Apolipoprotein C3 and circulating mediators of preadipocyte proliferation in states of lipodystrophy

Brasil, Brandao Bruna; Masaji, Sakaguchi; Martins, Batista, Thiago; Jiang, Hu; Song, Nie; Athena A, Schepmoes; Lucas, BonDurant; François, Moreau; Wei-Jun, Qian; Rohit, Kulkarni N.; Ronald, Kahn, C.

doi:10.1016/j.molmet.2022.101572

Title: Apolipoprotein C3 and circulating mediators of preadipocyte proliferation in states of lipodystrophy

Journal Article · Sat Oct 01 00:00:00 EDT 2022 · Molecular Metabolism

DOI:https://doi.org/10.1016/j.molmet.2022.101572· OSTI ID:1882007

; Masaji, Sakaguchi; Martins, Batista, Thiago; Jiang, Hu; Song, Nie; Athena A, Schepmoes; Lucas, BonDurant; François, Moreau; Wei-Jun, Qian; Rohit, Kulkarni N.; Ronald, Kahn, C.

Adipogenesis is a complex process controlled by intrinsic and extrinsic factors that regulate preadipocyte proliferation, adipogenic capacity and maturation of metabolic function. Here we shown that insulin and IGF-1 receptor are essential for mature adipocyte survival and that deletion of both IR and IGF1R specifically in fat (Ai-DKO) using a tamoxifen inducible-AdipoQ-Cre leads to rapid and severe loss of adipocytes in all depots associated with a metabolic syndrome characterized by hypertriglyceridemia, hyperglycemia, and hyperinsulinemia, fatty liver, and pancreatic beta cell proliferation. In this model, this pathological phenotype reverses over few weeks, in large part, due to preadipocyte proliferation and adipose tissue regeneration. Reducing the hyperglycemia by treatment with an SGLT2 inhibitor does not affect the adipose phenotype or its regeneration. Incubation of preadipocytes with serum from the Ai-DKO mice in vitro stimulates cell proliferation indicating presence of a circulating preadipocyte growth factor. This effect can be mimicked by conditioned media from liver slices of Ai-DKO mice in vitro, but not by media of cultured Ai-DKO preadipocytes, indicating hepatic origin of the growth factor. Proteomic analysis of serum reveals apolipoprotein C3, a protein secreted by liver, as one of the most upregulated proteins in the Ai-DKO mice, and in vitro, purified/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. One of these is APOC3, which contributes to preadipocyte proliferation, but other still-unidentified circulating growth factors are also present in Ai-DKO mice. Identification of these factors may provide a new approach to regulation of adipose mass in health and disease.

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Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH); Joslin Diabetes Research Center

Grant/Contract Number:: AC05-76RL0-1830; AC05-76RL01830; R01DK031036; R01DK082659; R01DK122160; U01DK124020; R01DK67536; P30DK036836

OSTI ID:: 1882007

Alternate ID(s):: OSTI ID: 1888565; OSTI ID: 1888566

Report Number(s):: PNNL-SA-171123; S2212877822001417; 101572; PII: S2212877822001417

Journal Information:: Molecular Metabolism, Journal Name: Molecular Metabolism Vol. 64 Journal Issue: C; ISSN 2212-8778

Publisher:: ElsevierCopyright Statement

Country of Publication:: Germany

Language:: English

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Title: Apolipoprotein C3 and circulating mediators of preadipocyte proliferation in states of lipodystrophy

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