EDITORIAL FOCUS
Addressing leptin resistance

Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2

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LEPTIN WAS CLONED IN 1994 and shown to be secreted from adipocytes (5). This and subsequent studies demonstrated that leptin is made and secreted in proportion to the fat content of individual adipocytes (4). Under normal physiological conditions, the concentration of circulating leptin is inversely related to body fat, or energy, content (2). It is transported past the blood-brain barrier and acts via specific receptors in the arcuate nucleus of the hypothalamus to activate anorexigenic pathways; that is, leptin reduces food (energy) intake. Leptin also increases energy expenditure (2). Thus it is eminently reasonable to hypothesize that leptin is a lipostatic signal.

As might have been expected from such an important control system, the story is turning out to be much more complex. In diet-induced obesity, circulating leptin level is very high and the relationship between the body's content of fat/energy and leptin concentration is lost (2).

These and similar findings have led to the concept of leptin resistance, which is thus defined as a failure of leptin signaling leading to dysregulation of energy balance and body weight.

Analogous events do occur in other endocrine control systems. For instance, high circulating levels of ANG II lead to downregulation at many peripheral sites of the major subtype, AT1, of the angiotensin receptor (3). Nevertheless, the concept of leptin resistance remains poorly understood. The study in this issue by Bowen et al. (1) reports a well conceived, designed, and executed set of experiments that examine leptin resistance. The authors provide evidence that many factors contribute to leptin resistance. Some, such as strain and gender, are intrinsic to the organism, whereas others, such as housing conditions, are clearly environmental. Furthermore, the experiments point to interactions between leptin signaling and both extrinsic and intrinsic modifying factors.

	FOOTNOTES

Address for reprint requests and other correspondence: W. A. Cupples, SMBD-Jewish General Hospital, 3755 Cote-Ste-Catherine Rd., Montreal, Quebec, Canada H3T 1E2 (E-mail: will.cupples{at}mcgill.ca).

10.1152/ajpregu.00629.2002

	REFERENCES

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1.   Bowen, H, Mitchell TD, and Harris RBS Method of leptin dosing, strain, and group housing influence leptin sensitivity in high-fat-fed weanling mice. Am J Physiol Regul Integr Comp Physiol 284: R87-R100, 2003[Abstract/Free Full Text].

2.   Harris, RBS Leptinmuch more than a satiety signal. Annu Rev Nutr 20: 45-75, 2000[Web of Science][Medline].

3.   Regitz-Zagrosek, V, Auch-Schwelk W, Neuss M, and Fleck E. Regulation of the angiotensin receptor subtypes in cell cultures, animal models and human diseases. Eur Heart J 15: 92-97, 1994.

4.   Zhang, Y, Guo KY, Diaz PA, Heo M, and Leibel RL. Determinants of leptin gene expression in fat depots of lean mice. Am J Physiol Regul Integr Comp Physiol 282: R226-R234, 2002[Abstract/Free Full Text].

5.   Zhang, Y, Proenca R, Maffei M, Barone M, Leopold L, and Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 372: 425-432, 1994[Medline].