Abstract
Age‐related increased adiposity is an important contributory factor in the development of insulin resistance (IR) and is associated with metabolic defects. Caloric restriction (CR) is known to induce weight loss and to decrease adiposity while preventing metabolic risk factors. Here, we show that moderate 20% CR delays early deleterious effects of aging on white and brown adipose tissue (WAT and BAT, respectively) function and improves peripheral IR. To elucidate the role of CR in delaying early signs of aging, young (3 months), middle‐aged (12 months), and old (20 months) mice fed al libitum and middle‐aged and old mice subjected to early‐onset CR were used. We show that impaired plasticity of subcutaneous WAT (scWAT) contributes to IR, which is already evident in middle‐aged mice. Moreover, alteration of thyroid axis status with age is an important factor contributing to BAT dysfunction in middle‐aged animals. Both defects in WAT and BAT/beige cells are ameliorated by CR. Accordingly, CR attenuated the age‐related decline in scWAT function and decreased the extent of fibro‐inflammation. Furthermore, CR promoted scWAT browning. In brief, our study identifies the contribution of scWAT impairment to age‐associated metabolic dysfunction and identifies browning in response to food restriction, as a potential therapeutic strategy to prevent the adverse metabolic effects in middle‐aged animals.
Highlights
Aging is associated with an increased risk of metabolic disorders such as obesity, insulin resistance (IR), and other manifestations of metabolic syndrome in both humans and rodents
Aging has been associated with the development of peripheral IR and other metabolic complications
Our data demonstrate that middle‐aged (12 m) SV129 mice already show peripheral IR, as de‐ duced by HOMAIR and insulin tolerance test (ITT) data
Summary
Aging is associated with an increased risk of metabolic disorders such as obesity, insulin resistance (IR), and other manifestations of metabolic syndrome in both humans and rodents. The expression of Ym1, a mac‐ rophage anti‐inflammatory marker, was significantly higher in 12mCR animals in scWAT (Figure 3a) These differences were observed when the levels of expression were directly compared among them in each adipose depot without referring the data to 3 m (Supporting Information Figure S3c). The mRNA levels of most of the genes analyzed (Ucp‐1, Cpt1α, Bmp8b, Dio, Cidea, Prdm, Pgc1α, Pgc1β, Pparγ, and Fgf‐21) were significantly higher in cold‐ exposed animals under CR than in 12‐m mice, suggesting that these animals may have presented a better response of BAT. We could not appreciate significant differences on UCP‐1 immunostaining between young and middle‐aged mice, a strongest immunoreactivity for UCP‐1 in scWAT was found in 12mCR animals at 4oC (Figure 6), indicating an induced beige‐like appearance This was confirmed by increased gene expression of zfp5l6, a browning marker, in 12mCR compared to 12‐m mice at 4oC.
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