Insulin and IGF1 receptors (IR/IGF1R) control adipose tissue development. We previously demonstrated that mice with an inducible adipocyte-specific knockout of IR/IGFR (Ai-DKO) develop severe lipodystrophy, insulin resistance, glucose intolerance, hepatosteatosis, islet hyperplasia with hyperinsulinemia. This phenotype resolves over 10-30 days due to proliferation of preadipocytes (PAds) and regeneration of adipose tissue. Here, we sought to identify circulating factors that trigger PAds proliferation by treating primary wild type PAds with serum from either WT or Ai-DKO mice. To exclude the hyperglycemia effect, we also incubated cells with serum from WT and Ai-DKO mice treated with the SGLT2 inhibitor Remogliflozin (Remo). Serum from either, chow or Remo-treated Ai-DKO mice, induced primary PAds proliferation of approximately 30%. Serum proteomics analysis revealed that Cathepsin D and multiple apolipoproteins, including C2 and C3, were significantly upregulated in Ai-DKO serum (FC>1 and FDR<0.1). Cathepsin D is known to induce fibroblast proliferation, however, when serum Cathepsin D was neutralized with its antibody, we observed an increase of 25% in PAds proliferation, indicating that, in this context, this protein has the potential to block proliferation. Apolipoproteins are mainly secreted by the liver. We found that ex-vivo liver culture conditioned media from Ai-DKO mice induced PAds proliferation in approximately 40% compared to control. Striking, this phenomenon was mimicked when PAds were treated with purified Apo C2 or C3. Taken together, our data suggest that loss of insulin signaling in mature adipocytes initiates a complex crosstalk between liver and preadipocytes resulting in PAds proliferation and adipose tissue regeneration. Further characterization of these factors will provide important insights into adipose tissue biology during insulin resistant states and contribute to reverse the metabolic syndrome associated with lipodystrophy.
B. Brandao: None. M. Sakaguchi: None. T.M. Batista: None. W. Qian: None. C. Kahn: Advisory Panel; Self; ERX Pharmaceuticals, Kaleido Biosciences. Consultant; Self; AntriaBio, Flagship Pioneering, Sana-Cobalt.
National Institutes of Health (R01DK082659-11)