Homeobox gene Sax2 deficiency causes an imbalance in energy homeostasis

The brain, in particular the hypothalamus and the brainstem, plays a critical role in the regulation of energy homeostasis by incorporating signals from the periphery and translating them into feeding behavior. Here we show that the homeobox gene Sax2, which is expressed predominantly in the brainstem, in the vicinity of serotonergic neurons, contributes to this physiological balance. Sax2 deficiency results in a decrease of fat and glycogen storage, reduced blood glucose levels, and raised serotonin levels in the hindbrain. Surprisingly, in the brainstem the expression levels of pro-opiomelanocortin and neuropeptide Y were indicative of a fasting condition, opposed to the observed high serotonin levels implying satiation. Furthermore, Sax2-directed lacZ expression reveals a dramatic change of the distribution of Sax2-expressing cells in the null mutant occurring during perinatal development. These data strongly suggest that Sax2 is required for the coordinated crosstalk of factors involved in the maintenance of energy homeostasis.