|Preproglucagon neurons are the source of brain GLP-1 and affect food intake under stress or after large meals|
|MK HOLT1, JE RICHARDS1, DR COOK1, DI BRIERLEY1, F REIMANN2, FM GRIBBLE2, S TRAPP1
1Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, UCL, London, United Kingdom/2Metabolic Research Laboratories University of Cambridge, Cambridge, United Kingdom
| Glucagon-like peptide-1 (GLP-1) injected into the brain suppresses food intake. Similarly, chemogenetic activation of preproglucagon (PPG) neurons suppresses feeding. However, the physiological relevance of these effects remains unclear. Here we investigated under which conditions PPG neurons mediate suppression of feeding. First, we proved that PPG neurons are the main source of GLP-1 within the brain. Selective ablation of NTS PPG neurons by viral expression of diphtheria toxin subunit A (DTA) substantially reduced active GLP-1 concentrations in brainstem, hypothalamus, and spinal cord. Interestingly, these mice exhibited no difference in body weight to their littermates injected with control virus. In contrast, short term food intake was affected; DTA-ablated mice ate more chow over a two hour test period following an overnight fast, and substantially more chow after a 15 min Ensure liquid diet preload as compared to control littermates. Using chemogenetic inhibition, we further explored the importance of PPG neuron activity in the control of food intake. We assessed the role of PPG neurons during ad libitum intake, after overnight food deprivation, and following restraint stress. hM4Di-expressing PPG neurons were inhibited in vivo with intraperitoneal injection of 2mg/kg CNO. Acute inhibition of PPG neuron activity did not affect normal feeding, but increased intake after food deprivation and abolished stress-induced suppression of food intake. Our results indicate a role for PPG neurons in hypophagic responses to both large meals and psychogenic stress. These findings suggest that PPG neurons do not simply reduce intake to meet metabolic needs, but are involved in more complex decisions about whether food intake is appropriate in a given physiological context.|
Supported By: Medical Research Council UK, Grants MR/N02589X/1 and MR/J013293/2 to ST.