, 2002) and the lateral hypothalamus (Leinninger et al., 2009). The VMH is a site of interest given that gene knockout of SF1 causes abnormal VMH development and obesity (Majdic et al., 2002 and Zhao

et al., 2004). To investigate SF1 neurons, we generated Sf1-Cre, Leprlox/lox mice ( Dhillon et al., 2006). These animals developed a small increase in body fat MAPK inhibitor and body weight (∼5 g increase in body weight at 2–3 months old). Thus, as with LEPRs on POMC and AgRP neurons, the effect of LEPRs on SF1 neurons is small. Another group has obtained qualitatively similar results regarding the role of LEPRs on SF1 neurons ( Bingham et al., 2008). Based on the above, the list of genetically verified, body weight-regulating, first-order, leptin-responsive neurons includes POMC (Balthasar et al., 2004), AgRP (van de Wall et al., 2008), and SF1 neurons (Bingham et al., 2008 and Dhillon et al., 2006). Given this, and the realization that these neurons account for only a portion of leptin’s effects (thus other neurons must also be involved), it has been proposed that leptin action is mediated by a distributed network of leptin-responsive neurons (Leinninger and Myers, 2008, Myers et al., 2009 and Scott et al., 2009). With such a distributed model

in mind, it is of interest to determine if any deeper logic underlies first-order, leptin-responsive neurons and/or their mode of communication with selleckchem energy balance-regulating neurocircuits.

Because the obvious “first-order” candidates have already been directly tested, a new approach is needed for narrowing in on these “unidentified” first-order neurons. In the present study we evaluate if leptin’s effects are mediated primarily by excitatory (glutamatergic, VGLUT2+) or inhibitory (GABAergic, VGAT+) neurons. This approach has two important features. First, it casts a wider net and provides insight into the neurotransmitter identity of the neurons mediating leptin’s antiobesity Cathepsin O effects. Second, it provides information regarding the function of the leptin-responsive neurons (excitatory versus inhibitory). With this goal in mind, we have generated mice that express Cre recombinase in either glutamatergic (Vglut2-ires-Cre knockin mice) or GABAergic neurons (Vgat-ires-Cre knockin mice). VGLUT2 is one of three synaptic vesicle glutamate transporters ( Takamori, 2006). VGLUT1 is expressed primarily by neurons in the cortex while VGLUT3 is expressed by isolated, select groups of neurons, none of which are in the hypothalamus. Consequently, VGLUT2 is the transporter utilized by glutamatergic neurons in the hypothalamus, thalamus, midbrain, and hindbrain and thus it is relevant to our investigation of leptin-responsive neurons. VGAT, on the other hand, is the only transporter capable of importing GABA into synaptic vesicles; hence, VGAT is expressed by all GABAergic neurons ( Wojcik et al., 2006).