Heme biosynthesis regulates BCAA catabolism and thermogenesis in brown adipose tissue

With age, people tend to accumulate body fat and reduce energy expenditure[1][1]. Brown (BAT) and beige adipose tissue dissipate heat and increase energy expenditure via the activity of the uncoupling protein UCP1 and other thermogenic futile cycles[2][2],[3][3]. The activity of brown and beige depots inversely correlates with BMI and age[4][4]–[11][5], suggesting that promoting thermogenesis may be an effective approach for combating age-related metabolic disease[12][6]–[15][7]. Heme is an enzyme cofactor and signaling molecule that we recently showed to regulate BAT function[16][8]. Here, we show that heme biosynthesis is the primary contributor to intracellular heme levels in brown adipocytes. Inhibition of heme biosynthesis leads to mitochondrial dysfunction and reduction in UCP1. Although supplementing heme can restore mitochondrial function in heme-synthesis-deficient cells, the downregulation of UCP1 persists due to the accumulation of the heme precursors, particularly propionyl-CoA, which is a product of branched-chain amino acids (BCAA) catabolism. Cold exposure promotes BCAA uptake in BAT, and defects in BCAA catabolism in this tissue hinder thermogenesis[17][9]. However, BCAAs’ contribution to the TCA cycle in BAT and WAT never exceeds 2% of total TCA flux[18][10]. Our work offers a way to integrate current literature by describing heme biosynthesis as an important metabolic sink for BCAAs. ### Competing Interest Statement JJC is a consultant for Thermo Fisher Scientific, 908 Devices, and Seer. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-11 [6]: #ref-12 [7]: #ref-15 [8]: #ref-16 [9]: #ref-17 [10]: #ref-18