Physiological significance of autocrine orexinergic signaling in extra‐hypothalamic tissues

Orexin-A and orexin-B, originally discovered as hypothalamic neuropeptides, have been detected in extra-hypothalamic tissues together with their receptors (OX₁R and OX₂R) since the early 2000s. This systematic review is the first to comprehensively synthesize evidence on the autocrine/paracrine effects of locally produced orexin across extra-hypothalamic tissues. Following PRISMA 2020 guidelines, a systematic search was conducted in PubMed, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and Google Scholar. Eligible studies were original, full-text, peer-reviewed articles reporting primary data on prepro-orexin/orexin peptide and/or OX₁R/OX₂R expression in non-neuronal extra-hypothalamic tissues, with evidence of co-expression within the same cell/tissue or functional effects reasonably attributable to locally produced orexin. From the 10 eligible studies, autocrine orexinergic signaling was functionally demonstrated in the adrenal gland (steroidogenesis via Gq/PLC/IP₃/Ca²⁺), male reproductive tract (testosterone secretion), adipose tissue (lipolysis/thermogenesis), heart (myocardial protection via PI3K/Akt/eNOS), pancreas (glucose-regulated insulin/glucagon modulation), and liver (lipogenesis via ERK1/2). OX₁R primarily activates the Gq/PLC/IP₃/Ca²⁺ pathway, resulting in ERK1/2 and p38 MAPK signaling (promoting secretion and proliferation), while OX₂R couples to Gs/Gi, modulating cAMP and PI3K/Akt (favoring cytoprotection and anti-apoptosis). Autocrine orexinergic signaling constitutes a legitimate, compartment-autonomous regulatory mechanism in peripheral tissues, enabling rapid, tissue-specific responses insulated from central fluctuations.