Hypothalamic AgRP/POMC circuits mediate sepsis-associated anorexia via cytokine and hormonal signaling

Sepsis is a severe, life-threatening syndrome characterized by a dysregulated host response to infection, leading to organ dysfunction. Despite the increased metabolic energy demands required to combat infection and sustain the inflammatory response, anorexia is a prominent and debilitating feature of sickness behavior during sepsis. Current standard-of-care primarily focuses on infection control and organ support, often overlooking the profound impact of anorexia on patient recovery and long-term outcomes. Understanding the neurobiological mechanisms underlying sepsis-associated anorexia is crucial for developing targeted interventions to improve patient nutrition and prognosis.

This comprehensive review synthesizes current understanding of how sepsis disrupts normal feeding behavior by focusing on the hypothalamic AgRP/NPY-expressing orexigenic neurons and POMC/CART-expressing anorexigenic neurons located in the arcuate nucleus. The authors meticulously examine the neural and humoral pathways involved in appetite regulation under basal conditions, including the role of the vagal nerve, blood-brain barrier, and circumventricular organs in mediating peripheral signal integration. Furthermore, the review discusses recent advances in how sepsis specifically affects these intricate appetite-controlling mechanisms, highlighting the impairment of central integration of peripheral inflammatory and metabolic signals.

The review elucidates that sepsis profoundly impacts hypothalamic appetite regulation by impairing the central integration of peripheral signals, leading to significant anorexia despite heightened metabolic needs. Inflammatory cytokines, such as IL-1β, TNF-α, and IL-6, are identified as key mediators that directly modulate the activity of both AgRP/NPY and POMC/CART neuronal circuits, shifting the balance towards anorexigenic signaling. Hormonal changes, including altered leptin and ghrelin sensitivity, further contribute to this dysregulation, exacerbating the anorexic state. The authors highlight that the vagal nerve and specialized brain regions like the circumventricular organs play critical roles in transmitting these peripheral inflammatory and metabolic cues to the hypothalamus. This intricate interplay results in a maladaptive central response to the body's energy demands during infection.

The review underscores that sepsis-associated anorexia is a complex neuro-endocrine-immune phenomenon, where the hypothalamus fails to appropriately respond to energy demands due to overwhelming inflammatory signaling and altered hormonal profiles.