Oral Presentation The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2017

The role of beta-cell Hif1α in the response of high fat diet-fed beta-TRAP mice to acute glucose challenge (#79)

Sing-Young Chen 1 , Michael Tsang 1 , Michael Swarbrick 1 2 , Jenny Gunton 1 2 3
  1. Centre for Diabetes, Obesity and Endocrinology, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
  2. School of Medical Sciences, University of New South Wales, Kensington, New South Wales, Australia
  3. Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia

Background: The study of beta-cell gene expression is challenged by the diversity of cells in the islets of Langerhans and their relative scarcity within the pancreas. Translating Ribosome Affinity Purification (TRAP) permits the extraction of mRNAs specifically from beta-cells using genetically modified (beta-TRAP) mice with enhanced green fluorescent protein-tagged ribosomes in insulin-expressing cells. The transcription factor Hif1α has previously been shown to positively influence insulin secretion in the beta-cell. In this study, the whole-body effects of a beta-cell-specific knockout of one allele of Hif1α (B-Hif1α+/-) in beta-TRAP mice is investigated.

Methods: Seven-week-old beta-TRAP mice, wild-type (WT) or B-Hif1α+/-, were fed chow or high fat diet (HFD). After 8 weeks, oral glucose tolerance and glucose-stimulated insulin secretion (GSIS) were assessed. Mice were sacrificed after 9 weeks and fat pads (inguinal, gonadal, retroperitoneal, mesenteric, brown adipose) were weighed.

Results: Both male and female beta-TRAP mice on HFD demonstrated impaired glucose tolerance compared to chow controls. Compared to female mice, HFD-fed males displayed more exacerbated increases in body weight, fat pad mass and extent of hyperinsulinaemia, compared to respective chow-fed controls. Among the HFD-fed male beta-TRAP, B-Hif1α+/- mice (n=12) were more glucose tolerant than WT (n=14) (area under curve 3393±293 vs 4401±331, p<0.05), with no significant difference in fasting glucose or GSIS. Body weight and fat pad mass did not differ between HFD-fed B-Hif1α+/- and WT males.

Conclusion: Heterozygous deletion of beta-cell Hif1α in HFD-fed male beta-TRAP mice improved glucose tolerance despite no significant change in insulin secretion, nor any measured change in body weight or fat pad mass. These results may be clarified by studying mice with a homozygous deletion of Hif1α in the beta-cells, where any change from WT would be more apparent.