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AGPAT2 is essential for postnatal development and maintenance of white and brown adipose tissue.

ABSTRACT: Characterize the cellular and molecular events responsible for lipodystrophy in AGPAT2 deficient mice.Adipose tissue and differentiated MEF were assessed using light and electron microscopy, followed by protein (immunoblots) and mRNA analysis (qPCR). Phospholipid profiling was determined by electrospray ionization tandem mass spectrometry (ESI-MS/MS).In contrast to adult Agpat2 (-/-) mice, fetuses and newborn Agpat2 (-/-) mice have normal mass of white and brown adipose tissue. Loss of both the adipose tissue depots occurs during the first week of postnatal life as a consequence of adipocyte death and inflammatory infiltration of the adipose tissue. At the ultrastructural level, adipose tissue of newborn Agpat2 (-/-) mice is virtually devoid of caveolae and has abnormal mitochondria and lipid droplets. Autophagic structures are also abundant. Consistent with these findings, differentiated Agpat2 (-/-) mouse embryonic fibroblasts (MEFs) also have impaired adipogenesis, characterized by a lower number of lipid-laden cells and ultrastructural abnormalities in lipid droplets, mitochondria and plasma membrane. Overexpression of PPAR?, the master regulator of adipogenesis, increased the number of Agpat2 (-/-) MEFs that differentiated into adipocyte-like cells but did not prevent morphological abnormalities and cell death. Furthermore, differentiated Agpat2 (-/-) MEFs have abnormal phospholipid compositions with 3-fold increased levels of phosphatidic acid.We conclude that lipodystrophy in Agpat2 (-/-) mice results from postnatal cell death of adipose tissue in association with acute local inflammation. It is possible that AGPAT2 deficient adipocytes have an altered lipid filling or a reduced capacity to adapt the massive lipid availability associated with postnatal feeding.

SUBMITTER: Cautivo KM

PROVIDER: S-EPMC4921804 | biostudies-other | 2016 Jul

REPOSITORIES: biostudies-other

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AGPAT2 is essential for postnatal development and maintenance of white and brown adipose tissue.

Cautivo Kelly M KM Lizama Carlos O CO Tapia Pablo J PJ Agarwal Anil K AK Garg Abhimanyu A Horton Jay D JD Cortés Víctor A VA

Molecular metabolism 20160513 7

<h4>Objective</h4>Characterize the cellular and molecular events responsible for lipodystrophy in AGPAT2 deficient mice.<h4>Methods</h4>Adipose tissue and differentiated MEF were assessed using light and electron microscopy, followed by protein (immunoblots) and mRNA analysis (qPCR). Phospholipid profiling was determined by electrospray ionization tandem mass spectrometry (ESI-MS/MS).<h4>Results</h4>In contrast to adult Agpat2 (-/-) mice, fetuses and newborn Agpat2 (-/-) mice have normal mass of ...[more]

PMID: 27408775

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Project description:Brown adipose tissue (BAT) is a specialized tissue that regulates non-shivering thermogenesis. In Syrian hamsters, interscapular adipose tissue is composed primarily of white adipocytes at birth, which is converted to BAT through the proliferation and differentiation of brown adipocyte progenitors and the simultaneous disappearance of white adipocytes. In this study, we investigated the regulatory mechanism of brown adipogenesis during postnatal BAT formation in hamsters. Interscapular adipose tissue of a 10-day-old hamster, which primarily consists of brown adipocyte progenitors and white adipocytes, was digested with collagenase and fractioned into stromal-vascular (SV) cells and white adipocytes. SV cells spontaneously differentiated into brown adipocytes that contained multilocular lipid droplets and expressed uncoupling protein 1 (Ucp1), a marker of brown adipocytes, without treatment of adipogenic cocktail such as dexamethasone and insulin. The spontaneous differentiation of SV cells was suppressed by co-culture with adipocytes or by the addition of white adipocyte-conditioned medium. Conversely, the addition of SV cell-conditioned medium increased the expression of Ucp1. These results indicate that adipocytes secrete factors that suppress brown adipogenesis, whereas SV cells secrete factors that promote brown adipogenesis. Transcriptome analysis was conducted; however, no candidate suppressing factors secreted from adipocytes were identified. In contrast, 19 genes that encode secretory factors, including bone morphogenetic protein (BMP) family members, BMP3B, BMP5, and BMP7, were highly expressed in SV cells compared with adipocytes. Furthermore, the SMAD and MAPK signaling pathways, which represent the major BMP signaling pathways, were activated in SV cells, suggesting that BMPs secreted from SV cells induce brown adipogenesis in an autocrine manner through the SMAD/MAPK signaling pathways. Treatment of 5-day-old hamsters with type I BMP receptor inhibitor, LDN-193189, for 5 days reduced p38 MAPK phosphorylation and drastically suppressed BAT formation of interscapular adipose tissue. In conclusion, adipocytes and stromal cells regulate brown adipogenesis through secretory factors during the postnatal white-to-brown conversion of adipose tissue in Syrian hamsters.

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AGPAT2 is essential for postnatal development and maintenance of white and brown adipose tissue.

Publications

AGPAT2 is essential for postnatal development and maintenance of white and brown adipose tissue.

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