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Mol Metab. 2017 Nov;6(11):1350-1359. doi: 10.1016/j.molmet.2017.08.009. Epub 2017 Sep 1.

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

Author information

1
Department of Respiratory and Critical Care Medicine, Binzhou Medical University Hospital, Binzhou, Shangdong 256603, China; USDA-ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: xmshi2002@yahoo.com.
2
USDA-ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
3
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
4
Department of Critical Care, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
5
Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
6
School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; USDA-ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: xguan@bcm.edu.

Abstract

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.

KEYWORDS:

Endogenous glucose production; Glucagon-Cre mice; Glucagon-like peptides; Gluconeogenesis; Insulin sensitivity; Preproglucagon neurons

PMID:
29107283
PMCID:
PMC5681239
DOI:
10.1016/j.molmet.2017.08.009
[Indexed for MEDLINE]
Free PMC Article

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