While central leptin signaling appears to play a major role in the regulation of food intake and energy metabolism, the physiological role of peripheral leptin signaling and its relative contribution to whole-body energy metabolism remain unclear. To address this question, we created a mouse model (Cre-Tam mice) with an intact leptin receptor (LEPR) in the brain but a near-complete deletion of the signaling domain of LEPR in liver, adipose tissue, and small intestine using a tamoxifen-inducible Cre-LoxP system. Cre-Tam mice developed marked hyperleptinemia ( 4 fold, P < 0.01) associated with 2.3 fold increase (P < 0.05) in post-transcriptional production of leptin. While this is consistent with the disruption of a negative feedback regulation of leptin production in adipose tissue, there were no discernable changes in energy balance, thermoregulation and insulin sensitivity. Hypothalamic phospho-STAT3 levels, neuropeptide expression, and food intake were not changed despite hyperleptinemia. The percentage of plasma bound leptin was marked increased (90.1% - 96% vs. 41.8% - 74.7%, P < 0.05), but plasma free leptin concentrations remained unaltered in Cre-Tam mice. We conclude from these results that 1) the relative contribution to whole-body energy metabolism from peripheral leptin signaling is insignificant in vivo, 2) leptin signaling in adipocyte constitutes a distinct short-loop negative feedback regulation of leptin production that is independent of tissue metabolic status, and 3) perturbation of peripheral leptin signaling alone, while increasing leptin production, may not be sufficient to alter the effective plasma levels of leptin because of the counter-regulatory increase in the level of leptin binding protein(s).