A New Perspective on Leptin in Health and Disease

Ut Southwestern Medical Center, Dallas TX

Investigators

Linked publications, trials & patents

Abstract

Abstract A New Perspective on Leptin in Health and Disease Over the past four years, the Scherer and Elmquist laboratories have worked on putting the concept to use that lowering peripheral leptin levels is beneficial for the metabolic well-being of the organism. The starting point was the generation of mouse models with an inducible reduction of leptin levels in adult animals and the use of monoclonal antibodies that neutralize leptin. In contrast to historical expectations, these interventions resulted in weight loss and enhanced insulin sensitivity. We have further elaborated on this concept in additional physiological and pathophysiological settings. We have shown that weight loss, including weight loss induced by incretins or FGF21, is critically dependent on leptin reduction and can be further enhanced by neutralizing additional leptin in the process. On the other hand, weight gain and insulin resistance induced by anti- psychotics can be prevented by leptin neutralization. All these observations indicate that leptin is not merely a passenger associated with obesity but serves as a driver of the obese phenotype. Furthermore, it conceptualizes the physiological role of leptin as an “energy- sufficiency” signal - it is primarily a drop in leptin levels that the system responds to, with further rises in leptin above baseline merely leading to pathological responses. Using a series of new tools we have developed over the past four years, we strive to expand these concepts further in this renewal application. We now propose to investigate the relationship of insulin and beta-adrenergic signaling to leptin production and release from adipocytes. This also entails further studies into the regulation of full-length, signaling-competent leptin receptors in peripheral tissues. In this context, we plan to elaborate on the pathophysiological aspects of leptin signaling in the periphery by examining its potential as a fibroinflammatory agent. Using a series of novel models and methods, we will examine the process of leptin-driven adipocyte delipidation, a phenomenon that is restricted to young animals. Leptin sensitivity of adipocytes is abruptly lost after 10 to 12 weeks of age. Most importantly, we are bearing future translational interventions in mind and have established a leptin- deficient ob/ob mouse line in which we can ectopically manipulate leptin levels in a pharmacological dose- dependent manner. This will allow us to precisely determine the lower threshold of circulating insulin levels below which adaptive energy-conserving mechanisms are triggered. This enables us to calibrate future clinical interventions with respect to minimal and maximal reductions of leptin that are therapeutically effective. While conceptually novel, the approaches used here that critically depend on making a ligand (leptin) more rate limiting, thereby leading to improved receptor (LEPRb) signaling, are fully compatible with the historical data in the field, particularly as it relates to central leptin action. At the same time, we emphasize the peripheral actions of leptin with respect to the fibroinflammatory milieu that it creates in several tissues critical for metabolic well-being, including the liver, kidney, and lung.