Novel metabolic role for BDNF in pancreatic \u03b2-cell insulin secretion

Gianluca Fulgenzi,Jodi Becker,Brad St Croix,Sudhirkumar Yanpallewar,Deborah Swing,Jürgen Wess,Colleen Barrick,Zhenyi Hong,Francesco Tomassoni-Ardori,Lino Tessarollo,Oksana Gavrilova,Luiz F Barella

doi:10.1038/s41467-020-15833-5

Gianluca Fulgenzi, Jodi Becker + Show 10 more

Open Access

https://doi.org/10.1038/s41467-020-15833-5

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Journal: Nature Communications	Publication Date: Apr 23, 2020
Citations: 64	License type: open-access

Affiliation: Cancer Genetics (United States)

Abstract

BDNF signaling in hypothalamic circuitries regulates mammalian food intake. However, whether BDNF exerts metabolic effects on peripheral organs is currently unknown. Here, we show that the BDNF receptor TrkB.T1 is expressed by pancreatic β-cells where it regulates insulin release. Mice lacking TrkB.T1 show impaired glucose tolerance and insulin secretion. β-cell BDNF-TrkB.T1 signaling triggers calcium release from intracellular stores, increasing glucose-induced insulin secretion. Additionally, BDNF is secreted by skeletal muscle and muscle-specific BDNF knockout phenocopies the β-cell TrkB.T1 deletion metabolic impairments. The finding that BDNF is also secreted by differentiated human muscle cells and induces insulin secretion in human islets via TrkB.T1 identifies a new regulatory function of BDNF on metabolism that is independent of CNS activity. Our data suggest that muscle-derived BDNF may be a key factor mediating increased glucose metabolism in response to exercise, with implications for the treatment of diabetes and related metabolic diseases.

Highlights

Brain Derived Neurotrophic Factor (BDNF) signaling in hypothalamic circuitries regulates mammalian food intake
Truncated TrkB is difficult to detect in unfractionated pancreatic tissue by immunoblotting, the identity of this receptor as TrkB.T1 was confirmed at the protein and mRNA level by immunoprecipitation and reverse-transcription PCR (RT-PCR), respectively, using pancreatic lysates from TrkB.T1+/+ or −/− mice (Fig. 1a and Supplementary Fig. 1)
room temperature (RT)-PCR analysis showed that TrkB.T1 is the most abundant Trk receptor isoform in islets since both TrkA and TrkC were present at negligible levels compared to TrkB.T1 (Supplementary Fig. 1)

Summary

Introduction

BDNF signaling in hypothalamic circuitries regulates mammalian food intake. whether BDNF exerts metabolic effects on peripheral organs is currently unknown. The day, islets were placed in a low (3.3 mM) glucose solution that does not stimulate insulin secretion before testing (Fig. 3a–e). While BDNF alone does not increase insulin secretion in β-TC-6 cells, it does have a synergistic action with high glucose as in isolated mouse islets (Fig. 5c).

Results

Conclusion