Leptin is a hormone that is derived from fat tissues which provides information to the brain about energy stores. Animals, including humans, that lack leptin display substantial hyperphagia that can be reversed with leptin treatment. How do higher brain centers interpret the messages that leptin communicates? How might this kind of information impact PWS, where hyperphagia is prominent and may be life threatening?

Two recent studies explored leptin processing and mechanisms of leptin communication in small pilot studies. In the first study, two teenaged individuals who were born with a very rare condition where they lack leptin were treated with leptin and examined for food intake and responses to images of food when measured in a functional magnetic resonance imaging scanner (fMRI) (Leptin Regulates Striatal regions and Human Eating Behavior , Farooqi et al., Science BREVIA, 2007). Leptin treatment in these two individuals significantly decreased food intake, as expected. Results from the fMRI study revealed that before leptin treatment, the subjects rated all foods they were shown as very desirable, even when the subjects were not hungry during testing. After leptin treatment, the likings ratings decreased. The main area of the brain that was activated as important for leptin-related information was the ventral striatum, which is known to represent how much someone actually "likes" food versus how much they "want" a food. This study provides evidence that leptin signaling involves not only the communication of nutritional state, but also interacts with higher brain regions that are responsible for how much an individual likes a food.

In the second study, a similar examination was made using three adults with a mutation in the ob gene from families of Pakistani origin (Leptin replacement alters brain response to food cues in genetically leptin-deficient adults , Baicy et al., PNAS, 2007). This mutation results in leptin deficiency and this study looked at leptin treatment's effects on responses to images presented in an fMRI scanner. Subjects were tested at baseline (with no leptin treatment), after 14 days of treatment, after 57 months of treatment, and after 33 days of withdrawing leptin treatment. As in the first experiment, leptin treatment reduced reports of hunger, especially after the longest duration of treatment. Lack of leptin was associated with increased activation of the insula (the primary taste cortex in the brain), and regions of the temporal and occipital lobes of the brain. The prefrontal cortex was activated as well, and this region is known to be important for the inhibition of inappropriate behavioral responses, which may be critical for understanding hyperphagic behaviors. Activation was also observed in the cerebellum, which has not traditionally been connected with eating behaviors, but does play a role in the reinforcement associated with drug cravings and may have relevance to food behaviors as well.

Together, these two studies provide strong evidence that leptin is indeed associated with higher brain areas that are known to be critical for the processing of food-related behaviors. Although these studies on their own may appear to have limited significance because leptin deficiency is so rare, the potential for this information to inform studies of PWS are great. Leptin has been examined already in those with PWS, and these two studies encourage a more detailed examination of the neural circuitry that may be associated with leptin in PWS.

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