Journal Article

Targeting senescent cells alleviates obesity‐induced metabolic dysfunction

Johnson, Kurt O., Tchkonia, Tamar, White, Thomas A., LeBrasseur, Nathan K., Jensen, Michael D., Schafer, Marissa J., Matveyenko, Aleksey, Weivoda, Megan M., Kirkland, James L., Dijk, Theo H., Hachfeld, Christine M., Verkade, Esther, Cubro, Hajrunisa, Hickson, LaTonya J., Jurk, Diana, Xu, Ming, Doornebal, Ewald J., Arriaga, Edgar A., Palmer, Allyson K., Campisi, Judith, Zhu, Yi, Grande, Joseph, Chini, Eduardo N., Ogrodnik, Mikolaj, Garovic, Vesna, Prata, Larissa G., Casaclang‐Verzosa, Grace, Kuipers, Folkert, Stout, Michael B., Pirtskhalava, Tamar, Demaria, Marco, Zglinicki, Thomas, Miller, Jordan D.

2019

Overview

Adipose tissue inflammation and dysfunction are associated with obesity‐related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug‐inducible “suicide” genes driven by the p16Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra‐abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity‐related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity‐related metabolic dysfunction and its complications. Obesity induces the formation of senescent cells, which contribute to inflammation, insulin resistance, and organ dysfunction. Senescent cell clearance may be an effective strategy for alleviating important elements of obesity‐related metabolic dysfunction.

• Publisher: John Wiley & Sons, Inc,Anatomical Society - Wiley,John Wiley and Sons Inc
• Subject: Adipocytes - cytology / Adipocytes - drug effects / Adipocytes - metabolism / Adipogenesis / Adipogenesis - drug effects / Adipogenesis - physiology / Adipose tissue / Adipose Tissue - drug effects / Adipose Tissue - metabolism / Adipose tissues / aging / Aging - metabolism / Aging - pathology / Animals / BASIC BIOLOGICAL SCIENCES / Cell Death - drug effects / Cell Death - genetics / Cell Death - physiology / Cell Line / cellular senescence / Cellular Senescence - drug effects / Cellular Senescence - genetics / Cellular Senescence - physiology / Cyclin-Dependent Kinase Inhibitor p16 - metabolism / dasatinib / Dasatinib - pharmacology / Development and progression / Dextrose / Diabetes / Diabetes mellitus / Female / Ganciclovir - pharmacology / Glucose / Glucose - metabolism / Glucose tolerance / Humans / Immunological tolerance / Inflammation / Inflammation - metabolism / INK4a protein / Insulin / Insulin resistance / Insulin Resistance - physiology / Leukocyte migration / Macrophages / Macrophages - drug effects / Macrophages - metabolism / Male / Metabolism / Mice / Mice, Inbred C57BL / Mice, Transgenic / Monocytes / Obesity / Obesity - metabolism / Original / p16 Protein / quercetin / Quercetin - pharmacology / Renal function / Senescence / senolytics / Suicide / Suicide genes / Type 2 diabetes