Hindbrain DPP-IV inhibition improves glycemic control and promotes negative energy balance

• DOI: 10.1016/j.physbeh.2017.01.038
• Publication Date: 2017-01-22T14:45:19Z
• Authors: Elizabeth G. Miet...; Lauren E. McGrath; Kieran Koch-Lasko...; Joanna Krawczyk; Tram Pham; Rinzin Lhamo; David J. Reiner; Matthew R. Hayes
• Keywords: Blood Glucose; Male; 2. Zero hunger; Dipeptidyl-Peptidase IV Inhibitors; 0303 health sciences; Dipeptidyl Peptidase 4; Body Weight; Sitagliptin Phosphate; Fasting; Glucose Tolerance Test; Diet, High-Fat; Rats; Rats, Sprague-Dawley; Rhombencephalon; Eating; 03 medical and health sciences; Area Under Curve; Animals; Energy Metabolism; Injections, Intraventricular

The beneficial glycemic and food intake-suppressive effects of glucagon-like peptide-1 (GLP-1) have made this neuroendocrine system a leading target for pharmacological approaches to the treatment of diabetes and obesity. One strategy to increase the activity of endogenous GLP-1 is to prevent the rapid degradation of the hormone by the enzyme dipeptidyl peptidase-IV (DPP-IV). However, despite the expression of both DPP-IV and GLP-1 in the brain, and the clear importance of central GLP-1 receptor (GLP-1R) signaling for glycemic and energy balance control, the metabolic effects of central inhibition of DPP-IV activity are unclear. To test whether hindbrain DPP-IV inhibition suppresses blood glucose, feeding, and body weight gain, the effects of 4th intracerebroventricular (ICV) administration of the FDA-approved DPP-IV inhibitor sitagliptin were evaluated. Results indicate that hindbrain delivery of sitagliptin improves glycemic control in a GLP-1R-dependent manner, suggesting that this effect is due at least in part to increased endogenous brainstem GLP-1 activity after sitagliptin administration. Furthermore, 4th ICV injection of sitagliptin reduced 24h body weight gain and energy intake, with a selective suppression of high-fat diet, but not chow, intake. These data reveal a novel role for hindbrain GLP-1R activation in glycemic control and also demonstrate that DPP-IV inhibition in the caudal brainstem promotes negative energy balance.