1108-OR: Tanycytic LRP2 Regulates Glucose Homeostasis via VMH SF1 Neurons

Introduction and Objective: Tanycytes are specialized ependymoglial cells lining the third ventricle that sense peripheral metabolic signals and relay them to the hypothalamus. LRP2 (Low-Density Lipoprotein Receptor-Related Protein 2) is expressed in tanycytes and has been implicated in the uptake/transport of circulating signals into the brain. However, the role of LRP2 in glucose metabolism remains unknown. Here, we investigated whether tanycytic LRP2 contributes to systemic glucose regulation and whether this effect engages steroidogenic factor 1 (SF1) neurons in the ventromedial hypothalamus (VMH). Methods: To selectively suppress LRP2 in tanycytes, we used a Cre-dependent AAV knockdown strategy. Cre-dependent AAV1/2-shLRP2-eGFP was co-injected with an AAV-Dio2-Cre (to drive Cre expression in tanycytes) into the 3rd ventricle of adult mice, generating LRP2TanKD mice. We confirmed that LRP2 expression in tanycytes of the median eminence was reduced by ~80% over controls. Results: LRP2TanKD mice displayed a 34% increase in body weight compared to controls at 20 weeks post-injection without changes in food intake. This weight gain was driven by an increase in lean mass rather than fat mass. Despite greater body weight, LRP2TanKD mice showed improved glucose tolerance on a chow diet, as evidenced by a lower AUC during the GTT. This effect is associated with enhanced glucose-stimulated insulin secretion. Concurrently, increased insulin sensitivity was also detected in LRP2TanKD mice. Importantly, suppression of tanycytic LRP2 leads to a marked increase in SF1 and c-fos gene expression, indicating enhanced SF1 neuronal activity. By deleting SF1 in the VMH, we found that the improvement in glucose tolerance and insulin sensitivity in LRP2TanKD mice is restored to normal levels, suggesting a functional connection between tanycytic LRP2 and SF1 neurons. Conclusion: Our findings demonstrate that tanycytic LRP2 modulates systemic glucose metabolism by regulating SF1 neuron activity in the VMH, highlighting a novel tanycyte-neuron crosstalk for maintaining glucose homeostasis. Disclosure F. Timzoura: None. I. Martinez-Corral: None. A.A. Uner: None. W. Yang: None. Y. Kim: None. V. Prevot: None. Funding R01AG080842