Diabetes and Adipocyte Dysfunction
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The global burden of obesity/diabetes and comorbidities continues to rise in many societies. Obesity predisposes to the development of diabetes and increases the mortality rate, particularly deaths from cardiovascular disease. Chronic sterile inflammation develops in visceral white adipose tissue (WAT) upon metabolic stress and promotes the production of pro-inflammatory adipokines and systemic insulin resistance (hyperinsulinemia). Systemic insulin resistance develops with metabolically unhealthy obesity and diabetes and promotes pathologies in these disorders. Studies indicate that cellular senescence is critically involved in the development of sterile adipose inflammation in obesity. In vitro studies showed that senescent cells have bystander effects to promote aging in surrounding younger cells, and depletion of senescent cells by the genetic manipulation or senolytic agents led to the inhibition of age-related organ dysfunction in rodents. Brown adipose tissue (BAT) is another type of fat initially identified and characterized as a tissue involved in thermogenesis. BAT is nowadays well accepted as an active metabolic organ, which has a potential to contribute for the maintenance of systemic metabolic health. In humans and rodents, obesity linked with reduced BAT function and, recently, capillary rarefaction was shown to have causal role for the functional decline of this organ, which led to systemic metabolic disorders in murine obese model. Metabolically healthy obesity (MHO) is characterized with less visceral adiposity associated with nonsignificant metabolic phenotypes. MHO individuals are enriched in subcutaneous WAT, and this specific fat pad is known to include beige cells that share functional similarities with brown adipocytes. The activation of beige cells contributes for systemic metabolic health in rodents, suggesting that in addition to classical brown adipocytes, targeting beige cells would become next-generation therapies for obesity and diabetes. Accumulating evidence indicates that maintenance of homeostasis in adipose tissues is critically important for systemic metabolic health.
KeywordsCellular senescence Inflammation Adipose tissue Insulin resistance
This work was supported by a Grant-in-Aid for Scientific Research, a Grant-in-Aid for Scientific Research on Innovative Areas (Stem Cell Aging and Disease, Grant number 26115008), and a Grant-in-Aid for Exploratory Research from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT, Grant number 15K15306) of Japan and grants from the Ono Medical Research Foundation, the Japan Diabetes Foundation, the Takeda Science Foundation, and the Takeda Medical Research Foundation (to T.M.) as well as by a Grants-in-Aid for Young Scientists (Start-up) (JSPS KAKENHI, Grant Number 26893080) and grants from the Uehara Memorial Foundation, Takeda Science Foundation, Kowa Life Science Foundation, Manpei Suzuki Diabetes Foundation, Kanae Foundation, Japan Heart Foundation Research Grant, The Senri Life Science Foundation, SENSHIN Medical Research Foundation, ONO Medical Research Foundation, Tsukada Grant for Niigata University Medical Research, The Nakajima Foundation, SUZUKEN memorial foundation, HOKUTO Corporation, Inamori Foundation, Mochida Memorial Foundation for Medical & Pharmaceutical Research, Banyu Foundation Research Grant, Grant for Basic Science Research Projects from The Sumitomo Foundation, Grants-in-Aid for Encouragement of Young Scientists (A) (JSPS KAKENHI Grant Number 16H06244), The Bayer Scholarship for Cardiovascular Research, and Japan Diabetes Foundation (to I.S.), by a Grants-in-Aid for Encouragement of Young Scientists (B) (JSPS KAKENHI Grant Number 16K19531), a Japan Heart Foundation Dr. Hiroshi Irisawa & Dr. Aya Irisawa Memorial Research Grant, Senshin Medical Research Foundation grant, SUZUKEN memorial foundation, Takeda Science Foundation, ONO Medical Research Foundation, Uehara Memorial Foundation, Research Foundation for Community Medicine, Kanae Foundation, Banyu Foundation Research Grant, and HOKUTO Corporation (to Y.Y.) and by a grant from Bourbon (to T.M., I.S., and Y.Y.).
Disclosures: Y.Y., I.S., and T.M. disclose no conflict of interest.
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