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In the present study, we examined the metabolic consequences of sustained attenuation of central leptin receptor signalling in lean rats. Adult animals received chronic\n i.c.v.<\/jats:sc>\n infusion of a rat\u2010specific leptin receptor antagonist (SLA) or vehicle for 21\u00a0days. 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\n in vivo<\/jats:italic>\n glucagon stimulation. SLA\u2010infused rats also exhibited elevated circulating total and branched\u2010chain amino acids, reduced hepatic branched\u2010chain \u03b1\u2010ketoacid dehydrogenase activity and increased fibroblast growth factor 21 levels, consistent with disrupted glucagon\u2013amino acid signalling. Together, these findings indicate that impaired central leptin signalling induces co\u2010ordinated 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 image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n Chronic attenuation of brain leptin signalling is associated with early metabolic dysfunction in lean rats.<\/jats:p>\n <\/jats:list-item>\n \n Central leptin disruption leads to hyperglucagonemia, hepatic glucagon resistance and altered amino acid metabolism.<\/jats:p>\n <\/jats:list-item>\n \n Elevated fibroblast growth factor 21 levels and impaired branched\u2010chain amino acid catabolism reflect early liver\u2013\u03b1\u2010cell axis dysregulation.<\/jats:p>\n <\/jats:list-item>\n \n This model provides insight into neuroendocrine drivers of non\u2010obese 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