The role of the hypothalamus in the development of cancer cachexia

Cachexia is a complex multiorgan syndrome associated with various chronic diseases, characterized by anorexia and increased tissue wasting in the context of chronic inflammation. A specific form of this syndrome, known as cancer cachexia (CC), occurs alongside different types of tumors. The pathogenesis of CC is multifactorial. Inflammatory mediators and hormones released by both tumor and host cells have a relevant role in driving the peripheral catabolic process through several direct mechanisms. Accumulating evidence indicates that the central nervous system (CNS) plays an integral role in the pathogenesis of CC. The hypothalamus has emerged as a critical brain region that senses and amplifies peripheral stimuli, generating inappropriate neuronal signaling and leading to the dysregulation of energy homeostasis under cachexia conditions. Circulating cytokines may act in concert with hormones and neurotransmitters and perturb critical hypothalamic neurocircuits shifting their activity towards the anorexigenic pathway and increase of energy expenditure. This review discusses the mechanisms mediating the hypothalamic homeostatic imbalance in the context of anorexia and cachexia associated with cancer.