Leptin: a novel link between obesity, diabetes, cardiovascular risk, and ventricular hypertrophy.

Abstract

Obesity and associated type 2 diabetes mellitus are the emerging epidemic of this new century. Identifying the key mechanism of the pathophysiology offers unique insights into potential prevention and therapy. One of the classic animal models of obesity and insulin resistance has been the ob/ob mouse. Zhang et al1 set the scientific world a-buzz in 1994 with the discovery that the obesity (ob) gene product was in fact leptin, and leptin deficiency accounted for the obesity in these mice. See p 754 Leptin is secreted by the fat cells, along with other tissues, to act on the hypothalamic leptin receptors (Ob-Rb) to decrease food intake and increase energy expenditure in the host.2 Under physiological conditions, the amount of leptin produced by fat tissues is directly related to the mass of adipose tissues.3 Both leptin deficiency (ob/ob mice) and leptin resistance (db/db mice having a defective leptin receptor) lead to hyperphagia and decreased energy expenditure in the host (Figure 1). Predictably, this leads to obesity, the insulin resistance type of diabetes, and a decrease in lean body mass.4,5 Correction of leptin deficiency in the ob/ob mouse causes a marked reduction in food intake and a normalization of its weight.2,3,6 Figure 1. Circles of feedback in primary leptin deficiency. This is the situation found in ob/ob mice, or rare human genetic mutations. In this setting, the adipose tissue will not be able to elaborate leptin commensurate with the fat tissue mass. This leaves the leptin receptor unoccupied. The receptor signals through janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathways, with cross talk from PI3 kinase (P13K) pathways. The receptor nonoccupancy leads to a number of adiposity signals, including increased food intake and decreased energy expenditure. This also leads to ventricular hypertrophy, …