the possibility that GCGR activity contributes to the endogenous control of whole body energy expenditure. Herein, we refine the mechanistic importance of these findings by using mouse genetics to test the relative importance of the murine BAT GCGR for the acute response to GCG administration, and the long term physiological control of energy homeostasis. Pharmacological GCG agonism produces weight loss through reduction in food intake and via potentiation of thermogenic mechanisms to increase energy expenditure [3], [4]. Indeed, GCG-containing peptide multi-agonists require a functional GCGR to reduce fat mass and generate weight loss in HFD-fed mice, actions reflecting a combination of reduced food intake and enhanced energy expenditure [42]. Similarly, the weight loss observed with the GCG-GLP-1 co-agonist MEDI0382 in preclinical studies was partially attributed to GCGR-dependent induction of energy expenditure [43]. Identification of the key tissues essential for the GCGR-dependent control of energy expenditure remains incomplete, and the available evidence supports a role for multiple organs, including liver and adipose tissue, in transducing GCGR-stimulated signals linked to enhanced oxygen consumption [3], [32]. Although GCG administration increased Ucp1 expression in BAT and increased Fgf21 mRNA transcripts in murine liver [12], [44], our current data demonstrate that Ucp1 is not required for acute GCG induction of oxygen consumption.