Glucagon-like Peptide-1 (GLP-1)

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Figure 1: Novel technique for the microinjection of shRNA into a rat nodose ganglion, developed and for the first time used in-vivo by us. The nodose ganglia contain the cell bodies of the vagal afferents
Figure 1: Novel technique for the microinjection of shRNA into a rat nodose ganglion, developed and for the first time used in-vivo by us. The nodose ganglia contain the cell bodies of the vagal afferents

The intestinal hormone GLP-1 is a potent incretin, i.e., it stimulates glucose-induced insulin release, and it inhibits gastric emptying. Also, strong evidence links GLP-1 to the control of eating. Endogenous intestinal GLP-1 is implicated in meal termination (= satiation) because (1) the presence of nutrients in the small intestine stimulates GLP-1 release, (2) exogenous GLP-1 inhibits eating primarily by reducing meal size, and (3) IP injection of the GLP-1R antagonist exendin-9 (Ex-9) stimulated eating under some conditions.

Figure 2: Green Fluorescent Protein (GFP) expression in the nodose ganglion of a rat injected with GLP-1R–targeting lentiviral particles  
Figure 2: Green Fluorescent Protein (GFP) expression in the nodose ganglion of a rat injected with GLP-1R–targeting lentiviral particles

Rapid degradation by dipeptidyl peptidase-IV (DPP-IV) limits GLP-1’s potential as an endocrine signal. Our recent studies indicate, however, that endogenous GLP-1 inhibits eating mainly through a paracrine effect on vagal afferents terminating in the wall of the small intestine. We are currently using different approaches to critically examine this hypothesis. One novel technique is the down-regulation of GLP-1 receptors in abdominal vagal afferents through RNA interference. This is accomplished by bilateral microinjections of a lentiviral vector with a short hairpin RNA into the nodose ganglia, which contain the cell bodies of vagal afferents (Figures 1 and 2).

Figure 3: GLP-1 receptor knockdown in vagal afferents leads to a persistent increase in meal size and meal duration that is compensated by a decrease in meal frequency (Krieger et al., Diabetes 65:34-43, 2016)  
Figure 3: GLP-1 receptor knockdown in vagal afferents leads to a persistent increase in meal size and meal duration that is compensated by a decrease in meal frequency (Krieger et al., Diabetes 65:34-43, 2016)
Figure 4: Triple labeling of the Nucleus tractus solitarii of a rat after intraperitoneal injection of Exendin-4 and microinjection of an AAV-GFP virus (green) in to the nodose ganglion.  Red: c-Fos, blue: dopamine-beta-hydroxylase.   
Figure 4: Triple labeling of the Nucleus tractus solitarii of a rat after intraperitoneal injection of Exendin-4 and microinjection of an AAV-GFP virus (green) in to the nodose ganglion.  Red: c-Fos, blue: dopamine-beta-hydroxylase. 

The GLP-1 receptor knockdown leads to permanent increases in meal size and meal duration (Figure 3). Interestingly, GLP-1 also improves glycemic control partly through this mechanism. In addition, we are trying to map the brain areas that are activated by peripheral GLP-1 to identify the neurochemical mechanisms mediating the effects of GLP-1 (Figure 4). Also, we started to unravel the interactions of the peripheral and central GLP-1 systems. All these questions are important for the development of GLP-1-based therapeutic approaches to fight obesity and type-2-diabetes (T2D) and for the putative role of GLP-1 in the obesity- and T2D-curbing effects of gastric bypass surgery.

 
 
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Sat Jun 24 01:05:10 CEST 2017
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