Metabolic, Reproductive, and Neurologic Abnormalities in Agpat1-Null Mice

• Published in: Endocrinology (Philadelphia) Vol. 158; no. 11; pp. 3954 - 3973
• Main Authors: Agarwal, Anil K, Tunison, Katie, Dalal, Jasbir S, Nagamma, Sneha S, Hamra, F Kent, Sankella, Shireesha, Shao, Xinli, Auchus, Richard J, Garg, Abhimanyu
• Format: Journal Article
• Language: English
• Published: Washington, DC Endocrine Society 01.11.2017; Oxford University Press
• Subjects: 1-Acylglycerol-3-Phosphate O-Acyltransferase - genetics; Abnormalities; Acyltransferase; Adipocytes; Animals; Auditory stimuli; Biosynthesis; Body fat; Body weight; Cells, Cultured; Defects; Diglycerides; Endocrinology; Energy metabolism; Epilepsy; Fatty acids; Female; FOXO1 protein; Gene expression; Glucagon; Gluconeogenesis; Gluconeogenesis - genetics; Glucose; Glycerol-3-Phosphate O-Acyltransferase - genetics; Gonadotropins; Hippocampus; Homeostasis; Homology; Infertility - genetics; Insulin; Insulin-like growth factor I; Isoenzymes; Lipid Metabolism - genetics; Lipids; Lipogenesis - genetics; Male; Meiosis; Metabolic Diseases - genetics; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Nervous System Diseases - genetics; Phosphates; Phosphatidic acid; Phospholipids; Physiology; Pituitary (anterior); Reproduction - genetics; Ribonucleic acid; RNA; Rodents; Seizures; Sperm; Spermatogenesis; Weaning
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2017-00511

Abstract Defects in the biosynthesis of phospholipids and neutral lipids are associated with cell membrane dysfunction, disrupted energy metabolism, and diseases including lipodystrophy. In these pathways, the 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) enzymes transfer a fatty acid to the sn-2 carbon of sn-1-acylglycerol-3-phosphate (lysophosphatidic acid) to form sn-1, 2-acylglycerol-3-phosphate [phosphatidic acid (PA)]. PA is a precursor for key phospholipids and diacylglycerol. AGPAT1 and AGPAT2 are highly homologous isoenzymes that are both expressed in adipocytes. Genetic defects in AGPAT2 cause congenital generalized lipodystrophy, indicating that AGPAT1 cannot compensate for loss of AGPAT2 in adipocytes. To further explore the physiology of AGPAT1, we characterized a loss-of-function mouse model (Agpat1−/−). The majority of Agpat1−/− mice died before weaning and had low body weight and low plasma glucose levels, independent of plasma insulin and glucagon levels, with reduced percentage of body fat but not generalized lipodystrophy. These mice also had decreased hepatic messenger RNA expression of Igf-1 and Foxo1, suggesting a decrease in gluconeogenesis. In male mice, sperm development was impaired, with a late meiotic arrest near the onset of round spermatid production, and gonadotropins were elevated. Female mice showed oligoanovulation yet retained responsiveness to gonadotropins. Agpat1−/− mice also demonstrated abnormal hippocampal neuron development and developed audiogenic seizures. In summary, Agpat1−/− mice developed widespread disturbances of metabolism, sperm development, and neurologic function resulting from disrupted phospholipid homeostasis. AGPAT1 appears to serve important functions in the physiology of multiple organ systems. The Agpat1-deficient mouse provides an important model in which to study the contribution of phospholipid and triacylglycerol synthesis to physiology and diseases. Loss-of-function mouse model for AGPAT1, a phospholipid-synthesizing enzyme, revealed critical roles in glucose homeostasis, spermatogenesis, and audiogenic seizures.