Activation of Stat3 Signaling in AgRP Neurons Promotes Locomotor Activity

Abstract

Over the last years, much of the research on obesity has focused on the study of leptin. This adipocyte-derived hormone circulates in proportion to fat mass and functions as an adiposity signal to decrease energy intake and increase energy expenditure in order to maintain energy homeostasis. Leptin signals informations on body energy stores to hypothalamic neurons located in the arcuate nucleus (ARC) of the hypothalamus. One of the leptin-regulated neuronal subtypes in the ARC are the orexigenic agouti-related peptide (AgRP)-producing neurons, which are directly inhibited by leptin. A key pathway downstream of the leptin receptor involves activation of the signal transducer and activator of transcription 3 (Stat3), but the role of Stat3 in the regulation of AgRP neurons remains controversial. In this study, analysis of Stat3-CAgRP mice expressing a constitutively active version of the Stat3 protein (Stat3-C) selectively in AgRP neurons reveals a crucial role for Stat3 in AgRP neurons in the regulation of energy expenditure in vivo. Stat3-CAgRP mice are lean and develop a relative resistance to diet-induced obesity accompanied by improved glucose homeostasis. The lean phenotype of Stat3-CAgRP mice appears in the presence of unaltered AgRP expression and caloric intake as a consequence of increased energy expenditure evoked by elevated locomotor activity. Consistent with the phenotype observed in Stat3-CAgRP mice, expression of Stat3-C in AgRP neurons of leptin deficient ob/ob mice diminishes the obese phenotype of ob/ob mice as a result of increased energy expenditure and locomotor activity in the presence of unaltered food intake. Analysis of brain catecholamines in Stat3-CAgRP mice revealed a trend towards elevated dopamine concentrations in the striatum and frontal cortex, which potentially account for the increased locomotor activity in those mice. Nevertheless, the anatomical interaction of AgRP neurons with neuronal centers that control locomotor activity and the exact molecular mechanism in AgRP neurons leading to Stat3-dependent activation of locomotor activity have to be defined further. Taken together, this thesis introduces a novel model according to which leptin-stimulated Stat3 activation in AgRP neurons directly regulates locomotor activity independent of the regulation of AgRP mRNA expression