The prolyl hydroxylase PHD3 maintains β-cell glucose metabolism during fatty acid excess

Abstract

22 23Character count (excluding abstract, references and figure legends). 37,922 24 25 2 ABSTRACT 26The alpha ketoglutarate-dependent dioxygenase, prolyl-4-hydroxylase 3 (PHD3), is a hypoxia-27 inducible factor target that uses molecular oxygen to hydroxylate proline. While PHD3 has 28 been reported to influence cancer cell metabolism and liver insulin sensitivity, relatively little 29is known about effects of this highly conserved enzyme in insulin-secreting β-cells. Here, we 30show that deletion of PHD3 specifically in β-cells (βPHD3KO) is associated with impaired 31 glucose homeostasis in mice fed high fat diet. In the early stages of dietary fat excess, 32 βPHD3KO islets energetically rewire, leading to defects in the management of pyruvate fate 33 and a shift away from glycolysis. However, βPHD3KO islets are able to maintain oxidative 34 phosphorylation and insulin secretion by increasing utilization of fatty acids to supply the 35 tricarboxylic acid cycle. This nutrient-sensing switch cannot be sustained and βPHD3KO islets 36 begin to show signs of failure in response to prolonged metabolic stress, including impaired 37 glucose-stimulated ATP/ADP rises, Ca 2+ fluxes and insulin secretion. Thus, PHD3 might be a 38 pivotal component of the β-cell glucose metabolism machinery by suppressing the use of fatty 39 acids as a primary fuel source, under obesogenic and insulin resistant states. 40 Keywords: beta cell, insulin, metabolic stress, hypoxia, prolyl hydroxylase domain proteins, 41 PHD3, Egln3. 42 43 SIGNIFICANCE STATEMENT 44