GLP-1 regulates the POMC neurons of the arcuate nucleus both directly and indirectly via presynaptic action

GLP-1 exerts its anorexigenic effect at least partly via the POMC neurons of the arcuate nucleus (ARC). These neurons are known to express GLP-1 receptor (GLP-1R). To determine whether in addition to its direct effect, GLP-1 also modulates, how neuronal inputs can regulate the POMC neurons by acting on presynaptic terminals, ultrastructural and electrophysiological studies were performed on tissues of adult male mice. GLP-1R-immunoreactivity was associated with the cell membrane of POMC neurons and with axon terminals forming synapses on these cells. The GLP-1 analog Exendin 4 (Ex4) markedly increased the firing rate of all examined POMC neurons and depolarized these cells. These effects of Ex4 were prevented by intracellular administration of the G-protein blocker GDP-β-S. Ex4 also influenced the miniature and evoked postsynaptic currents (PSCs) of POMC neurons. Ex4 increased the frequency of miniature excitatory PSCs and the amplitude of the evoked excitatory PSCs in half of the POMC neurons. Ex4 increased the frequency of miniature inhibitory PSCs and the amplitudes of the evoked inhibitory PSCs in one-third of neurons. These effects of Ex4 were not influenced by intracellular GDP-β-S, indicating that GLP-1-signaling directly stimulates a population of axon terminals innervating the POMC neurons. The different Ex4 responsiveness of their mPSCs indicates the heterogeneity of the POMC neurons of the ARC. In summary, our data demonstrate that in addition to its direct excitatory effect on the POMC neurons, GLP-1-signaling also facilitates the presynaptic input of these cells by acting on presynaptically localized GLP-1R

Hypothalamic Nesfatin-1 Resistance May Underlie the Development of Type 2 Diabetes Mellitus in Maternally Undernourished Non-obese Rats

Intrauterine growth retardation (IUGR) poses a high risk for developing late-onset, non-obese type 2 diabetes (T2DM). The exact mechanism underlying this phenomenon is unknown, although the contribution of the central nervous system is recognized. The main hypothalamic nuclei involved in the homeostatic regulation express nesfatin-1, an anorexigenic neuropeptide and identified regulator of blood glucose level. Using intrauterine protein restricted rat model (PR) of IUGR, we investigated, whether IUGR alters the function of nesfatin-1. We show that PR rats develop fat preference and impaired glucose homeostasis by adulthood, while the body composition and caloric intake of normal nourished (NN) and PR rats are similar. Plasma nesfatin-1 levels are unaffected by IUGR in both neonates and adults, but pro-nesfatin-1 mRNA expression is upregulated in the hypothalamus of adult PR animals. We find that centrally injected nesfatin-1 inhibits the fasting induced neuronal activation in the hypothalamic arcuate nucleus in adult NN rats. This effect of nesfatin-1 is not seen in PR rats. The anorexigenic effect of centrally injected nesfatin-1 is also reduced in adult PR rats. Moreover, chronic central nesfatin-1 administration improves the glucose tolerance and insulin sensitivity in NN rats but not in PR animals. Birth dating of nesfatin-1 cells by bromodeoxyuridine (BrDU) reveals that formation of nesfatin-1 cells in the hypothalamus of PR rats is disturbed. Our results suggest that adult PR rats acquire hypothalamic nesfatin-1-resistance, probably due to the altered development of the hypothalamic nesfatin-1 cells. Hypothalamic nesfatin-1-resistance, in turn, may contribute to the development of non-obese type T2DM