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

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

doi:10.1016/j.isci.2023.107806

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

iScience. 2023 Sep 1;26(10):107806. doi: 10.1016/j.isci.2023.107806. eCollection 2023 Oct 20.

Authors

Anil K Agarwal^{1

2}, Katie Tunison^{1

2}, Goncalo Vale^{2

3}, Jeffrey G McDonald^{2

3}, Xilong Li⁴, Philipp E Scherer⁵, Jay D Horton^{2

3}, Abhimanyu Garg^{1

2}

Affiliations

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

Abstract

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 hAGPAT2 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 hAGPAT2 in vivo resulted in total loss of regenerated adipose tissue, clear evidence that Agpat2 is essential for adipocyte differentiation in vivo.

Keywords: cell biology; cellular physiology; physiology.

Abstract

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