Abstract
[11C]SNAP-7941 and its radiofluorinated, fluoro-ethyl derivative [18F]FE@SNAP have been developed as the first positron emission tomography tracers for melanin-concentrating hormone receptor 1 (MCHR1) imaging. Accumulation of these MCHR1 PET-tracers in rat brown adipose tissue (BAT) in vivo provided first indication of MCHR1 expression in rodent BAT. To rule out off-target binding, affinity of both MCHR1 ligands toward adrenergic beta-3 receptors (ADRB3) was examined. Further, specific binding of [11C]SNAP-7941 to brown adipocytes and effects of MCHR1 ligands on brown adipocyte activation were investigated. SNAP-7941 and FE@SNAP evinced to be highly selective toward MCHR1. [11C]SNAP-7941 binding to brown adipocytes was shown to be mainly MCHR1-specific. This data strongly indicates MCHR1 expression in rodent BAT and moreover, a peripheral, anti-obesity effect of MCHR1 antagonists directly exerted in BAT is proposed. Moreover, MCHR1 expression in murine brown adipocytes was confirmed by protein and mRNA analysis. We conclude that MCHR1 PET imaging contributes to basic research in endocrinology by elucidating the involvement of the MCH system in peripheral tissues, such as BAT.
Highlights
The physiological relevance of brown adipose tissue (BAT) was underestimated for a long time, it nowadays attracts scientific interest as a therapeutic target for obesity and related metabolic diseases such as type 2 diabetes [1,2,3]
Highest Mchr1 mRNA levels were found in mouse brain, whereas low expression was detected in mouse lung and murine brown adipocytes
The adrenergic beta receptor antagonist (S)-propranolol exerted no BAT activating effect. These results prove the expression of functional adrenergic beta-3 receptors (ADRB3) on the cultivated brown adipocytes used within this study
Summary
The physiological relevance of brown adipose tissue (BAT) was underestimated for a long time, it nowadays attracts scientific interest as a therapeutic target for obesity and related metabolic diseases such as type 2 diabetes [1,2,3]. MCHR1 in Murine Brown Adipocytes that BAT activity, quantified as [18F]FDG uptake, was negatively correlated to body mass index and percent body fat indicated a potential role of BAT in energy expenditure in humans [4,5,6]. Besides [18F]FDG, other PET-tracers were investigated to study BAT function, namely [11C]meta-hydroxyephedrine, [11C]acetate, 14-[18F]fluoro-6-thiaheptadecanoic acid, and (S,S)-O-[methyl11C] methylreboxetine thereby enhancing the understanding of BAT activation, control, and metabolism [7,8,9]. Evolutionary, BAT functions as an energy dissipating organ by exerting non-shivering thermogenesis and maintaining body temperature during cold exposure. This heat-producing process is controlled by the sympathetic nervous system leading to noradrenaline release followed by activation of adrenergic beta-3 receptors (ADRB3) in brown adipocytes. Thereby, BAT regulates fuel metabolism by increasing glucose and triglyceride uptake, decreasing blood glucose and lipids, and by serving as glycogen storage [1, 10,11,12,13,14]
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