Abstract
To identify factors involved in the earliest phase of the differentiation of human embryonic stem cells (hESCs) into brown adipocytes (BAs), we performed multi-time point microarray analyses. We found that growth/differentiation factor 15 (GDF15) expressions were specifically upregulated within three days of differentiation, when expressions of immature hESC markers were sustained. Although GDF15 expressions continued to increase in the subsequent differentiation phases, GDF15-deficient hESCs differentiated into mature BAs (Day 10) without apparent abnormalities. In addition, GDF15-deficient mice had normal brown adipose tissue (BAT) and were metabolically healthy. Unexpectedly, we found that interleukin-6 (IL6) expression was significantly lowered in the BAT of GDF15-/- mice. In addition, GDF15-/- hESCs showed abortive IL6 expressions in the later phase (>Day 6) of the differentiation. Interestingly, GDF15 expression was markedly repressed throughout the whole course of the differentiation of IL6-/- hESCs into BAs, indicating IL6 is essential for the induction of GDF15 in the differentiation of hESCs. Finally, intraperitoneally transplanted BAT grafts of GDF15-/- donor mice, but not those of wild-type (WT) mice, failed in the long-term survival (12 weeks) in GDF15-/- recipient mice. Collectively, GDF15 is required for long-term survival of BAT grafts by creating a mutual gene induction loop with IL6.
Highlights
Obesity is one of the major risk factors for lifestyle diseases such as cardiovascular diseases (CVDs), diabetes, and cancers
We show that growth/differentiation factor 15 (GDF15) and IL6 gene expressions are mutually induced in the course of a directed differentiation of human embryonic stem cells into brown adipocytes (BAs)
We found that IL6 expressions were considerably lowered in the interscapular BAT (iBAT) of
Summary
Obesity is one of the major risk factors for lifestyle diseases such as cardiovascular diseases (CVDs), diabetes, and cancers. There is a puzzling phenomenon known as “obesity paradox”, where patients with CVD show a better prognosis if classified as overweight or class I obese [1]. Overweight and class I obese patients, as long as they are aiming to get adequate exercise in their everyday lives, may behave better owing to the relatively greater lean mass compared to normal or underweight patients. It is preferable to take a more natural approach to the maintenance of body weight. From this standpoint, brown adipose tissue (BAT), which exerts a high thermogenic activity and is commonly known as “a burning fat” or “a slenderizing fat”, has been attracting increasing attention as a target for the development of weight reduction methods
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