Abstract
Iron homeostasis is essential for maintaining cellular function in a wide range of cell types. However, whether iron affects the thermogenic properties of adipocytes is currently unknown. Using integrative analyses of multi‐omics data, transferrin receptor 1 (Tfr1) is identified as a candidate for regulating thermogenesis in beige adipocytes. Furthermore, it is shown that mice lacking Tfr1 specifically in adipocytes have impaired thermogenesis, increased insulin resistance, and low‐grade inflammation accompanied by iron deficiency and mitochondrial dysfunction. Mechanistically, the cold treatment in beige adipocytes selectively stabilizes hypoxia‐inducible factor 1‐alpha (HIF1α), upregulating the Tfr1 gene, and thermogenic adipocyte‐specific Hif1α deletion reduces thermogenic gene expression in beige fat without altering core body temperature. Notably, Tfr1 deficiency in interscapular brown adipose tissue (iBAT) leads to the transdifferentiation of brown preadipocytes into white adipocytes and muscle cells; in contrast, long‐term exposure to a low‐iron diet fails to phenocopy the transdifferentiation effect found in Tfr1‐deficient mice. Moreover, mice lacking transmembrane serine protease 6 (Tmprss6) develop iron deficiency in both inguinal white adipose tissue (iWAT) and iBAT, and have impaired cold‐induced beige adipocyte formation and brown fat thermogenesis. Taken together, these findings indicate that Tfr1 plays an essential role in thermogenic adipocytes via both iron‐dependent and iron‐independent mechanisms.
Highlights
We found that transferrin receptor 1 (Tfr1)-mediated iron uptake is essential for white adipocyte beigeing and the function of brown adipose tissue
We found no significant differences in body weight (Figure 3A) or white adipose tissue mass including inguinal white adipose tissue (iWAT) and epididymal WAT (eWAT) (Figure 3B and Figure S3A, Supporting Information) between Tfr1Adp/Adp mice and controls
We found that HIF1α was likely involved in beige adipocyte differentiation but not essential to support adaptive thermogenesis in BAT by mechanism of transcriptionally promoting Tfr1 expression, which is consistent with the previous report that HIF1α binds to the Tfr1 promoter in hepatocytes.[32]
Summary
Obesity occurs from an imbalance between energy intake and the body’s consumption of energy, and excessive accumulation of fat contributes to the development of obesity. The body contains three types of adipose tissues, namely brown adipose tissue (BAT), white adipose tissue (WAT), and a form of WAT in which WAT cells can be converted to BAT-like adipocytes via a process known as “beigeing”, resulting in beige (or “brite”) adipocytes. WAT is composed primarily of large unilocular lipid droplets that store triglycerides. BAT is composed primarily of small multilocular lipid droplets that contain a large number of mitochondria, which burn systemic glucose and lipids in order to generate heat, a process known as thermogenesis. Beige adipose tissue is derived from WAT that has undergone beigeing due to environmental cold or other stimuli such as β3-adrenergic signaling.[1].
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