Leptin Resistance and Endoplasmic Reticulum Stress: ER Proteostasis as a Proposed Convergence Node—A Mechanistic Synthesis of Preclinical Evidence

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, and PTP1B), 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, and PTP1B) whose direction of effect is context-dependent, and receptor quality control can operate without activation of the PERK arm, indicating that the ER’s role is not confined to the canonical 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.