Hypothalamic prostaglandins facilitate recovery from hypoglycemia but exacerbate recurrent hypoglycemia in mice

Abstract

AbstractThe hypothalamus regulates systemic glucose metabolism by monitoring glucose levels. In response to hypoglycemia, glucose-inhibited (GI) neurons promote counter-regulatory responses (CRRs) stimulating glucagon, epinephrine, and cortisol secretions. Recurrent hypoglycemia (RH) attenuates CRRs. Here, we show that prostaglandins are produced in the hypothalamus during hypoglycemia to activate GI neurons and thus increase glucagon secretion. RH attenuated glucose production by decreasing glucagon secretion. RH caused a metabolic adaptation and preserved intermediates of glycolysis and amino acids in the hypothalamus during hypoglycemia. Inhibition of prostaglandin production by using short-hairpin RNA (shRNA) against cytosolic phospholipase A2 (cPLA2) in the hypothalamus decreased the attenuation of CRRs by RH. CRR hormones and the activity of GI neurons were not changed in the shRNA-treated group. Our data suggest that hypothalamic prostaglandins are critical for recovering from acute hypoglycemia by affecting glucose-sensing neurons. Hypothalamic prostaglandins are also essential to develop an attenuation of CRRs during RH.Graphical Abstract