Apolipoprotein C3 and circulating mediators of preadipocyte proliferation in states of lipodystrophy
Adipogenesis is a complex process controlled by intrinsic and extrinsic factors that regulate preadipocyte proliferation, adipogenic capacity and maturation of metabolic function. Here we show that insulin and IGF-1 receptors are essential for mature adipocyte survival and that deletion of both IR a...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-10-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877822001417 |
| _version_ | 1818057221475401728 |
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| author | Brandao Bruna Brasil Sakaguchi Masaji Batista, Thiago Martins Hu Jiang Nie Song Schepmoes Athena A BonDurant Lucas Moreau François Qian Wei-Jun Kulkarni N. Rohit Kahn, C. Ronald |
| author_facet | Brandao Bruna Brasil Sakaguchi Masaji Batista, Thiago Martins Hu Jiang Nie Song Schepmoes Athena A BonDurant Lucas Moreau François Qian Wei-Jun Kulkarni N. Rohit Kahn, C. Ronald |
| author_sort | Brandao Bruna Brasil |
| collection | DOAJ |
| description | Adipogenesis is a complex process controlled by intrinsic and extrinsic factors that regulate preadipocyte proliferation, adipogenic capacity and maturation of metabolic function. Here we show that insulin and IGF-1 receptors are essential for mature adipocyte survival and that deletion of both IR and IGF1R specifically in fat using a tamoxifen inducible-AdipoQ-Cre (Ai-DKO) leads to rapid and severe loss of adipocytes in all depots, associated with a metabolic syndrome characterized by hypertriglyceridemia, hyperglycemia, hyperinsulinemia, fatty liver, and pancreatic beta cell proliferation. In this model, this pathological phenotype reverses over a few weeks, in large part, due to preadipocyte proliferation and adipose tissue regeneration. Incubation of preadipocytes with serum from the Ai-DKO mice in vitro stimulates cell proliferation, and this effect can be mimicked by conditioned media from liver slices of Ai-DKO mice, but not by media of cultured Ai-DKO adipocytes, indicating a hepatic origin of the growth factor. Proteomic analysis of serum reveals apolipoprotein C3 (APOC3), a protein secreted by liver, as one of the most upregulated proteins in the Ai-DKO mice. In vitro, purified and delipidated APOC3 stimulates preadipocyte proliferation, however, knockdown of hepatic APOC3 in vivo in Ai-DKO mice is not sufficient to block adipose regeneration. Thus, lipodystrophy is associated with presence of increased preadipocyte-stimulating growth factors in serum. Our study indicates that APOC3 is one contributing factor to preadipocyte proliferation, however, other still-unidentified circulating growth factors are also likely present in Ai-DKO mice. Identification of these factors may provide a new approach to regulation of adipose mass in health and disease. |
| first_indexed | 2024-12-10T12:41:17Z |
| format | Article |
| id | doaj.art-485b206b95a246cd93c323de93b87a1b |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-10T12:41:17Z |
| publishDate | 2022-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-485b206b95a246cd93c323de93b87a1b2022-12-22T01:48:32ZengElsevierMolecular Metabolism2212-87782022-10-0164101572Apolipoprotein C3 and circulating mediators of preadipocyte proliferation in states of lipodystrophyBrandao Bruna Brasil0Sakaguchi Masaji1Batista, Thiago Martins2Hu Jiang3Nie Song4Schepmoes Athena A5BonDurant Lucas6Moreau François7Qian Wei-Jun8Kulkarni N. Rohit9Kahn, C. Ronald10Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USASection of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA; Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanSection of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USASection on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Dept. of Medicine, BIDMC, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USABiological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99354, United StatesBiological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99354, United StatesAlnylam Pharmaceuticals, Cambridge, MA, USASection of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USABiological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99354, United StatesSection on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Dept. of Medicine, BIDMC, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USASection of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA; Corresponding author. Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA.Adipogenesis is a complex process controlled by intrinsic and extrinsic factors that regulate preadipocyte proliferation, adipogenic capacity and maturation of metabolic function. Here we show that insulin and IGF-1 receptors are essential for mature adipocyte survival and that deletion of both IR and IGF1R specifically in fat using a tamoxifen inducible-AdipoQ-Cre (Ai-DKO) leads to rapid and severe loss of adipocytes in all depots, associated with a metabolic syndrome characterized by hypertriglyceridemia, hyperglycemia, hyperinsulinemia, fatty liver, and pancreatic beta cell proliferation. In this model, this pathological phenotype reverses over a few weeks, in large part, due to preadipocyte proliferation and adipose tissue regeneration. Incubation of preadipocytes with serum from the Ai-DKO mice in vitro stimulates cell proliferation, and this effect can be mimicked by conditioned media from liver slices of Ai-DKO mice, but not by media of cultured Ai-DKO adipocytes, indicating a hepatic origin of the growth factor. Proteomic analysis of serum reveals apolipoprotein C3 (APOC3), a protein secreted by liver, as one of the most upregulated proteins in the Ai-DKO mice. In vitro, purified and delipidated APOC3 stimulates preadipocyte proliferation, however, knockdown of hepatic APOC3 in vivo in Ai-DKO mice is not sufficient to block adipose regeneration. Thus, lipodystrophy is associated with presence of increased preadipocyte-stimulating growth factors in serum. Our study indicates that APOC3 is one contributing factor to preadipocyte proliferation, however, other still-unidentified circulating growth factors are also likely present in Ai-DKO mice. Identification of these factors may provide a new approach to regulation of adipose mass in health and disease.http://www.sciencedirect.com/science/article/pii/S2212877822001417AdipogenesisInter-cellular crosstalkApolipoproteinMetabolic syndromeCirculating growth factor |
| spellingShingle | Brandao Bruna Brasil Sakaguchi Masaji Batista, Thiago Martins Hu Jiang Nie Song Schepmoes Athena A BonDurant Lucas Moreau François Qian Wei-Jun Kulkarni N. Rohit Kahn, C. Ronald Apolipoprotein C3 and circulating mediators of preadipocyte proliferation in states of lipodystrophy Molecular Metabolism Adipogenesis Inter-cellular crosstalk Apolipoprotein Metabolic syndrome Circulating growth factor |
| title | Apolipoprotein C3 and circulating mediators of preadipocyte proliferation in states of lipodystrophy |
| title_full | Apolipoprotein C3 and circulating mediators of preadipocyte proliferation in states of lipodystrophy |
| title_fullStr | Apolipoprotein C3 and circulating mediators of preadipocyte proliferation in states of lipodystrophy |
| title_full_unstemmed | Apolipoprotein C3 and circulating mediators of preadipocyte proliferation in states of lipodystrophy |
| title_short | Apolipoprotein C3 and circulating mediators of preadipocyte proliferation in states of lipodystrophy |
| title_sort | apolipoprotein c3 and circulating mediators of preadipocyte proliferation in states of lipodystrophy |
| topic | Adipogenesis Inter-cellular crosstalk Apolipoprotein Metabolic syndrome Circulating growth factor |
| url | http://www.sciencedirect.com/science/article/pii/S2212877822001417 |
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