Acute activation of GLP-1-expressing neurons promotes glucose homeostasis and insulin sensitivity

Xuemei Shi, Shaji Chacko, Feng Li, Depei Li, Douglas Burrin, Lawrence Chan, Xinfu Guan

In response to food intake, glucagon-like peptides (GLP-1/2) are co-released from enteroendocrine L cells in the gut as well as preproglucagon (PPG) neurons in the nucleus of the solitary tract (NTS) of the brainstem, which together constitute the key nutritional signals for the control of energy balance and glucose homeostasis. Shi and colleagues determined whether activation of PPG neurons per se modulates glucose homeostasis and insulin sensitivity in vivo. They show in Gcg-Cre lean mice infected with excitatory hM3Dq virus in the brainstem NTS that acute activation of Gcg neurons (which include the PPG neurons) enhances glucose tolerance, suppresses basal endogenous glucose production, and augments hepatic insulin sensitivity.

Objective: Glucagon-like peptides are co-released from enteroendocrine L cells in the gut and preproglucagon (PPG) neurons in the brainstem. PPG-derived GLP-1/2 are probably key neuroendocrine signals for the control of energy balance and glucose homeostasis. The objective of this study was to determine whether activation of PPG neurons per se modulates glucose homeostasis and insulin sensitivity in vivo.

Methods: We generated glucagon (Gcg) promoter-driven Cre transgenic mice and injected excitatory hM3Dq-mCherry AAV into their brainstem NTS. We characterized the metabolic impact of PPG neuron activation on glucose homeostasis and insulin sensitivity using stable isotopic tracers coupled with hyperinsulinemic euglycemic clamp.

Results: We showed that after ip injection of clozapine N-oxide, Gcg-Cre lean mice transduced with hM3Dq in the brainstem NTS downregulated basal endogenous glucose production and enhanced glucose tolerance following ip glucose tolerance test. Moreover, acute activation of PPG neuronsNTS enhanced whole-body insulin sensitivity as indicated by increased glucose infusion rate as well as augmented insulin-suppression of endogenous glucose production and gluconeogenesis. In contrast, insulin-stimulation of glucose disposal was not altered significantly.

Conclusions: We conclude that acute activation of PPG neurons in the brainstem reduces basal glucose production, enhances intraperitoneal glucose tolerance, and augments hepatic insulin sensitivity, suggesting an important physiological role of PPG neurons-mediated circuitry in promoting glycemic control and insulin sensitivity.