Uncoupling metabolism and coupling leptin to cardiovascular disease.

Abstract

In the past eight years, beginning with the discovery of leptin, 1 there has been an avalanche of knowledge and a conceptual revolution in understanding the regulation of body fat. Central to this revolution has been the recognition that adipose tissue is a tremendously active and important endocrine and paracrine tissue. In this regard, adipose tissue is to the last decade what the endothelium was to the previous decade—a large tissue previously relatively ignored that was found with a single discovery to be of great interest and importance. See page 961 The interest in leptin focused initially on appetite, metabolism, and adiposity, but there is mounting evidence that leptin participates in sympathetic and arterial pressure regulation and in vascular biology. Leptin increases sympathetic nerve activity2 to thermogenic brown adipose tissue through a central neural action. This is not surprising, but leptin also increases sympathetic activity to the kidney and extremities.2 This sympathoexcitatory action would be expected to increase arterial pressure. Of perhaps greater interest to the readers of this Journal is the mounting evidence that the arterial wall is a target of leptin action. The signaling form of the leptin receptor was initially said to be expressed only in the hypothalamus, but we now know that it is also expressed in peripheral tissues. For example, the long, signaling form of the leptin receptor is expressed in endothelial cells.3,4⇓ Lembo et al3 and Vecchione et al5 reported that leptin stimulates increases in endothelial NO synthesis. Leptin promotes accumulation of reactive oxygen species in human umbilical vascular endothelial cells (HUVECs).6,7⇓ It upregulates endothelin-1 production in HUVECs.8 It promotes angiogenesis.4,9⇓ And an astonishing finding: Parhami et al10 demonstrated that leptin regulates …