Poster only 3rd Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity 2022

Deletion of TRIM28 in the hypothalamus protects against high fat diet-induced obesity and glucose intolerance (#55)

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 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.

To examine the role of hypothalamic TRIM28, we generated Trim28fl/flLepR-Cre mice with deletion of Trim28 specifically in LepR-expressing neurons. Chow fed male Trim28fl/flLepR-Cre mice exhibited modest but significantly increased body weight compared to their Trim28fl/fl counterparts, with preserved glucose tolerance and insulin sensitivity. Interestingly, chow fed female Trim28fl/flLepR-Cre mice displayed remarkably improved glucose tolerance and insulin sensitivity, with no changes in body weight.

To eliminate the effects of developmental compensation, mice with post-developmental deletion of Trim28 were generated by injecting adeno-associated virus expressing Cre into the ARC of adult Trim28fl/fl mice. Chow fed male mice with Trim28 deletion in the ARC gained significant more weight and fat mass than mice injected with a control virus, with modestly impaired glucose tolerance. Similarly, chow fed female mice with Trim28 deletion in the ARC exhibited modest increased body weight and fat mass, with no changes in glucose tolerance. These data demonstrate that when fed a chow diet, post-developmental deletion of Trim28 in the ARC can preserve glucose tolerance in the face of increased adiposity.

Interestingly, when fed on a high fat diet, male Trim28fl/flLepR-Cre mice gained significantly less body weight and fat mass. Insulin sensitivity was remarkably improved in those mice. In high fat diet-fed female Trim28fl/flLepR-Cre mice, glucose tolerance was significantly improved, with no changes in body weight.

This exciting finding warrants further investigation to determine whether post-developmental deletion of Trim28 in the hypothalamus can protect against diet-induced obesity and glucose intolerance, and to understand mechanisms by which TRIM28 mediates these effects.