Abstract Metabolic Benefits of Leptin Reduction Adipocytes have moved to center stage with respect to systemic metabolic control. They regulate metabolic homeostasis for a variety of tissues. Adipocytes achieve this regulation on the basis of their unsurpassed ability to store and neutralize excess lipids. Importantly, they interact with other critical organs through the use of adipokines. Leptin and adiponectin are the two most prominent factors that have been widely studied. The availability of floxed versions of both genes encoding these factors has offered us the opportunity to eliminate both adipokines in the adult stage to varying degrees. Reducing leptin levels in adult obese animals has yielded a number of surprising findings. We recently published these findings in Cell Metabolism, in which we showed that a reduction in systemic leptin levels results in enhanced leptin and insulin sensitivity. In contrast, elevating leptin levels in a transgenic manner, by as little as 50%, results in further leptin and insulin resistance. Here, we aim to better define the mechanistic aspects of this phenomenon. This includes: a) determining which anti-diabetic regimens rely on leptin-lowering effects to achieve their established actions; b) elucidating the signaling mechanisms underlying leptin sensitization upon reducing the ligand concentrations; c) gaining a firm understanding on the control of leptin production at the level of different fat-pads. Our proposed experiments should provide significant new insights into leptin production and leptin action. We can address these questions with a series of new and unique mouse models that we recently generated. Specifically, we aim to: I) Determine the effects of acute and chronic leptin reduction on peripheral leptin and insulin sensitivity. We will manipulate leptin receptor levels and downstream signaling mediators, obtain in vivo signaling information for both leptin and insulin signaling in real time, address sexually dimorphic responses to leptin reduction and investigate the impact of adiponectin on leptin expression. II) We will examine whether anti-diabetic interventions rely on leptin lowering prior to weight loss. Here, we will focus on a number of different established pharmacological agents for which we will “clamp” leptin levels transgenically at baseline levels during treatment, or further reduce leptin levels with neutralizing anti-leptin antibodies to enhance the effects of these agents. III) We will assess whether the improvements in central leptin action that we established by lowering leptin levels, require central leptin receptor action to achieve improved read-outs. If so, which subpopulation of neurons is critically involved in this process? IV) Determine the critical mediators that govern leptin production and release, particularly in the visceral adipocyte. We will examine whether 3 and 2a adrenergic receptors regulate leptin levels in the mature adipocyte. The Scherer/Elmquist te...