Insulin decreases glutamate signaling in the rat dorsomedial hypothalamus through insulin receptors and insulin-like growth factor 1 receptors.

Insulin, an important regulator of peripheral blood glucose levels, can also act in the brain to influence energy metabolism. Insulin receptors are expressed in the dorsomedial hypothalamus (DMH), but nothing is known about the effects of insulin on synaptic function in this region. To determine the effect of insulin on glutamate transmission in the DMH, we used whole cell patch clamp electrophysiology to examine glutamatergic currents in DMH neurons of young male and female Sprague-Dawley rats. Insulin decreased evoked glutamate current amplitude in both sexes and variance analysis suggested this was due to a postsynaptic change in quantal size. Blocking insulin receptors failed to remove the effect of insulin in both sexes, and further experiments revealed that both insulin receptors (IRs) and insulin-like growth factor-1 receptors (IGF-1Rs), and mechanistic target of rapamycin (mTOR), were necessary to completely block the effects of insulin. Tonic insulin significantly decreased glutamate transmission in the DMH through an IR and mTOR-mediated pathway. Overall, our data suggest that insulin acts through IRs and IGF-1Rs to alter synaptic transmission in the DMH and tonic insulin controls the activity of DMH neurons. This research contributes to our understanding of how insulin acts in the hypothalamus to alter synaptic function, with potential implications for diabetes and obesity research.NEW & NOTEWORTHY Although insulin is well known for regulating blood glucose levels and energy metabolism, its role in the dorsomedial hypothalamus (DMH) is not well understood. This study shows that insulin reduces glutamatergic transmission in the DMH of both sexes, through both insulin receptors and insulin-like growth factor 1 receptors. Endogenous insulin also decreases glutamate transmission, primarily through insulin receptors. These findings demonstrate insulin's actions at a key site of appetite regulation and energy metabolism.