Differential remodeling of subcutaneous white and interscapular brown adipose tissue by long-term exercise training in aged obese female mice

Abstract

Obesity exacerbates aging-induced adipose tissue dysfunction. This study aimed to investigate the effects of long-term exercise on inguinal white adipose tissue (iWAT) and interscapular brown adipose tissue (iBAT) of aged obese mice. Two-month-old female mice received a high-fat diet for 4 months. Then, six-month-old diet-induced obese animals were allocated to sedentarism (DIO) or to a long-term treadmill training (DIOEX) up to 18 months of age. In exercised mice, iWAT depot revealed more adaptability, with an increase in the expression of fatty acid oxidation genes (Cpt1a, Acox1), and an amelioration of the inflammatory status, with a favorable modulation of pro/antiinflammatory genes and lower macrophage infiltration. Additionally, iWAT of trained animals showed an increment in the expression of mitochondrial biogenesis (Pgc1a, Tfam, Nrf1), thermogenesis (Ucp1), and beige adipocytes genes (Cd137, Tbx1). In contrast, iBAT of aged obese mice was less responsive to exercise. Indeed, although an increase in functional brown adipocytes genes and proteins (Pgc1a, Prdm16 and UCP1) was observed, few changes were found on inflammation-related and fatty acid metabolism genes. The remodeling of iWAT and iBAT depots occurred along with an improvement in the HOMA index for insulin resistance and in glucose tolerance. In conclusion, long-term exercise effectively prevented the loss of iWAT and iBAT thermogenic properties during aging and obesity. In iWAT, the long-term exercise program also reduced the inflammatory status and stimulated a fat-oxidative gene profile. These exercise-induced adipose tissue adaptations could contribute to the beneficial effects on glucose homeostasis in aged obese mice.

Keywords: Aging; Brown adipose tissue; Female; Obesity; Treadmill training; White adipose tissue.

Fig. 1

Effects of long-term exercise training on glucose homeostasis and insulin resistance in 18 months old DIO female mice. A. Fasting glucose and insulin, as well as the derived HOMA-IR index. B. Glucose excursion curves after the glucose tolerance test. Data are mean ± SEM. (n = 6–9). ^*P < 0.05

Fig. 2

Effects of long-term exercise training on genes controlling fat accumulation and deposition, and on the phosphorylation levels of HSL at Ser⁵⁶³ in iWAT (A, B) and iBAT (C, D) of 18 months old DIO female mice. Data are mean ± SEM. (n = 6–8). ^*P < 0.05, ^***P < 0.001

Fig. 3

Effects of long-term exercise training on pro and anti-inflammatory genes in iWAT (A) and iBAT (B) in 18 months old DIO female mice. Data are mean ± SEM. (n = 6–8). ^*P < 0.05, ^**P < 0.01, ^***P < 0.001

Fig. 4

Effects of long-term exercise training on immune cell populations in iWAT. A-D: Analysis of adipose tissue SVF by flow cytometry. Representative dot plots and quantification of A. total macrophages (F4/80⁺/CD11b⁺), B. B lymphocytes (CD19⁺/CD3⁻), C. T lymphocytes (CD19⁻/CD3⁺) and D. granulocytes (Gr1⁺) in relation to total immune cells. Data are mean ± SEM. (n = 5–8). ^*P < 0.05

Fig. 5

Effects of long-term exercise training on thermogenic function markers in iWAT and iBAT of 18 months old DIO female mice. A. mRNA levels of genes involved in mitochondrial biogenesis (Pgc1a, Tfam, Nrf1), thermogenic function and adipose tissue browning (Prdm16, Ucp1, Fndc5) and beige adipocytes selective genes (Cd137, Tbx1 and Tmem26) (Left panel) in iWAT, as well as protein levels of the thermogenic UCP1 (middle panel) in iWAT. The right panel shows mRNA levels of Fgf21 and signaling pathway genes in iWAT of DIO and DIOEX mice. B. iBAT genes involved in mitochondrial biogenesis and thermogenic function (left panel) and UCP1 protein levels (middle panel). The right panel shows mRNA levels of Fgf21 and signaling pathway genes in iBAT of DIO and DIOEX mice. Data are mean ± SEM. (n = 6–8). ^*P < 0.05, ^**P < 0.01, ^***P < 0.001; ^†P = 0.057