Glutamate gets fat

Cell Metab. 18, 860–870 (2013)

The activity of melanocortin receptor 4 (Mc4r) in Single-minded homolog 1 (Sim1)-expressing neurons in the paraventricular nucleus of the hypothalamus (PVH) is important for body weight homeostasis, but the neurotransmitter that mediates Mc4r function in these neurons is not known. In the mouse PVH, Xu et al. noted that the vesicular glutamate transporter 2 (Vglut2), which loads the neurotransmitter glutamate into vesicles for presynaptic release, was coexpressed with Mcr4. In sections from mice with genetic deletion of Vglut2 in Sim1-expressing neurons of the PVH, glutamate release was decreased compared with sections from wild-type mice. In obese Mc4r-null mice, selective restoration of Mc4r expression in Sim1 neurons decreased body weight. Restoration of Mc4r in combination with selective Vglut2 deletion in the same neurons countered the effect of Mc4r expression, indicating that Mc4r's impact on body weight depends on glutamate. In the mice lacking Mc4r expression or in those expressing Mc4r but not Vglut2, O₂ consumption was decreased compared with wild-type mice, indicating that a change in energy expenditure might be responsible for changes in body weight. Consistent with this notion in wild-type mice, a synthetic Mc4r agonist led to increased O₂ consumption compared with vehicle. Taken together, these data indicate that Mc4r alters energy expenditure to control body weight, and the activity of Mc4r in Sim1 positive neurons depends on glutamate release from the neurons.