Transferrin Receptor 1 Regulates Thermogenic Capacity and Cell Fate in Brown/Beige Adipocytes

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.

Transferrin receptor (Tfr1) ablation in satellite cells impacts skeletal muscle regeneration through the activation of ferroptosis

“…Under physiological conditions, ferric iron in the form of transferrin-bound iron (TBI) recognized by membrane Tfr1 is absorbed in peripheral tissues, such as liver, adipose tissue, skeletal muscle, and bone marrow (23, 41, 42) . Multiple studies have shown that Tfr1 -deficiency results in functional disorder and even death.…”

“…Mice with Tfr1 conditional knockout in hematopoietic stem cells died within one week after birth (43) . Our previous study demonstrated that Tfr1 regulates adipocyte thermogenesis and cell fate determination (44) . Adipocytes with Tfr1 ablation exhibit reduced thermogenic capacity and beigeing potential (44) .…”

Fat and Iron Don't Mix

“…To study the effects of adipocyte-specific iron homeostasis on metabolism, models in which iron import and export proteins have been ablated, provide important insights. Adipocyte-targeted knock down of iron handling proteins [ 31 , 40 ] in vitro and in vivo are generally associated with dysfunctional elevation in inflammation and reductions in insulin signaling. For example, human adipocytes lacking lactoferrin showed increased expression of inflammatory genes [ 31 ].…”

“…On a high-fat diet, these mice have increased markers of AT inflammation, dysregulated lipid metabolism, mount a defective thermogenic response, and develop insulin resistance. Interestingly, these effects were thought to be regulated by HIF1α activation in beige adipocytes [ 40 ]. This is entirely in line with the observations noted above in the KK/HIJ and obese anemic mice [ 32 , 37 ].…”

“…This is entirely in line with the observations noted above in the KK/HIJ and obese anemic mice [ 32 , 37 ]. Adipocyte iron overload is also a recurring theme in studies investigating the effects of iron excess on metabolic homeostasis [ 40 - 42 ]. In fact, the above-mentioned effects of iron in decreasing adiponectin and leptin have been replicated in mouse models of adipocyte-specific iron overload [ 38 , 39 , 43 ].…”