Background: Leptin regulates a constellation of neuroendocrine processes that control energy homeostasis. The infusion of leptin in rodents lacking endogenous leptin promotes physical activity energy expenditure (PAEE) and improves insulin signalling, whereas hyperleptinemia is associated with physical inactivity and insulin resistance (IR). Methods & Results: We tested whether baseline leptin levels predict changes in PAEE and IR over time, independently of obesity. We also assessed whether the relationship between leptin and change in IR is mediated by PAEE. The population consisted of 288 non-diabetic UK Caucasian adults (mean age: 49.4 SD: 0.7 yrs), in whom leptin, insulin, glucose, PAEE (via HR monitoring with individual calibration by indirect calorimetry), and anthropometric characteristics had been measured at baseline and 5yrs later. In linear regression models, baseline leptin levels inversely predicted follow-up PAEE (p=0.033). On average, individuals with low leptin levels (below sex-specific median) increased their daily activity 35% more during the 5yr follow-up period than those with above median leptin levels. Baseline leptin level also predicted worsening IR (fasting, 30-min and 2hr insulins, and HOMA-IR: all p<0.01). Associations were independent of potential confounders such as adiposity, age and sex. Including baseline PAEE as a cofactor in the leptin-insulin models reduced the strength (1-4% reduction) and significance of the associations, suggesting that PAEE mediates the leptin-insulin relationships. Conclusions: Hyperleptinemia predicts a relative decline in PAEE and worsening insulin resistance, possibly via shared molecular pathways.