Ma, X. et al.University Laboratory of Physiology, Oxford, United Kingdom
The Journal of Neuroscience
July 4, 2007 [PubMed]
Central Conclusion of Paper (Reason for Being)
GLP1 exerts its appetite suppressive effect by activating proopiomelanocortin (POMC) neurons in the hypothalamus. The activation takes place by way of GLP1 binding to its receptor, activation of PKA, and increasing of L-type Ca2 current.
Discussion of Paper
This Brief Communication provides the experimental evidence for a hypothesis that already had substantial circumstantial evidence. It is known that GLP1 regulates appetite and weight. It is also known that the POMC neurons are the mediators of the appetite control by the hypothalamus. Finally, it is known that the receptor for GLP1 is expressed in the region of the hypothalamus that contains the POMC neurons. Now, this paper provides the data to show the direct interaction of GLP1 and the POMC neurons.
All of the experiments were done using brain slices containing eGFP-expressing POMC neurons. This allowed for the measurement of individual neurons. First the authors showed that treatment with GLP1 increased action potential firing (in 7 of 8 neurons surveyed). Culturing the neurons with both GLP1 with GLP1R antagonist exendin 9-39 abolished the GLP1 effect on the neurons. They repeated the experiment in the presence of blockers of AMPA receptors, NMDA receptors, and GABA receptors. GLP1 still increased firing indicating that GLP1 specifically acts through its receptor. Although, it had already been established, they showed that GLP1 stimulates electrical activities by increasing cytosolic calcium. Again, replicating others' results, the authors showed that GLP1 increased cAMP levels in the neurons. Forskolin, which also elevates cAMP, was also able to increase neuron firing indicating this is the likely signaling pathway that GLP1 uses. Blocking PKA activity with Rp-8-Bromo-cAMPS blocks the effects of GLP1.
Other Notes from the Paper
GLP1 is known to be produced by neurons in the nucleus of the solitary tract (NTS) in addition to the L-cells of the small intestine.
Intracerebroventricular and repeated central injections of GLP1 have been used to show that it reduces feeding and body weight in rats.
GLP1 levels are reduced in obese men and teenage girls (links to eating disorders) and rise with weight loss.
Subcutaneous injection of GLP1 over 5 days reduces weight in obese subjects.
GLP1R is densely expressed in the arcuate nucleus (ARC), paraventricular nucleus (PVN), and supraoptic nuclei of the hypothalamus
GLP-1 also stimulates the electrical activity of orexin/hypocretin neurons but has an opposite effect on Ca2 currents - activation of orexin/hypocretin neurons leads to hyperphagia.
GLP1 exerts its appetite suppressive effect by activating proopiomelanocortin (POMC) neurons in the hypothalamus. The activation takes place by way of GLP1 binding to its receptor, activation of PKA, and increasing of L-type Ca2 current.
Discussion of Paper
This Brief Communication provides the experimental evidence for a hypothesis that already had substantial circumstantial evidence. It is known that GLP1 regulates appetite and weight. It is also known that the POMC neurons are the mediators of the appetite control by the hypothalamus. Finally, it is known that the receptor for GLP1 is expressed in the region of the hypothalamus that contains the POMC neurons. Now, this paper provides the data to show the direct interaction of GLP1 and the POMC neurons.
All of the experiments were done using brain slices containing eGFP-expressing POMC neurons. This allowed for the measurement of individual neurons. First the authors showed that treatment with GLP1 increased action potential firing (in 7 of 8 neurons surveyed). Culturing the neurons with both GLP1 with GLP1R antagonist exendin 9-39 abolished the GLP1 effect on the neurons. They repeated the experiment in the presence of blockers of AMPA receptors, NMDA receptors, and GABA receptors. GLP1 still increased firing indicating that GLP1 specifically acts through its receptor. Although, it had already been established, they showed that GLP1 stimulates electrical activities by increasing cytosolic calcium. Again, replicating others' results, the authors showed that GLP1 increased cAMP levels in the neurons. Forskolin, which also elevates cAMP, was also able to increase neuron firing indicating this is the likely signaling pathway that GLP1 uses. Blocking PKA activity with Rp-8-Bromo-cAMPS blocks the effects of GLP1.
Other Notes from the Paper
GLP1 is known to be produced by neurons in the nucleus of the solitary tract (NTS) in addition to the L-cells of the small intestine.
Intracerebroventricular and repeated central injections of GLP1 have been used to show that it reduces feeding and body weight in rats.
GLP1 levels are reduced in obese men and teenage girls (links to eating disorders) and rise with weight loss.
Subcutaneous injection of GLP1 over 5 days reduces weight in obese subjects.
GLP1R is densely expressed in the arcuate nucleus (ARC), paraventricular nucleus (PVN), and supraoptic nuclei of the hypothalamus
GLP-1 also stimulates the electrical activity of orexin/hypocretin neurons but has an opposite effect on Ca2 currents - activation of orexin/hypocretin neurons leads to hyperphagia.
