Abstract
ABSTRACT Insulin plays an important role during adipogenic differentiation of animal preadipocytes and the maintenance of mature phenotypes. However, its role and mechanism in dedifferentiation of adipocyte remains unclear. This study investigated the effects of insulin on dedifferentiation of mice adipocytes, and the potential mechanisms. The preadipocytes were isolated from the subcutaneous white adipose tissue of wild type (WT), TNFα gene mutant (TNFα-/-), leptin gene spontaneous point mutant (db/db) and TNFα-/-/db/db mice and were then induced for differentiation. Interestingly, dedifferentiation of these adipocytes occurred once removing exogenous insulin from the adipogenic medium. As characteristics of dedifferentiation of the adipocytes, downregulation of adipogenic markers, upregulation of stemness markers and loss of intracellular lipids were observed from the four genotypes. Notably, dedifferentiation was occurring earlier if the insulin signal was blocked. These dedifferentiated cells regained the potentials of the stem cell-like characteristics. There is no significant difference in the characteristics of the dedifferentiation between the adipocytes. Overall, the study provided evidence that insulin plays a negative regulatory role in the dedifferentiation of adipocytes. We also confirmed that both dedifferentiation of mouse adipocytes, and effect of the insulin on this process were independent of the cell genotypes, while it is a widespread phenomenon in the adipocytes.
Highlights
Dedifferentiation of cells is a reversal of the developmental process, such as in cases of differentiated mature cells with specialized functions that produce undifferentiated progenitor cells [1,2,3] or they undergo a self-repair mechanism [4,5] under certain physiological and/or pathological conditions
To test the role of insulin on adipocyte dedifferentiation, we first compared the differences in morphology for the four genotype adipocytes under the following conditions: 1) neither without supplement exogenous insulin nor without inhibition of insulin signal; 2) without exogenous insulin but with inhibition of insulin signal; 3) contain exogenous insulin but inhibition of insulin signal at same time; and 4)
Oil red O (ORO) staining indicated that preadipocytes differentiated to mature adipocytes containing numerous lipid droplets in the cytoplasm (Figure 2(a), D8/DD0)
Summary
Dedifferentiation of cells is a reversal of the developmental process, such as in cases of differentiated mature cells with specialized functions that produce undifferentiated progenitor cells [1,2,3] or they undergo a self-repair mechanism [4,5] under certain physiological and/or pathological conditions. Spalding et al reported that approximately 10% of adipocytes in human white adipose tissue are renewed annually during adult age [1]. It remains unclear whether these new mature adipocytes originated from stem cells, or were derived partially from mature adipocytes that undergo a renewal cycle, i.e. mature adipocyte → dedifferentiation→proliferation→ adipogenic redifferentiation, thereby producing more adipocytes. It is reported that reducing body weight by 5–10% can improve blood lipid abnormality and insulin resistance in humans [6]. Since hyperproliferation and hypertrophy of adipocytes are a typical phenomenon in overweight individuals and obese patients, induction and promotion of dedifferentiation of adipocytes within a controlled range may become a strategy to prevent and reduce such abnormal phenomena of adipocytes. On the other hand, dedifferentiated cells are considered to be an attractive cell source that can be used in regenerative medicine and cell therapy field [3,7,8]
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