Key result
Hepatic APOC3 stimulates preadipocyte proliferation to reverse lipodystrophy caused by insulin and IGF-1 receptor deletion.
Why the study?
Lipodystrophy is associated with increased circulating factors that stimulate preadipocyte proliferation, but the specific mediators and their roles are not fully understood.
APOC3 is identified as a contributing factor to preadipocyte proliferation in lipodystrophy, though other circulating factors are also necessary for adipose regeneration.
APOC3 may contribute to adipose regeneration in lipodystrophy models; leaves open therapeutic targeting of hepatic factors in patients.
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.
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Brandão et al. (2022) studied Lipodystrophy. Deletion of IR and IGF1R in fat (Ai-DKO) was evaluated on Preadipocyte proliferation and adipose tissue regeneration. Deletion of insulin and IGF-1 receptors in fat caused severe lipodystrophy that reversed via preadipocyte proliferation stimulated by circulating hepatic factors including APOC3.
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