Oral Presentation ANZOS Annual Scientific Meeting 2021

Deletion of TRIM28 in the hypothalamus induces obesity but preserves glucose tolerance (#82)

Yi Wang 1 , Christine Yang 1 , Anna C Calkin 1 , Geoff Head 1 , Christian Vaisse 2 , Brian G Drew 1
  1. Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
  2. Diabetes Center, University of California, San Francisco, San Francisco, California, USA

Tripartite motif-containing 28 (TRIM28) is a multi-domain protein that interacts with chromatin to suppress gene transcription. TRIM28 haploinsufficiency in humans triggers obesity. Moreover, Trim28 haploinsufficient mice and adipose specific Trim28 KO mice develop obesity that influences whole body metabolism. TRIM28 is highly expressed in hypothalamic nuclei that regulate energy and glucose metabolism, including the arcuate nucleus (ARC). However, the importance of neuronal TRIM28 in energy and glucose metabolism remains to be determined.

Here, we utilised genetically modified mouse models to examine the role of neuronal TRIM28 in regulating energy and glucose metabolism. Trim28fl/fl mice were crossed with Leptin receptor (LepR)-Cre mice to generate Trim28fl/flLepR-Cre mice with deletion of Trim28 specifically in LepR-expressing neurons. At 10 weeks of age, male Trim28fl/flLepR-Cre mice did not exhibit differences in metabolic phenotypes including body weight, fat/lean mass, fasting glucose or glucose tolerance (ipGTT, 2 g/kg lean mass) compared to their Trim28fl/fl counterparts. Interestingly, there was a trend for increased fat mass in female Trim28fl/flLepR-Cre mice, and this was associated with significantly improved glucose tolerance compared with littermate control mice.

To eliminate the effects of developmental compensation, adeno-associated virus (AAV) expressing Cre was injected into the ARC of 10-week old male Trim28fl/fl mice, to generate mice with post-developmental Trim28 deletion in the ARC. After just 10 weeks, these mice exhibited a 23% increase in body weight compared to mice injected with a control AAV. This effect was attributed to an increase in fat mass, with no difference in lean mass observed. Interestingly, fasting glucose and glucose tolerance were not affected in mice with Trim28 deletion in the ARC.

Together, these studies suggest that deletion of TRIM28 in the hypothalamus induces obesity but preserves glucose tolerance. Further studies are warranted to understand the underlying mechanisms by which TRIM28 mediates these effects.