SUMMARY Glucagon-like peptide-1 (GLP-1) and its analogs act as appetite suppressants and have been proven to be clinically efficacious in reducing body weight in obese individuals. Central GLP-1 is expressed in a small population of brainstem cells located in the nucleus tractus solitarius (NTS), which project to a wide range of brain areas. However, it remains unclear how endogenous GLP-1 released in the brain contributes to appetite regulation. By using chemogenetic tools, we discovered that central GLP-1 acts on the midbrain ventral tegmental area (VTA) and suppresses high-fat food intake. We used integrated pathway tracing and synaptic physiology to further demonstrate that activation of GLP-1 receptors specifically reduces the excitatory synaptic strength of dopamine (DA) neurons within the VTA that project to the nucleus accumbens (NAc) medial shell. These data suggest that GLP-1 released from NTS neurons can reduce highly palatable food intake by suppressing mesolimbic DA signaling.

Gain-of-toxic-function mutations in Seipin (Asparagine 88 to Serine (N88S) and Serine 90 to Leucine (S90L) mutations, both of which disrupt the N-glycosylation) cause autosomal dominant motor neuron diseases. However, the mechanism of how these missense mutations lead to motor neuropathy is unclear. Here, we analyze the impact of disruption of N-glycosylation of Seipin on synaptic transmission by overexpressing mutant Seipin in cultured cortical neurons via lentiviral infection. Immunostaining shows that over-expressed Seipin is partly colocalized with synaptic vesicle marker synaptophysin. Electrophysiological recordings reveal that the Seipin mutation significantly decreases the frequency, but not the amplitudes of miniature excitatory post-synaptic currents and miniature inhibitory post-synaptic currents. The amplitude of both evoked excitatory post-synaptic currents and inhibitory post-synaptic current is also compromised by mutant Seipin over-expression. The readily releasable pool and vesicular release probability of synaptic vesicles are both altered in neurons over-expressing Seipin-N88S, whereas neither c-amino butyric acid (GABA) nor a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) induced whole cell currents are affected. Moreover, electron microscopy analysis reveals decreased number of morphologically docked synaptic vesicles in Seipin-N88S-expressing neurons. These data demonstrate that Seipin-N88S mutation impairs synaptic neurotransmission, possibly by regulating the priming and docking of synaptic vesicles at the synapse. Keywords: AMPA receptor, EPSC, GABA, glutamate, IPSC, neurotransmission. J. Neurochem. (2014) 129, 328-338.Berardinelli-Seip Congenital Lipodystrophy Type 2 (BSCL2), a rare autosomal recessive disease, is characterized by a loss of adipose tissue and often accompanied by severe hypertriglyceridemia, insulin resistance, and moderate intellectual impairment (Agarwal et al. 2003;Fu et al. 2004;Magre et al. 2001). The BSCL2 gene encodes Seipin, which is important for lipid droplet morphology and adipocyte differentiation (Chen et al. 2012;Cui et al. 2011). Most mutations of Seipin associated with lipodystrophy contain non-sense, frame-shift, or aberrant splicing mutations that produce Received September 16, 2013; revised manuscript received November 18, 2013; accepted December 12, 2013. Address correspondence and reprint requests to Weiping Han, #02-02 Helios, 11 Biopolis Way, Singapore 138667. E-mail: weiping_han@ sbic.a-star.edu.sg or Zhiping Pang, 89 French Street, New Brunswick, NJ 08901, USA. E-mail: Zhiping.pang@rutgers.eduAbbreviations used: AMPA, a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; dHMN-V, distal hereditary motor neuropathy type V; EPSC, miniature excitatory post-synaptic currents; mIPSC, miniature inhibitory post-synaptic currents; PBS, phosphate-buffered saline; PPR, paired-pulse ratio; RRP, readily releasable pool. 328