Abstract
The melanocortin-3 receptor (MC3R) gene is pleiotropic, influencing body composition, natriuresis, immune function, and entrainment of circadian rhythms to nutrient intake. MC3Rs are expressed in hypothalamic and limbic regions of the brain and in peripheral tissues. To investigate the roles of central MC3Rs, we inserted a "lox-stop-lox" (LoxTB) 5' of the translation initiation codon of the mouse Mc3r gene and reactivated transcription using neuron-specific Cre transgenic mice. As predicted based on earlier observations of Mc3r knock-out mice, Mc3r(TB/TB) mice displayed reduced lean mass, increased fat mass, and accelerated diet-induced obesity. Surprisingly, rescuing Mc3r expression in the nervous system using the Nestin-Cre transgene only partially rescued obesity in chow-fed conditions and had no impact on the accelerated diet-induced obesity phenotype. The ventromedial hypothalamus (VMH), a critical node in the neural networks regulating feeding-related behaviors and metabolic homeostasis, exhibits dense Mc3r expression relative to other brain regions. To target VMH MC3R expression, we used the steroidogenic factor-1 Cre transgenic mouse. Although restoring VMH MC3R signaling also had a modest impact on obesity, marked improvements in metabolic homeostasis were observed. VMH MC3R signaling was not sufficient to rescue the lean mass phenotype or the regulation of behaviors anticipating food anticipation. These results suggest that actions of MC3Rs impacting on energy homeostasis involve both central and peripheral sites of action. The impact of central MC3Rs on behavior and metabolism involves divergent pathways; VMH MC3R signaling improves metabolic homeostasis but does not significantly impact on the expression of behaviors anticipating nutrient availability.
Highlights
Conditional gene targeting methods were used to investigate the role of melanocortin-3 receptors (MC3Rs)
MC3Rs expressed in the brain are not sufficient to defend against diet-induced obesity but can improve metabolic homeostasis
ventromedial hypothalamus (VMH) MC3R signaling was not sufficient to rescue the lean mass phenotype or the regulation of behaviors anticipating food anticipation. These results suggest that actions of MC3Rs impacting on energy homeostasis involve both central and peripheral sites of action
Summary
Conditional gene targeting methods were used to investigate the role of melanocortin-3 receptors (MC3Rs). VMH MC3R signaling was not sufficient to rescue the lean mass phenotype or the regulation of behaviors anticipating food anticipation These results suggest that actions of MC3Rs impacting on energy homeostasis involve both central and peripheral sites of action. Ways; VMH MC3R signaling improves metabolic homeostasis but does not significantly impact on the expression of behaviors anticipating nutrient availability. The obese phenotype is only partially rescued in Nes-Cre;Mc3rTB/TB mice, suggesting that functions of peripheral MC3Rs impact on adiposity. We investigated the impact of restoring MC3R signaling in the VMH on energy homeostasis using steroidogenic factor-1 (SF-1) Cre transgenic mice [35]. Analysis of SF1Cre;Mc3rTB/TB mice indicates that the action of VMH MC3R results in a partial rescue of the body composition phenotype, attenuating the change in fat mass while not affecting lean mass, and markedly improves metabolic homeostasis. Actions of MC3R in neurons residing outside the VMH are required for the expression of food anticipatory activity
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