Abstract

People with childhood-onset obesity have greater risk of type 2 diabetes than people with adult-onset obesity. However, we do not understand the mechanisms contributing to this disease risk discrepancy or whether these mechanisms can be reversed. A decline in subcutaneous adipose tissue (SAT) function (i.e., the ability to safely store lipids and regulate adipokine production) is linked to type 2 diabetes and may therefore vary by age of obesity onset. This dissertation aimed to compare markers of regional SAT (dys)function between people with childhood-onset and adult-onset obesity.

Original article 1 investigated the longstanding yet controversial notion that SAT is hyperplastic (has many small adipocytes) in childhood-onset obesity and hypertrophic (has fewer large adipocytes) in adult-onset obesity. This notion held true only for abdominal SAT in females. The degree of abdominal SAT hypertrophy or hyperplasia was unaffected by age of obesity onset in males. In contrast, femoral SAT was hypertrophic in both males and females with childhood-onset obesity compared to their counterparts with adult-onset obesity.

Original articles 2 & 3 examined preadipocyte DNA damage (γH2AX), senescence markers (p53 and p21), and SAT immune cell profiles in females with childhood-onset and adult-onset obesity, both before and after moderate (~10%) weight loss. Compared to females with adult-onset obesity, those with childhood-onset obesity had a greater proportion of preadipocytes with DNA damage and senescence markers in abdominal and femoral SAT, but a slightly lower proportion of M1-like ‘pro-inflammatory’ macrophages in abdominal SAT. The proportions of M1-like macrophages in femoral SAT and M2-like ‘anti-inflammatory’ macrophages, CD3+CD4+ T cells, and CD3+CD8+ T cells in abdominal and femoral SAT did not differ between groups. After weight loss, preadipocyte DNA damage declined in both females with childhood-onset and adult-onset obesity. Other changes, however, occurred only in females with adult-onset obesity: the intensity of p21 in p53+p21+ femoral preadipocytes and the proportion of M1-like macrophages in abdominal SAT decreased, while the proportion of CD3+CD4+ T cells in abdominal and femoral SAT increased.

Recognizing the differences in markers of SAT (dys)function between people with childhood-onset and adult-onset obesity may help guide the development of tailored treatment strategies.