Physiological significance of autocrine orexinergic signaling in extra‐hypothalamic tissues

Abstract Orexin‐A and orexin‐B, originally discovered as hypothalamic neuropeptides, have been detected in extra‐hypothalamic tissues together with their receptors (OX 1 R and OX 2 R) 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 OX 1 R/OX 2 R 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/IP 3 /Ca 2+ ), 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). OX 1 R primarily activates the Gq/PLC/IP 3 /Ca 2+ pathway, resulting in ERK1/2 and p38 MAPK signaling (promoting secretion and proliferation), while OX 2 R 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.