A liver-fat crosstalk for iron flux during healthy beiging of adipose tissue

Abstract

Beiging of adipocytes is characteristic of a higher number of mitochondria, the central hub of metabolism in the cell. However, studies show that beiging can improve metabolic health or cause metabolic disorders. Here we discuss a liver-fat crosstalk for iron flux associated with healthy beiging of adipocytes. Deletion of the transcription factor FoxO1 in adipocytes (adO1KO mice) induces a higher iron flux from the liver to white adipose tissue, concurrent with augmented mitochondrial biogenesis that increases iron demands. In addition, adO1KO mice adopt an alternate mechanism to sustain mitophagy, which enhances mitochondrial quality control, thereby improving mitochondrial respiratory capacity and metabolic health. However, the liver-fat crosstalk is not detectable in adipose Atg7 knockout (ad7KO) mice, which undergo beiging of adipocytes but have metabolic dysregulation. Autophagic clearance of mitochondria is blocked in ad7KO mice, which accumulates dysfunctional mitochondria and elevates mitochondrial content but lowers mitochondrial respiratory capacity. Mitochondrial biogenesis is comparable in the control and ad7KO mice, and the iron influx into adipocytes and iron efflux from the liver remain unchanged. Therefore, activation of the liver-fat crosstalk is critical for mitochondrial quality control that underlies healthy beiging of adipocytes.

Keywords: Adipose beiging; Atg7; FoxO1; iron flux; liver-fat crosstalk.

Figure 1.

Mitochondrial regulation in ad7KO mice. (A-B) Western blotting (panel A) and densitometric (panel B) analyses of mitochondrial biogenesis markers (Pgc1α and Pgc1β) and mitochondrial content marker (COXIV) in visceral adipose tissues from control and ad7KO male mice. n=6. (C-D) Western blotting (panel C) and densitometric (panel D) analyses of mitophagy markers (Pink1, Bnip3, and Fundc1) in visceral adipose tissues from control and ad7KO male mice. n=6. (E-F) Western blotting (panel E) and densitometric (panel F) analyses of mitochondrial dynamics proteins (Drp1, pDrp1-S637, and OPA1) in visceral adipose tissues from control and ad7KO male mice. n=6. *p < 0.05, **p < 0.01; ***p<0.001.

Figure 2.

Iron metabolism in ad7KO mice. (A-C) the contents of non-heme iron in visceral adipose tissue (panel A), the liver (panel B), and serum (panel C) in control and ad7KO male mice. n= 6-9. (D-E) Western blotting (panel D) and densitometric (panel E) analyses of iron regulating proteins in visceral adipose tissues from control and ad7KO male mice. n=6. (F-G) Western blotting (panel F) and densitometric (panel G) analyses of iron regulating proteins in liver tissues from control and ad7KO male mice. n=6. *p < 0.05; n.s., not significant.

Figure 3.

Schematic view of the liver-fat crosstalk during beiging of adipocytes. In adO1KO mice, active crosstalk between the liver and adipose tissue supplies iron required for augmented mitochondrial biogenesis during beiging of adipocytes. Increased mitochondrial biogenesis plus sustained mitophagy upregulates mitochondrial content and respiratory capacity, improving systemic metabolism. In ad7KO mice, however, a higher mitochondrial content results from impairment in mitophagy and accumulation of poor-quality-controlled mitochondria, thereby reducing mitochondrial capacity. As mitochondrial biogenesis is unchanged, the liver-fat crosstalk is silenced. ↔, unchanged; ↑, upregulated; ↓, downregulated. The gray dashed line indicates the absence of activation of a liver-fat crosstalk for iron supply.