, 1992). The above findings suggest the following model: leptin binds directly

to LEPRs on AgRP and POMC neurons, inhibiting AgRP neurons and activating POMC neurons, and this accounts for its antiobesity actions. If this model is correct and if it is the sole mechanism by which leptin regulates energy balance, then deletion of LEPRs on AgRP and POMC neurons should result in massive obesity, similar to that seen in mice with total lack of leptin action (i.e., Lepob/ob mice and Leprdb/db mice). To investigate this, we see more generated mice that lack LEPRs on POMC neurons (i.e., Pomc-Cre, Leprlox/lox mice), on AgRP neurons (i.e., Agrp-Cre, Leprlox/lox mice), and on both POMC and AgRP neurons (i.e., Pomc-Cre, Agrp-Cre, Leprlox/lox mice) ( Balthasar et al., 2004, Hill et al., 2010 and van de Wall et al., 2008). Of note, mice lacking LEPRs on either POMC neurons or on AgRP neurons developed very

mild obesity (increase in body weight of ∼5 g at 2–3 months old) ( Balthasar et al., 2004 and van de Wall et al., 2008). This effect was much smaller than expected, especially when one compares this with the 26 g increase in body weight in 10-week-old mice with global deficiency of LEPRs ( van de Wall et al., 2008). One possible explanation for the smaller than expected effect is that deletion of LEPRs in one class of neurons (for example, the POMC neurons) might be compensated by increased leptin action on the other class of neurons (for example, the AgRP neurons), or vice versa. However, this was not Sorafenib the case because an additive and still much smaller

than expected effect was observed in mice lacking LEPRs on both POMC and AgRP neurons ( van de Wall et al., 2008). In total, the above findings suggest that direct leptin action on POMC and AgRP neurons plays a small role in controlling energy Thiamine-diphosphate kinase balance and that there are likely to be other first-order, leptin-responding neurons that contribute importantly to leptin’s antiobesity actions. Areas beyond the arcuate could mediate important actions of leptin. Of note, LEPRs are present in many sites outside the arcuate. Within the hypothalamus, LEPRs are found in the ventromedial hypothalamus (VMH), the dorsomedial hypothalamus (DMH), the lateral hypothalamus (LH), and the ventral premammillary nucleus (PMv) (in addition to the arcuate); within the midbrain in the ventral tegmental area and raphe; and within the brainstem, in the parabrachial nucleus, periaqueductal gray, and dorsal vagal complex (Elias et al., 2000, Figlewicz et al., 2003, Fulton et al., 2006, Grill et al., 2002, Hommel et al., 2006, Leinninger et al., 2009, Leshan et al., 2009, Mercer et al., 1996, Mercer et al., 1998, Münzberg, 2008 and Scott et al., 2009). Strong arguments have been made that neurons outside the arcuate are well-positioned to play important roles in regulating appetite (Berthoud, 2002 and Grill and Kaplan, 2002).