Aging-associated impairment in metabolic compensation by subcutaneous adipose tissue promotes diet-induced fatty liver disease in mice

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome, and its progression is associated with aging-associated impairment in metabolic homeostasis. Recently, energy metabolism in adipose tissue has been the subject of renewed interest, because significant energy expenditure can be induced in cells derived from white adipose tissue progenitors, in addition to brown adipose tissue (BAT). Here we evaluated whether aging-associated change in various adipose tissue depots affects the progression of NAFLD. METHODS: Six-week-old male C57BL/6NCrSlc mice were fed control chow (C) or high-fat diet (60% fat; HF) for 12 or 24 weeks (12w/C, 12w/HF, 24w/C and 24w/HF groups, respectively) or switched from C to HF diet at 18 weeks of age (24w/C/HF group) and fed for a further 24 weeks. Some 24w/HF mice received a subcutaneous transplantation of adipose progenitors (10(6) cells/mouse) from young donor mice. Basal energy expenditure, glucose tolerance, and liver and adipose tissue histology were then evaluated. In addition, features of senescence and the capacity of adipose progenitors to “brown” were compared in mice of various ages. RESULTS: 12w/HF mice demonstrated compensation in the forms of hypertrophy of interscapular classical BAT and the appearance of subcutaneous beige adipocytes, consistent with improved metabolic homeostasis. In contrast, 24w/HF and 24w/C/HF mice developed obesity, glucose intolerance, and severe NAFLD, with accelerated senescence and loss of adipose progenitors in subcutaneous fat tissues. Recruitment of adipose progenitors ameliorated these findings in 24w/HF mice. CONCLUSION: Impaired metabolic compensation in adipose tissue resulted in the progression of NAFLD, which was associated with aging-related deterioration in adipose progenitors. A new approach targeting adipose tissue progenitors might represent a potential strategy for the prevention of NAFLD.