Novel metabolic role for BDNF in pancreatic β-cell insulin secretion

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 musclederived 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.

α2-Adrenergic Disruption of β Cell BDNF-TrkB Receptor Tyrosine Kinase Signaling

“…BDNF can indirectly regulate islet hormones, like glucagon, through actions in the hypothalamus and innervation of the islet ( Gotoh et al, 2013 ) and was suggested to have direct effects on α cells ( Hanyu et al, 2003 ). However, TrkB is expressed in both rodent and human β and α cells, as supported by our data and others ( Shibayama and Koizumi, 1996 ; Hanyu et al, 2003 ; Uhlen et al, 2015 ; DiGruccio et al, 2016 ; Segerstolpe et al, 2016 ; Fulgenzi et al, 2020 ). TrkB is expressed as two splice isoforms, full-length TrkB (TrkB.FL) and TrkB.T1 which is missing the cytosolic kinase domain, instead containing a short distinct cytosolic tail ( Fenner, 2012 ).…”

“…TrkB is expressed as two splice isoforms, full-length TrkB (TrkB.FL) and TrkB.T1 which is missing the cytosolic kinase domain, instead containing a short distinct cytosolic tail ( Fenner, 2012 ). Recent work from Fulgenzi et al (2020) has demonstrated that the TrkB splice isoform, TrkB.T1, is involved in BDNF-induced insulin secretion and that BDNF can induce insulin secretion from human islets at low glucose concentrations. The relative amounts of TrkB.FL and TrkB.T1 in islet β and α cells has not been defined and could potentially explain the different staining patterns we observe with antibodies to different epitopes.…”

Resistance exercise training improves glucose homeostasis by enhancing insulin secretion in C57BL/6 mice

“…In fact, conditioned medium from white-glycolytic muscle cells (which are predominantly stimulated by resistance exercise) was more efficient than conditioned medium from red-oxidative muscle cells (which are predominantly stimulated by endurance exercise) to preserve insulin secretion, proliferation and survival, as well as reduced beta-cell death under pro-inflammatory conditions 40 , 41 . Besides, several muscle-derived factors released in response to exercise might act upon beta-cell function and survival 42 , such as: IL-6 11 , irisin 43 , BnDF 44 , GDF-15 45 , myostatin, follistatin 46 , angiogenin and osteoprotegerin 40 .…”

Mitochondria Homeostasis and Oxidant/Antioxidant Balance in Skeletal Muscle—Do Myokines Play a Role?

“…It has been suggested that the skeletal muscle-generated BDNF acted solely as an autocrine because overexpression of BDNF in the muscle did not alter its concentration in blood [ 53 ]. Using the muscle-specific BDNF knockout (MBKO) mice, however, we and Fulgenzi et al have found recently that BDNF can be secreted into circulation [ 54 , 55 ]. We and Matthews et al have also shown that BDNF is a positive regulator of mitochondrial activity in the cultured muscle cells [ 53 , 54 ].…”