Glucose as fuel for HPA axis regulation: A narrative review on energy metabolism, stress reactivity, and early life adversity

Abstract

Stress physiology and energy metabolism are inherently linked. While the physiological stress response mobilizes energy, early experimental work by Clemens Kirschbaum and colleagues demonstrated that glucose availability in turn shapes the stress response: Fasting attenuates cortisol reactivity, whereas glucose administration restores or amplifies it. Since then, an active line of research on this topic evolved, yet the role of glucose availability in shaping stress regulation still remains incompletely understood.

In this targeted, narrative review, we first synthesize evidence from the last 30 years that showed that blood glucose acts as a physiological modulator of acute HPA axis responsivity to stress. Second, we discuss these observations within the framework of the Selfish Brain Theory, which conceptualizes the endocrine stress axis and sympathetic nervous system as allocative systems that prioritize cerebral energy supply under conditions of acute stress. Third, we review potential consequences of the glucose-stress link in the context of stress occurring chronically or during sensitive developmental periods, such as early life adversity (ELA). Finally, we argue that future work should adopt a multisystemic perspective integrating more than just glucose as metabolic modulator as well as sympathetic, parasympathetic, endocrine processes alongside changes in affect. Here, we call for moving beyond controlled laboratory settings to investigate how energy metabolism and food intake shape stress perception in daily life. Such approaches may improve our understanding of how stress physiology and energy regulation jointly contribute to shaping the risk for metabolic and stress-related disorders.