Abstract
Most existing reviews treat endoplasmic reticulum (ER) stress as one mechanism among several in leptin resistance. This review advances a different claim: ER proteostasis may act as a central convergence node, translating metabolic, inflammatory, developmental, and nutrient-derived signals into a shared effector signature. In common obesity, leptin responsiveness is blunted despite hyperleptinaemia—the principal obstacle to leptin-based therapy. Leptin resistance is examined at the intersection of intracellular signalling networks (JAK2/STAT3, PI3K/Akt, MAPK, AMPK, mTOR, FoxO1, SOCS3, PTP1B) and hypothalamic ER stress and the unfolded protein response (UPR). This narrative synthesis incorporates 22 primary studies, with PRISMA 2020 principles used to document study selection transparently. The ER shapes leptin signalling at three levels: receptor biogenesis (SEL1L–HRD1 ERAD), receptor bioavailability (CHOP-mediated soluble receptor), and post-receptor inhibition (SOCS3/PTP1B). Distinct stressors converge on a narrow effector set (CHOP, SOCS3, PTP1B), and receptor quality control can operate independently of ER stress, demonstrating that the ER's role is not confined to a stress response. The framework yields three testable hypotheses with an explicit falsification criterion, and proposes that leptin resistance comprises phenotypically distinct subtypes. The evidence base is entirely preclinical (17 rodent in vivo; 5 in vitro studies); translation to humans remains untested.