Tanycyte Bmal1 sex-specifically regulates weight gain and hypothalamic neurogenesis in female mice

The hypothalamic radial-glia-like tanycyte population plays important and intertwined roles in feeding and metabolism, reproduction, and seasonality. Although these processes are circadian-regulated and clock genes reportedly show robust cycling along the 3rd ventricle, the role of the clock in tanycytes has not yet been examined. We report here that clock genes cycle with much higher amplitude in ventral tanycytes compared to more dorsal ependymocytes of the 3rd ventricle, and that specific disruption of the tanycyte clock can be achieved by adult Bmal1 deletion using the RaxCreER driver. Adult tanycyte Bmal1 deletion did not affect circadian rhythms of wheel-running and sleep, but did inhibit weight gain on high-fat diet in female mice. Altered tanycyte-derived hypothalamic neurogenesis, which can regulate feeding and weight gain by contributing new neurons to nearby feeding-relevant nuclei, is one mechanism that likely contributes to this phenotype. Fate mapping studies showed that female mice have higher baseline tanycyte-derived neurogenesis than males, with many of the resulting neurons localizing to the feeding-relevant arcuate nucleus. Female but not male mice show reduced tanycyte-derived arcuate neurogenesis after adult tanycyte Bmal1 deletion and an increased percentage of newborn arcuate neurons take on a feeding-suppressing POMC neuropeptidergic fate. Thereby, skewing of feeding and satiety promoting fates link the weight homeostasis and neurogenesis effects. Together, our data establish tanycyte Bmal1 as a sexually dimorphic regulator of weight homeostasis, likely mediated at least in part by a female-specific neurogenesis effect in the feeding circuitry.