| First Author | Nasteska D | Year | 2021 |
| Journal | JCI Insight | Volume | 6 |
| Issue | 16 | PubMed ID | 34264866 |
| Mgi Jnum | J:312995 | Mgi Id | MGI:6792985 |
| Doi | 10.1172/jci.insight.140288 | Citation | Nasteska D, et al. (2021) Prolyl-4-hydroxylase 3 maintains beta cell glucose metabolism during fatty acid excess in mice. JCI Insight 6(16) |
| abstractText | The alpha-ketoglutarate-dependent dioxygenase, prolyl-4-hydroxylase 3 (PHD3), is an HIF target that uses molecular oxygen to hydroxylate peptidyl prolyl residues. Although PHD3 has been reported to influence cancer cell metabolism and liver insulin sensitivity, relatively little is known about the effects of this highly conserved enzyme in insulin-secreting beta cells in vivo. Here, we show that the deletion of PHD3 specifically in beta cells (betaPHD3KO) was associated with impaired glucose homeostasis in mice fed a high-fat diet. In the early stages of dietary fat excess, betaPHD3KO islets energetically rewired, leading to defects in the management of pyruvate fate and a shift from glycolysis to increased fatty acid oxidation (FAO). However, under more prolonged metabolic stress, this switch to preferential FAO in betaPHD3KO islets was associated with impaired glucose-stimulated ATP/ADP rises, Ca2+ fluxes, and insulin secretion. Thus, PHD3 might be a pivotal component of the beta cell glucose metabolism machinery in mice by suppressing the use of fatty acids as a primary fuel source during the early phases of metabolic stress. |
