How does obesity induce insulin resistance?

DOI IR IR (HANDLE)
  • TOBE Kazuyuki
    Research Center for Pre-Disease Science, Faculty of Education and Research Promotion

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  • 肥満でなぜインスリン抵抗性をきたすのか？

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Macrophages (MФ) residing in the adipose tissue have garnered attention for their role in regulating adipocyte function and controlling systemic metabolism. These macrophages are typically classified into two subtypes, M1 and M2, based on their distinct functions. M1 MФ, whose counts are increased in obesity, originate from the bone marrow; they secrete pro-inflammatory cytokines and induce insulin resistance. In contrast, M2 MФ predominantly reside in the adipose tissue of non-obese individuals and secrete anti-inflammatory cytokines, such as interleukin-10 (IL-10), which are believed to play a role in maintaining insulin sensitivity. The widely accepted “phenotypic switch theory” posits that obesity induces a shift in macrophage polariztion, i.e., from the anti-inflammatory M2 phenotype to the inflammatory M1 phenotype. However, our 2017 study challenged this view. We generated transgenic mice where M2 MФ could be selectively eliminated at will and found that depletion of M2 MФ unexpectedly resulted in improved glucose tolerance and insulin resistance. This was associated with increased number of smaller adipocytes and enhanced proliferation of adipocyte progenitors. Using a mechanistic approach, we demonstrated that M2 MФ inhibit the proliferation and differentiation of adipocyte progenitors into mature adipocytes through the secretion of TGFβ, thereby preventing unnecessary cell division and cellular senescence, maintaining progenitor cell quality, and regulating both systemic obesity and insulin sensitivity. This study has prompted a revision of the traditional “phenotypic switch theory.” Additionally, our research revealed that the depletion of M2 MФ facilitates recovery from skeletal muscle injury by inducing the activation of fibro-adipogenic progenitors (FAPs), which are mesenchymal stem cell-like cells within the skeletal muscle, challenging the generally accepted view that M2 MФ play a more reparative role during the recovery phase of injury. These findings suggest that targeting M2 MФ and reducing TGFβ signaling could offer a therapeutic breakthrough, addressing both obesity-induced insulin resistance and sarcopenia in aging populations.

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