From its discovery in obese mice, it was clear that the hormone leptin had a function in metabolism and energy homeostasis. The lipostasis theory of energy balance had already predicted that the amount of fat stored by the body was regulated by the central nervous system based on the action of a circulating product of fat metabolism on the hypothalamus (Zhang et al., 1994). The isolation of the product of the obese gene, later named leptin, provided validation for this theory. Leptin is sometimes called an “adipostat,” as it signals the status of the body’s energy stores to the brain and thus acts in metabolic regulation (Houseknecht and Portocarrero, 1998). Generally, the level of circulating leptin indicates the amount of energy stored as fat in the body.
Leptin acts through binding leptin receptors, known as OB-R. One isoform of this receptor (OB-Ra) is found in many different tissues, including the lung, kidney, liver, and B cells of the pancreas (reviewed in Houseknecht and Portocarrero, 1998). Another isoform (OB-Rb) is predominantly expressed in the ventromedial hypothalamus, a region of the brain known to be important in energy homeostasis, and particularly appetite regulation. When leptin binds OB-R, two receptors dimerize and can activate a Jak-Stat signaling pathway, or other signaling pathways, leading to the activation of a complex pathway of appetite enhancing and suppressing neuropeptides to adjust food intake (Houseknecht and Portocarrero, 1998; Kelesidis et al., 2010). For example, leptin inhibits the synthesis of neuropeptide Y (NPY), a peptide which stimulates appetite and is often increased in models of obesity (Stephens et al., 1995).
 |
| Figure 1: Leptin / leptin receptor mechanism of action. Originally from Houseknecht and Portocarrero, 1998. |
A homozygous mutation in the leptin gene results in extreme obesity in both mice and humans. The leptin deficient ob/ob mice were observed to overeat (hyperphagia), and to have neuroendocrine abnormalities and diabetes, and be infertile (reviewed in Kelesidis et al., 2010). A similar pathology is seen in human patients with congenital leptin deficiency. Treatment with recombinant leptin is very effective in such patients, causing a reduction in weight due to decreased appetite, which highlights the importance of leptin in regulating food intake (Farooqi et al., 1999; Kelesidis et al., 2010). However, as leptin deficiency accounts for only a small percentage of obesity in humans, the hormone does not give us an ‘obesity cure’ as was originally hoped upon its discovery. Obesity instead is usually due to a resistance or intolerance to leptin, likely as a result of defective OB-R, and patients in fact have higher than normal leptin levels correlating to a larger mass of adipose tissue (Houseknecht and Portocarrero 1998; Kelesidis et al., 2010). In both cases, the hypothalamus does not receive any signal to indicate that the body has sufficient stores of fat, so no suppression of appetite occurs.
Leptin as more than just the “obese gene”:
Recent studies have shown that the more important role of leptin is to indicate energy deficiency, rather than to prevent obesity (Kelesidis et al., 2010). During fasting, levels of the hormone drop drastically and very quickly. This induces a neuroendocrine response which includes a decrease in gonadotropins and sex steroids, decreasing fertility; as well as a decrease in thyroxine levels, slowing metabolism (Ahima et al., 1996). Leptin injection during starvation has been shown to alleviate these effects.Understanding this role of leptin has led to the finding that hypoleptinemia (decreased leptin) is associated with anorexia nervosa and hypothalamic amenorrhea (cessation of menstruation, often due to strenuous exercise), both of which are characterized by decreased body fat (Kelesidis et al., 2010). Trials have indicated that leptin treatment of hypothalamic amenorrhea is quite effective, restoring levels of estrogen, thyroxine and IGF1, and restoring menstruation (Welt et al., 2004). Effects on markers of bone formation were also observed, indicating a role of leptin in that process.
 | |
| Figure 2: Effects of leptin and leptin deficiency in both overfed (energy excess) and underfed (energy deficiency) states. Originally from Kelesidis et al., 2010) |
. . . Of course the above only gives a partial list of the actions and interactions of leptin. A complete description of the roles of leptin in energy homeostasis would take far more space than can be given here!
References:
Ahima, R.S., Prabakaran, D., Mantzoros, C., Qu, D., Lowell, B., Maratos-Flier E., and Flier, J.S. (1996). Role of leptin in the neuroendocrine response to fasting. Nature 382(6588) 250-252.
Farooqi, I.S., Jebb, S.A., Langmack, G., Lawerence, E., Cheetham, C.H., Prentice, A.M., et al. (1999). Effects of recombinant leptin therapy in a child with congenital leptin deficiency. New England Journal of Medicine. 341 879-884.
Houseknecht, K.L., and Portocarrero, C.P. (1998). Leptin and its receptors: regulators of whole-body energy homeostasis. Domestic Animal Endocrinology 15(6) 457-475.
Kelesidis, T., Kelesidis, I., Chou, S., and Mantzoros, C.S. (2010). Narrative review: the role of leptin in human physiology: emerging clinical applications. Annals of Internal Medicine 152(2) 93-100.
Stephens, T.W., Basinski, M., Bristow, P.K., Bue-Valleskey, J.M., Burgett, S.G., Craft, L., et al. (1995). The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 377(6549) 530-532.
Welt, C.K., Chan, J.L., Bullen, J., Murphy, R., Smith, P., DePaoli, A.M., Karalis, A., and Mantzoros, C.S. (2004). Recombinant human leptin in women with hypothalamic amenorrhea. New England Journal of Medicine 351(10) 987-997.
Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., and Friedman, J.M. (1994). Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505) 425-32.
