Metformin requires tanycytic leptin transport to mediate its anti-obesity effect

Abstract

Obesity is a global epidemic driven by an imbalance between food intake and energy expenditure. Leptin, an adipokine, regulates energy homeostasis by reducing food intake and increasing energy expenditure via actions in the hypothalamus. In diet-induced obesity (DIO), however, circulating leptin fails to reach target neurons in the mediobasal hypothalamus (MBH). Tanycytes—specialized glial cells lining the third ventricle—facilitate leptin transport into the MBH through ERK- and leptin receptor (LepR)-dependent mechanisms. In DIO mice, ERK reactivation restores this transport, while tanycyte-specific LepR knockout (LeprTanKO) impairs it.

We investigated whether metformin, an anti-diabetic drug known to promote weight loss and improve leptin sensitivity, can influence leptin transport in DIO. Chronic metformin treatment reduced body weight by decreasing food intake in DIO mice. Hypothalamic microdialysis showed that weight loss coincided with restored leptin transport.

Importantly, tanycyte-specific LepR deletion blunted metformin's effects on leptin transport and weight loss, indicating that its anti-obesity actions require functional tanycytic transport. In cultured tanycytes, metformin directly stimulated exocytosis of internalized leptin. To explore the mechanisms, we examined whether metformin's effects depend on AMPK, a common target of the drug. Tanycyte-specific AMPKα1/2 knockout did not block weight loss, suggesting AMPK is not required. However, combined metformin and leptin treatment activated ERK, pointing to ERK as a key mediator.

These findings suggest that metformin restores leptin transport early in obesity by reactivating ERK signaling in tanycytes, halting disease progression. Metformin may thus represent a valuable early intervention strategy to reduce dependence on stronger, less understood weight-loss drugs.