Regulated adipose tissue-specific expression of human AGPAT2 in lipodystrophic Agpat2 -null mice results in regeneration of adipose tissue

iScience · 8 authors, 5 centres

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TL;DR

Doxycycline-regulated expression of human AGPAT2 in adipose tissue of Agpat2-null mice regenerated fat depots to approximately 30%–50% of wild-type levels, but turning off hAGPAT2 expression led to progressive adipose tissue loss that was almost undetectable by 12 weeks.

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The study used transgenic Agpat2-null mice with doxycycline-regulated adipose tissue-specific expression of human AGPAT2 to investigate the role of AGPAT2 in adipose tissue development and maintenance. Turning off hAGPAT2 expression by removing doxycycline resulted in progressive adipose tissue loss across all depots, with tissue becoming almost undetectable by 12 weeks after doxycycline removal. The study is limited by its preclinical mouse model design, relatively small group sizes (n = 3–12), and the use of a heterologous promoter rather than the endogenous Agpat2 promoter.

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other

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preclinical research

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ORIGINAL PAPER

PMC10518674

Regulated adipose tissue-specific expression of human AGPAT2 in lipodystrophic Agpat2 -null mice results in regeneration of adipose tissue

iScience

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ABSTRACT

Summary Genetic loss of Agpat2 in humans and mice results in congenital generalized lipodystrophy with near-total loss of adipose tissue and predisposition to develop insulin resistance, diabetes mellitus, hepatic steatosis, and hypertriglyceridemia. The mechanism by which Agpat2 deficiency results in loss of adipose tissue remains unknown. We studied this by re-expressing human AGPAT2 (hAGPAT2) in Agpat2 -null mice, regulated by doxycycline. In both sexes of Agpat2 -null mice, adipose-tissue-specific re-expression of h AGPAT2 resulted in partial regeneration of both white and brown adipose tissue (but only 30%–50% compared with wild-type mice), which had molecular signatures of adipocytes, including leptin secretion. Furthermore, the stromal vascular fraction cells of regenerated adipose depots differentiated ex vivo only with doxycycline, suggesting the essential role of Agpat2 in adipocyte differentiation. Turning off expression of h AGPAT2 in vivo resulted in total loss of regenerated adipose tissue, clear evidence that Agpat2 is essential for adipocyte differentiation in vivo . Subject areas: physiology, cellular physiology, cell biology

CITATION EXPORT

Anil K Agarwal, Katie Tunison, Goncalo Vale et al.. Regulated adipose tissue-specific expression of human AGPAT2 in lipodystrophic Agpat2-null mice results in regeneration of adipose tissue. iScience. (2023). https://doi.org/10.1016/j.isci.2023.107806

AUTHORS

8 · 5 CENTRES

Anil K Agarwal, Katie Tunison, Goncalo Vale, Jeffrey G McDonald, Xilong Li, Philipp E Scherer, Jay D Horton, Abhimanyu Garg

1Section of Nutrition and Metabolic Diseases, Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
2Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX 75390, USA
3Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX 75390, USA
4Peter O’Donnell Jr. School of Public Health, UT Southwestern Medical Center, Dallas, TX 75390, USA
5Touchstone Center for Diabetes Research, UT Southwestern Medical Center, Dallas, TX 75390, USA