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Leptin

The Study of Obesity: What to Measure

Our understanding of adipose tissue has matured in recent years as a result of scientific breakthroughs in the obesity research field.  What was once considered a passive, lipid storage tissue is now understood to be a very active endocrine tissue.

Leptin is a 16 kDa hormone secreted mainly by adipose tissue in proportion to adipose tissue mass. The structure of leptin is composed of four alpha-helices with one short strand segment and two interconnected loops. It can be found in circulation in its free form as well as bound to its soluble receptor (1). The name of the protein is derived from the Greek word leptos meaning thin and refers to its ability to regulate energy intake and energy expenditure.

The effects of leptin were first observed by studying overweight mice with a mutation in the obese (ob) gene (2). Administration of leptin to these mice resulted in weight loss, decreased food intake and a reduction of body fat (3,4,5). Subsequent research has shown that humans with high fat mass have high levels of leptin in the blood (6). This observation indicates that most obese individuals are leptin resistant rather than leptin deficient.  Sex also plays a role in dictating serum leptin levels as women tend to have higher levels than men (6).

Since the discovery of the ob gene product, the biological action of leptin has been broadened. Apart from its metabolic effects, leptin has also been reported to be involved in immune function and reproduction as well as associated with atherosclerotic disease.

In 2008, a group led by Dr. Roger Unger at the University of Texas, Southwestern Medical Center published their work on the use of leptin as a monotherapy for T1DM.  In the absence of exogenous (or endogenous) insulin, leptin therapy resulted in significant benefits in several different T1DM rodent models.  Some of the most notable results were normalization of blood glucose and glucagon levels, activation of insulin signaling molecules in skeletal muscle and positive increases in body weight and linear growth. (7)

In a 2010 follow-up publication, this group went on to show that leptin therapy also results in positive effects on various hepatic metabolites in mice (8).  These and other studies on leptin as a potential treatment for T1DM shine an interesting light on this energy-regulating adipokine.  Further studies are needed to determine if these findings will translate to similar benefits in humans.  Whether or not this turns out to be beneficial for the treatment of T1DM in humans, a deeper understanding of how leptin can regulate physiology is important.

References

  1. Sinha et al. (1996) J Clin Invest 98:1277-1282
  2. Zhang et al. (1994) Nature 372:425-432
  3. Pelleymounter et al. (1995) Science 269:540-543
  4. Halaas et al. (1995) Science 269:543-546
  5. Rentsch et al. (1995) Biochem Biophys Res Commun 214:131-136
  6. Rosenbaum et al. (1996) J Clin Endocrinol Metab 81:3424-3427
  7. Yu et al. (2008) PNAS 105:14070-14075
  8. Wang et al. (2010) PNAS 107:4813-4819