["The Journal of Physiology, EarlyView. ", "\nAbstract figure legend Central leptin signalling blockade induces early metabolic dysfunction. Intracerebroventricular infusion of a leptin receptor antagonist (SLA) in rats disrupts hypothalamic leptin signalling, leading to reduced signal transducer and activator of transcription 3 (STAT3) activation, decreased Socs3 and Pomc expression, and increased Agrp/Npy activity in arcuate nucleus neurons. This central leptin signalling deficiency triggers systemic metabolic alterations. In the liver, increased ChREBP‐β expression and triacylglycerol (TAG) accumulation occur alongside reduced branched‐chain α‐ketoacid dehydrogenase (BCKDH) activity and the development of hepatic insulin resistance. Circulating metabolic markers are altered, including increased glucose, glucagon, insulin, fibroblast growth factor 21 (FGF21) and branched‐chain amino acids (BCAAs), with reduced urea levels. In pancreatic islets, α‐cell hypertrophy is observed together with increased glucagon content and lipid accumulation. Collectively, these changes produce a phenotype characterized by insulin resistance, impaired glucose tolerance and glucagon resistance, supporting this model as an early stage of metabolic dysfunction induced by impaired central leptin signalling.\n\n\n\n\n\n\n\n\n\nAbstract\nBrain leptin signalling plays a central role in the regulation of energy balance and glucose homeostasis, yet its contribution to early metabolic dysfunction preceding overt obesity remains uncertain. In the present study, we examined the metabolic consequences of sustained attenuation of central leptin receptor signalling in lean rats. Adult animals received chronic i.c.v. infusion of a rat‐specific leptin receptor antagonist (SLA) or vehicle for 21 days. SLA administration increased food intake with modest gains in body weight and visceral adiposity at the same time as maintaining normoleptinemia, and induced hepatic and pancreatic lipid accumulation, hyperinsulinemia, impaired glucose tolerance and hyperglucagonemia. These alterations were accompanied by hepatic glucagon resistance, as indicated by attenuated gluconeogenic gene induction and reduced CREB phosphorylation following in vivo glucagon stimulation. SLA‐infused rats also exhibited elevated circulating total and branched‐chain amino acids, reduced hepatic branched‐chain α‐ketoacid dehydrogenase activity and increased fibroblast growth factor 21 levels, consistent with disrupted glucagon–amino acid signalling. Together, these findings indicate that impaired central leptin signalling induces co‐ordinated endocrine and metabolic disturbances in the absence of obesity, supporting a role for altered central neuroendocrine regulation in the early development of metabolic dysfunction.\n\n\n\n\n\n\n\n\n\nKey points\n\nChronic attenuation of brain leptin signalling is associated with early metabolic dysfunction in lean rats.\nCentral leptin disruption leads to hyperglucagonemia, hepatic glucagon resistance and altered amino acid metabolism.\nElevated fibroblast growth factor 21 levels and impaired branched‐chain amino acid catabolism reflect early liver–α‐cell axis dysregulation.\nThis model provides insight into neuroendocrine drivers of non‐obese prediabetes.\n\n\n"]