We have cloned two novel adipocyte-specific enzymes that catalyze opposing reactions in triacylglycerol (TAG) metabolism. We identified these enzymes by employing the unique criteria of adipocyte-specific expression patterns and the presence of structural motifs for lipid metabolism, and we have named them desnutrin and adipocyte phospholipid acyltransferase (APAT). Desnutrin is an adipocyte-specific TAG lipase whereas APAT is an adipocyte-specific acyltransferase. Expression of these two novel enzymes in adipocytes is inversely regulated during fasting/feeding, a prediction of their opposing physiological roles in adipocyte TAG metabolism. Together, these enzymes may govern TAG storage and, therefore, adipocyte size. Desnutrin has been characterized as a TAG lipase increasing TAG hydrolysis in cultured cells but its function in vivo needs to be demonstrated. In contrast, the importance of APAT in TAG storage in adipocytes has been shown by in vivo studies with knockout mice, but in vitro characteristics of APAT have not been established.
Aim 1 is to characterize desnutrin and APAT in vitro for their substrate specificity as well as their preference for fatty acids in terms of chain length and saturation using purified enzyme preparations. In addition, physiological functions of these enzymes will be examined in cultured cells overexpressing desnutrin and APAT or in cells deficient in these enzymes.
Aim 2 is to examine their subcellular localization by using antibodies that we raised, by expressing desnutrin or APAT as GFP- fusion proteins, and by classic subcellular fractionation. We will examine the potential translocation of desnutrin during lipolytic stimulation and the localization of APAT when esterification is favored. Possible involvement of phosphorylation/dephosphorylation mechanisms as well as interactions of desnutrin and APAT with other cellular proteins for translocation/regulation will be examined also.
Aim 3 is to generate desnutrin and APAT null mice to demonstrate the functional significance of these enzymes and their effects on TAG metabolism/storage in adipose tissue and on glucose/insulin homeostasis in vivo. Elucidating the properties and functions of these two novel adipocyte-specific enzymes would be critical in understanding adipocyte TAG metabolism, and in developing future'therapeutic strategies against metabolic diseases such as obesity/diabetes. ? ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Haft, Carol R
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University of California Berkeley
Schools of Earth Sciences/Natur
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Tang, Tianyi; Abbott, Marcia J; Ahmadian, Maryam et al. (2013) Desnutrin/ATGL activates PPAR? to promote mitochondrial function for insulin secretion in islet ? cells. Cell Metab 18:883-95
Ahmadian, Maryam; Abbott, Marcia J; Tang, Tianyi et al. (2011) Desnutrin/ATGL is regulated by AMPK and is required for a brown adipose phenotype. Cell Metab 13:739-48
Ahmadian, Maryam; Wang, Yuhui; Sul, Hei Sook (2010) Lipolysis in adipocytes. Int J Biochem Cell Biol 42:555-9
Wang, Yuhui; Hudak, Carolyn; Sul, Hei Sook (2010) Role of preadipocyte factor 1 in adipocyte differentiation. Clin Lipidol 5:109-115
Duncan, Robin E; Wang, Yuhui; Ahmadian, Maryam et al. (2010) Characterization of desnutrin functional domains: critical residues for triacylglycerol hydrolysis in cultured cells. J Lipid Res 51:309-17
Wong, Roger H F; Sul, Hei Sook (2010) Insulin signaling in fatty acid and fat synthesis: a transcriptional perspective. Curr Opin Pharmacol 10:684-91
Abbott, Marcia J; Tang, Tianyi; Sul, Hei Sook (2010) The Role of Phospholipase A(2)-derived Mediators in Obesity. Drug Discov Today Dis Mech 7:e213-e218
Ahmadian, Maryam; Duncan, Robin E; Sul, Hei Sook (2009) The skinny on fat: lipolysis and fatty acid utilization in adipocytes. Trends Endocrinol Metab 20:424-8
Jaworski, Kathy; Ahmadian, Maryam; Duncan, Robin E et al. (2009) AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency. Nat Med 15:159-68
Ahmadian, Maryam; Duncan, Robin E; Varady, Krista A et al. (2009) Adipose overexpression of desnutrin promotes fatty acid use and attenuates diet-induced obesity. Diabetes 58:855-66

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