Obesity remains a major health problem in US and causes metabolic complications such as diabetes, dyslipidemia and insulin resistance. Similar complications also occur in patients with familial lipodystrophies, monogenic disorders characterized by partial (familial partial lipodystrophy, FPL) or almost complete (congenital generalized lipodystrophy, CGL) lack of body fat. In the last few years, several genes, namely, 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2), for the autosomal recessive, CGL;lamin A/C (LMNA), peroxisome proliferator-activated receptor-D (PPARG), and v-AKT murine thymoma oncogene homolog 2 (AKT2) for the autosomal dominant FPL;and LMNA and zinc metalloproteinase (ZMPSTE24) for mandibuloacral dysplasia associated lipodystrophies have been identified. However, affected subjects from many pedigrees lack mutations in these genes suggesting additional loci. Furthermore, the genetic basis of many extremely rare varieties of lipodystrophies associated with SHORT and neonatal progeroid syndromes remains unknown. Thus, the first aim of this proposal is to identify additional gene(s) involved in adipocyte biology, development and differentiation that cause lipodystrophies. Our laboratory has also been studying the functional role of various isoforms of AGPAT (mainly AGPAT1 and 2) either in vitro or by developing knockout mouse models. The Agpat2-/- mice reproduce many features of human CGL such as extreme lack of body fat, early onset hyperglycemia, hyperinsulinemia, hypertriglyceridemia and hepatic steatosis. Interestingly, our studies reveal that in these null mice, dietary triglycerides are major contributors to hepatic steatosis. The Agpatl-/- mice also have profound lack of body fat but the detailed phenotype remains to be characterized. Furthermore, the biological function of BSCL2-encoded protein, seipin, still remains unknown and thus how BSCL2 mutations cause lipodystrophy remains puzzling. Therefore, the second aim of this proposal is to further characterize Agpat2- /- and Agpatl-/- mice and to develop Bscl2 knockout mouse model to gain insights into biological role of various genes implicated in generalized lipodystrophies and to understand molecular mechanisms involved in causation of insulin resistance and its associated morbidities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054387-12
Application #
7787429
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Mckeon, Catherine T
Project Start
1999-05-15
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
12
Fiscal Year
2010
Total Cost
$590,898
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Agarwal, Anil K; Tunison, Katie; Dalal, Jasbir S et al. (2017) Metabolic, Reproductive, and Neurologic Abnormalities in Agpat1-Null Mice. Endocrinology 158:3954-3973
Agarwal, Anil K; Tunison, Katie; Dalal, Jasbir S et al. (2016) Mogat1 deletion does not ameliorate hepatic steatosis in lipodystrophic (Agpat2-/-) or obese (ob/ob) mice. J Lipid Res 57:616-30
Sankella, Shireesha; Garg, Abhimanyu; Agarwal, Anil K (2016) Characterization of the Mouse and Human Monoacylglycerol O-Acyltransferase 1 (Mogat1) Promoter in Human Kidney Proximal Tubule and Rat Liver Cells. PLoS One 11:e0162504
Cautivo, Kelly M; Lizama, Carlos O; Tapia, Pablo J et al. (2016) AGPAT2 is essential for postnatal development and maintenance of white and brown adipose tissue. Mol Metab 5:491-505
Garg, Abhimanyu; Kircher, Martin; Del Campo, Miguel et al. (2015) Whole exome sequencing identifies de novo heterozygous CAV1 mutations associated with a novel neonatal onset lipodystrophy syndrome. Am J Med Genet A 167A:1796-806
Patni, Nivedita; Alves, Crésio; von Schnurbein, Julia et al. (2015) A Novel Syndrome of Generalized Lipodystrophy Associated With Pilocytic Astrocytoma. J Clin Endocrinol Metab 100:3603-6
Garg, Abhimanyu; Xing, Chao (2014) De novo heterozygous FBN1 mutations in the extreme C-terminal region cause progeroid fibrillinopathy. Am J Med Genet A 164A:1341-5
Sankella, Shireesha; Garg, Abhimanyu; Horton, Jay D et al. (2014) Hepatic gluconeogenesis is enhanced by phosphatidic acid which remains uninhibited by insulin in lipodystrophic Agpat2-/- mice. J Biol Chem 289:4762-77
Agarwal, Anil K; Sankella, Shireesha (2014) Phosphatidic acid: a new therapeutic lead to suppress hepatic glucose production. Diabetes Manag (Lond) 4:323-326
Cortés, Víctor A; Cautivo, Kelly M; Rong, Shunxing et al. (2014) Leptin ameliorates insulin resistance and hepatic steatosis in Agpat2-/- lipodystrophic mice independent of hepatocyte leptin receptors. J Lipid Res 55:276-88

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