Loss of Thermogenic Energy Expenditure via Targeted Deletion of Transferrin Receptor 1 in Adipocytes Instigates Hepatic Steatosis and Insulin Resistance

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ObjectivesAdipocytes are critical for keeping the whole-body energy balance by depositing energy into TG, secreting fatty acids, and burning energy into heat. We recently reported that iron metabolism in adipose tissue is regulated in a depot-specific manner, and plays an important role in thermogenesis. However, it is poorly understood whether adipocyte iron status alters systemic energy balance. This study aimed to investigate the metabolic impact of the adipocyte-specific deletion of transferrin receptor 1 (Tfr1), the single most critical iron transporter. MethodsAdipocyte-specific Tfr1 knockout mice (ASKO) were generated by crossing the adiponectin-Cre transgenic mice with the Tfr1-floxed mice. The metabolic phenotypes of ASKO mice were characterized in basal level and high fat (HF)-fed status. The insulin sensitivity was assessed by glucose (GTT) and insulin tolerance test (ITT). To evaluate the thermogenic capacity, the mice were employed to the heat/cold cycle (31°C for 14 days to normalize the baseline, followed by at 4°C for 7 days). ResultsIn the basal level, the targeted deletion of adipocyte Tfr1 resulted in the reductions in fat mass (p < 0.05) and the iron content (p < 0.01) both in the WAT and BAT, and the impairment of BAT development, including bleached color. ASKO displayed diminished thermogenic function (p < 0.05), but no overt metabolic adaptation was examined compared to the wildtype littermates. However, the HF-diet challenge instigated the glucose intolerance (p < 0.01), insulin resistance (p < 0.01), and hepatic TG content (p < 0.01) in the ASKO mice compared to wildtype without differences in body weight. Furthermore, the heat/cold cycle treatment in the ASKO caused 1) abolished beige fat formation, 2) augmented immune cell infiltration in WAT, 3) enlarged liver due to massive TG accumulation, and 4) elevated serum NEFA and cholesterol levels. ConclusionsDysregulation of adipocyte iron metabolism by deletion of Tfr1 significantly destroys the thermogenic capacity, leading to hepatic steatosis, insulin resistance, and dyslipidemia. Our works have revealed the metabolic contribution of adipose iron homeostasis to maintain systemic energy balance via thermogenic energy expenditure. Funding SourcesNational Institutes of Health Grant 1R21HD094273