[Frontiers in Bioscience 12, 3531-3544, May 1, 2007]

Elevated leptin: consequence or cause of obesity?

Philip J. Scarpace1, Yi Zhang 1,2

1 Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida 32610; 2Research Service, Department of Veterans Affairs Medical Center, Gainesville, Florida 32608

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Leptin is a potent anorexic agent in lean animals
4. Diet-induced leptin resistance
5. Age-related leptin resistance
6. Hypothalamic leptin signaling
7. Leptin signaling with central leptin resistance
7.1. Adult-onset obesity
7.2. High-fat feeding
8. Relationship between leptin signaling and leptin physiological responses
9. Leptin-induced leptin resistance
7. Leptin resistance exacerbates diet-induced obesity
11. Insights from a leptin antagonist
12. Enhancing leptin signaling and responses with vanadium
13. Perspective
14. Acknowledgements
15. References

1. ABSTRACT

Leptin is an adipocyte-derived, satiety-regulating hormone that acts within the hypothalamus and other brain sites. Obese humans and animals are largely resistant to central actions of leptin. Rising leptin levels associated with progressing obesity are generally regarded as simply a consequence rather than a causative factor in the leptin resistance and obesity. Several lines of evidence suggest otherwise. Chronic overexpression of central leptin induces a leptin resistance that mimics many of the characteristics associated with diet-induced or adult-onset obesity including reduced leptin receptors, diminished signaling, and impaired responsiveness to exogenous leptin. Moreover, these animals have increased susceptibility to diet-induced obesity. New data with a leptin antagonist demonstrate that blockade of leptin receptors also exaggerates diet-induced obesity. These findings suggest an important role for elevated leptin in the development of leptin resistance and obesity, especially in today's society with an overabundance of readily available high caloric food. Once leptin resistance takes hold, each subsequent exposure to high-density food faces diminished counter-regulatory responses, leading to exacerbated weight gain.