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

Author
item SHI, XUEMEI - Children'S Nutrition Research Center (CNRC)
item CHACKO, SHAJI - Children'S Nutrition Research Center (CNRC)
item LI, FENG - Baylor College Of Medicine
item LI, DEPEI - Md Anderson Cancer Center
item Burrin, Douglas - Doug
item CHAN, LAWRENCE - Baylor College Of Medicine
item GUAN, XINFU - Children'S Nutrition Research Center (CNRC)

Submitted to: Molecular Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/23/2017
Publication Date: 9/1/2017
Citation: Shi, X., Chacko, S., Li, F., Li, D., Burrin, D., Chan, L., Guan, X. 2017. Acute activation of GLP-1-expressing neurons promotes glucose homeostasis and insulin sensitivity. Molecular Metabolism. 6(11):1350-1359. http://dx.doi.org/10.1016/j.molmet.2017.08.009.

Interpretive Summary: Peptides similar to hormone glucagon are released from certain neuronal cells in the brain. It is not known if these neuroendocrine signals are associated in the regulation of glucose concentration in the body. The objective of this research was to determine whether activation of this neuronal population in the brain stem modulates glucose metabolism in the body. This study demonstrated that activation of these specific neuronal cell population in the brainstem reduced glucose production and increased insulin sensitivity in the body. The findings from this study indicate that this neuronal cell population is associated in the regulation of glucose concentration in the body via insulin action. This suggests that these specific neuronal cells in the brain may be a potential target for treating type 2 diabetes and obesity.

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