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Click here to learn more about leptin from a useful website by the University of Edinburgh.

After Coleman's intriguing parabiosis experiments, scientists began to search for a bloodborne protein that traveled from the bloodstream of the normal mouse and corrected the overeating and subsequent obesity in the ob/ob mouse. Surprisingly, researchers did not isolate the leptin protein until 1994. Adipose cells produce leptin, which travels from its release site at the fat cells to the hypothalamus where it can directly signal satiety and increase energy expenditure. Conversely, when fat reserves are low, less leptin is released. Low leptin levels signal the animal to increase consumption of food and decrease energy expenditure. Less than a year after the identification of leptin, researchers were able to clone the ob gene and isolate the ob protein product - leptin. In a 1995 experiment by Campfield et al., researchers used ob/ob knock-out mice to show that daily administration of leptin could counteract the obesity induced by lack of leptin. Knock-out mice that received the recombinant leptin reduced food consumption and body weight.

Given these observations, it is not surprising that leptin was intially heralded as a miracle cure for obesity. Some individuals do have mutations of the leptin gene, and in these patients, leptin administration does help reduce food intake and body weight (Bear et al., 2006). However, for most individuals, leptin treatment will not result in dramatic weight loss. In fact, many obese people actually have increased leptin levels. This finding implies that neurons are less sensitive to leptin in obese people. Thus, leptin deficiency seems similar to Type II diabetes and insulin receptor insensitivity. In other words, because obese people have more adipose tissue, they produce more leptin, and so the receptors might desensitize slightly.

Neurons in the arcuate nucleus respond to changing leptin levels by releasing various neuropeptides that can either stimulate or inhibit feeding behavior (Schwartz et al., 2000). For instance, when blood leptin decreases, arcuate nucleus neurons release Neuropeptide Y (NPY) and Agouti-related peptide (AgRP). These two neuropeptides increase feeding behavior by acting on neurons in the lateral hypothalamus, particularly those that produce melanin-concentrating hormone (MCH). Conversely, when leptin increases, such as right after a meal, other neurons in the arcuate nucleus release alpha-melanocyte-stimulating hormone (alpha MSH) and cocaine-and-amphetamine-regulated transcript (CART), which both decrease feeding behavior. These alpha MSH and CART neurons project to many locations, including the lateral hypothalamus. The image below from the Schwartz et al. paper demonstrates the sheer complexity of central nervous system involvement in feeding behavior via leptin.

Clearly, obesity is not just a character flaw or a deficiency of one biological compound. In considering possible therapeutics, one must consider the many targets of leptin, as shown in the above pathways. Perhaps overwhelmingly, then, leptin itself is only a small piece to the puzzle. Neurotransmitters like serotonin and dopamine also play a role in feeding behavior. In fact, based on experiments that alter dopamine signaling, the dopaminergic pathway also modulates long-term feeding regulation.




Publication Information


Campfield, L.A. et al.


Recombinant Mouse OB Protein: Evidence for a Peripheral Signal Linking Adiposity and Central Neural Networks

Science 269: 546-549


Schwartz, M.W., Woods, S.C., Porte, D., et al.


Central nervous system control of food intake

Nature 404: 661-671


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If you are currently reading the Kim et al. paper, click here to return to Figure 2.

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