Lipodystrophy and severe metabolic dysfunction in mice with adipose tissue-specific insulin receptor ablation
Guifen Qiang1, Hyerim Whang Kong1, Shanshan Xu1
1Department of Physiology & Biophysics, University of Illinois at Chicago, Chicago, IL, USA.
Objective:
Insulin 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.
Methods:
We generated and phenotyped a new adipose tissue-specific IR mouse model using the adipose tissue-specific Adipoq-Cre line.
Results:
Here 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.
Conclusions:
Our results demonstrate differential roles for insulin signaling for white, brown, and marrow adipocyte development and metabolic regulation.
Insights
Ablating the insulin receptor (IR) in adipose tissue causes lipodystrophy and metabolic dysfunction. Insulin signaling is crucial for white adipocyte lipid accumulation but not brown or marrow adipocyte development.
Area of Science:
- Endocrinology
- Metabolic research
- Molecular biology
Background:
- Insulin signaling is vital for tissue development and metabolism.
- Previous studies using aP2-Cre mice showed reduced adipose tissue mass upon insulin receptor (IR) ablation, but non-adipocyte recombination issues were noted.
- Re-evaluation of IR's role in adipocytes and systemic metabolism requires a more specific Cre mouse line.
Purpose of the Study:
- To investigate the role of insulin receptor (IR) in adipose tissue metabolism.
- To generate and characterize a new mouse model with adipose tissue-specific IR knockout (KO) using Adipoq-Cre.
- To clarify the distinct roles of insulin signaling in different adipocyte types.
Main Methods:
- Generation of a novel adipose tissue-specific IR knockout mouse model utilizing the Adipoq-Cre system.
- Comprehensive phenotyping of the generated mouse model to assess metabolic and developmental changes.
- Analysis of insulin signaling's impact on white, brown, and marrow adipocyte development and lipid accumulation.
Main Results:
- Adipose tissue-specific IR KO in mice resulted in lipodystrophy and significant metabolic dysfunction.
- Absence of insulin signaling impaired lipid accumulation in white and marrow adipocytes but did not affect brown adipocyte development.
- IR knockout mice exhibited severe insulin resistance, hyperglycemia, organomegaly, and altered adipokine secretion.
Conclusions:
- Insulin signaling plays differential roles in the development and metabolic regulation of white, brown, and marrow adipocytes.
- The study highlights the critical role of IR in white adipocyte function and systemic metabolic homeostasis.
- Findings underscore the importance of cell-type-specific analysis in metabolic research.
