Abstract
We previously reported brown adipocytes can proliferate even after differentiation. To test the involvement of mature adipocyte proliferation in cell number control in fat tissue, we generated transgenic (Tg) mice over-expressing cell-cycle inhibitory protein p27 specifically in adipocytes, using the aP2 promoter. While there was no apparent difference in white adipose tissue (WAT) between wild-type (WT) and Tg mice, the amount of brown adipose tissue (BAT) was much smaller in Tg mice. Although BAT showed a normal cellular morphology, Tg mice had lower content of uncoupling protein 1 (UCP1) as a whole, and attenuated cold exposure- or β3-adrenergic receptor (AR) agonist-induced thermogenesis, with a decrease in the number of mature brown adipocytes expressing proliferation markers. An agonist for the β3-AR failed to increase the number of proliferating brown adipocytes, UCP1 content in BAT, and oxygen consumption in Tg mice, although the induction and the function of beige adipocytes in inguinal WAT from Tg mice were similar to WT mice. These results show that brown adipocyte proliferation significantly contributes to BAT development and adaptive thermogenesis in mice, but not to induction of beige adipocytes.
Highlights
There are three types of adipocytes, white, brown, and beige, and they have contrasting physiological roles in energy metabolism[1, 2]
Cyclin-dependent kinase (CDK) inhibitor 1B (p27; known as p27Kip[1] or Kip1) is an endogenous CDK inhibitor that belongs to the CDK interacting protein/kinase inhibitory protein (Cip/Kip) family. p27 prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes by binding to the complex, resulting in the inhibition of cell-cycle progression during the G1 phase[27,28,29]
Using Tg mice with over-expression of p27 in mature adipocytes under the control of the aP2 promoter, we found that the white adipose tissue (WAT) of Tg mice was similar to that of WT mice, both in weight and morphology
Summary
There are three types of adipocytes, white, brown, and beige, and they have contrasting physiological roles in energy metabolism[1, 2]. Beige adipocytes are an inducible type of UCP1-expressing adipocyte, which appear in white adipose tissue (WAT) following chronic adrenergic stimulation such as cold exposure or treatment with a β3 adrenergic receptor (AR) agonist. Hyperplasia of brown adipose tissue (BAT), accompanied by an increase in brown adipocyte number, occurs in response to cold stimulation. With regard to BAT, we recently reported that the cell proliferation marker Ki67 was detected on UCP1-positive brown adipocytes, suggesting that brown adipocytes proliferate even after differentiation[26]. As the number of these cells increased after cold exposure, it is likely that the proliferation of mature brown adipocytes, in addition to the proliferation of preadipocytes, may contribute to BAT hyperplasia after cold exposure[26]. To extend the idea of mature adipocyte proliferation and to elucidate its possible contribution to the development of adipose tissues, we analyzed both brown and beige adipose tissue, and the induction of beige adipocytes, using adipocyte-specific p27-over-expressing mice
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