Lipodystrophy and severe metabolic dysfunction in mice with adipose tissue-specific insulin receptor ablation

•Adipoq-Cre-mediated IR KO leads to lipodystrophy in mice.•IR KO differentially affects white, brown and marrow fat development and metabolism.•IR KO affects marrow adipocytes lipid accumulation but not development.•Insulin signaling is required for UCP1 expression.

ObjectiveInsulin signaling plays pivotal roles in the development and metabolism of many tissues and cell types. A previous study demonstrated that ablation of insulin receptor (IR) with aP2-Cre markedly reduced adipose tissues mass and protected mice from obesity. However, multiple studies have demonstrated widespread non-adipocyte recombination of floxed alleles in aP2-Cre mice. These findings underscore the need to re-evaluate the role of IR in adipocyte and systemic metabolism with a more adipose tissue-specific Cre mouse line.MethodsWe generated and phenotyped a new adipose tissue-specific IR mouse model using the adipose tissue-specific Adipoq-Cre line.ResultsHere we show that the Adipoq-Cre-mediated IR KO in mice leads to lipodystrophy and metabolic dysfunction, which is in stark contrast to the previous study. In contrast to white adipocytes, absence of insulin signaling does not affect development of marrow and brown adipocytes, but instead is required for lipid accumulation particularly for the marrow adipocytes. Lipodystrophic IR KO mice have profound insulin resistance, hyperglycemia, organomegaly, and impaired adipokine secretion.ConclusionsOur results demonstrate differential roles for insulin signaling for white, brown, and marrow adipocyte development and metabolic regulation.