Hypothalamus-sympathetic-liver axis mediates the early phase of stress-induced hyperglycemia in the male mice

Rapid glucose supply is crucial for animal survival during stress response. How the timescale of stress-induced glucose release precisely controlled by hypothalamic corticotropin-releasing hormone (CRH) neurons remains unclear. Here, we show that stress-induced hyperglycemia can be divided into at least two stages in male mice: the first fast stage is mediated by hypothalamus (paraventricular to ventromedial hypothalamus)-sympathetic (raphe pallidus nucleus to intermediolateral nucleus)-liver (HSL) axis activity; the second delayed stage is mediated by adrenal activity. Blocking the activity of HSL axis impairs predatory evoked flight responses, indicating that the HSL pathway activity is necessary for stress coping. We further reveal the intracellular signal cascade for CRH signal in the hypothalamus, which is mediated by GABA A receptor β3 subunit phosphorylation at S408/409, results in prevention of GABA A receptor membrane recruitment. Thus, we uncovered the precise timescale of glucose supply during stress which is mediated by adrenal independent HSL and adrenal dependent pathway respectively. Adrenal activity is crucial for glucose release during stress, yet whether it is necessary for rapid glucose release remains unknown. Here, we show that adrenal independent hypothalamussympathetic-liver axis mediated fast glucose release, which is required for predatory evoked flight response.