In the intricate landscape of metabolic regulation, brown adipose tissue (BAT) has long fascinated researchers due to its remarkable ability to dissipate energy as heat, thus contributing to thermogenesis. A novel and compelling study now sheds light on an unexpected molecular player at the heart of BAT’s thermogenic machinery: haem biosynthesis. Historically, BAT’s characteristic brown hue has been attributed to its dense population of haem-rich mitochondria, but until recently, the detailed biochemical and regulatory interplay governing haem levels within brown adipocytes remained largely uncharted. This transformative research unravels the crucial role of intracellular haem production in modulating both branched-chain amino acid (BCAA) metabolism and the thermogenic capacity of BAT, painting a comprehensive picture that bridges mitochondrial biochemistry, epigenetics, and metabolic physiology.
At its core, the investigation pivots on the revelation that de novo haem synthesis within brown adipocytes serves as the principal source of cellular haem. Haem, an iron-containing porphyrin, is essential for multiple mitochondrial functions, serving as a prosthetic group for cytochromes involved in the electron transport chain and other redox proteins vital for oxidative phosphorylation. By experimentally impeding haem biosynthesis, the researchers uncovered a cascade of metabolic disturbances, most notably the intracellular accumulation of key BCAAs—valine and isoleucine. This accumulation is not a random byproduct but instead reflects the disruption of a metabolon—a highly coordinated enzymatic complex—that channels carbon skeletons derived from BCAAs directly into haem biosynthetic pathways. This novel metabolon fundamentally links amino acid catabolism with mitochondrial haem homeostasis, underscoring a previously underappreciated metabolic axis within BAT.
Diving deeper into the molecular consequences of impaired haem synthesis, the study reveals that brown adipocytes deficient in haem production suffer marked decreases in mitochondrial respiration rates. This respiratory decline is accompanied by a diminution of uncoupling protein 1 (UCP1) levels, a key thermogenic effector that enables proton leak and heat generation by BAT mitochondria. Such findings directly implicate haem availability as a determinant of BAT’s energy expenditure capacity. Intriguingly, although the application of exogenous haem restores intracellular haem to normal levels and rescues mitochondrial respiratory function, it fails to reverse the suppression of UCP1 expression. This suggests that the downregulation of UCP1 emerges from mechanisms independent of haem abundance per se, prompting further exploration of epigenetic regulatory pathways.
The researchers identified that UCP1 suppression following haem biosynthesis inhibition stems from epigenetic changes linked to the accumulation of propionyl-CoA. Propionyl-CoA, a metabolite generated during the catabolism of BCAAs and odd-chain fatty acids, builds up due to disrupted metabolic flux through haem-dependent pathways. Elevated propionyl-CoA levels are known to act as donors for histone propionylation, a reversible post-translational modification of histones that influences chromatin structure and gene transcription. This epigenetic remodeling exerts a repressive effect on UCP1 expression, revealing a novel axis by which metabolic intermediates can shape gene regulatory landscapes and ultimately impact thermogenic function.
Extending these biochemical insights into whole-organism physiology, the study probed the systemic consequences of haem biosynthesis disruption within BAT. Notably, mice genetically engineered to lack haem biosynthetic enzymes specifically in brown adipocytes displayed a markedly impaired thermogenic response upon cold exposure. These animals were less capable of maintaining core body temperature, underscoring haem biosynthesis as indispensable for effective heat generation by BAT in vivo. Perhaps most strikingly, this thermogenic deficiency was accompanied by altered circulating levels of BCAAs, highlighting the role of BAT not only as a heat-producing organ but also as a key metabolic regulator of amino acid homeostasis.
A fascinating dimension to the research emerged when exploring sex-specific effects. Female, but not male, mice showed significant impairments in clearing circulating BCAAs in response to cold stress when haem biosynthesis was disrupted in BAT. This sex-dependent metabolic phenotype implicates sex hormones in modulating the crosstalk between haem metabolism, amino acid catabolism, and thermogenesis. Although the underlying molecular mechanisms of these sex differences remain an intriguing subject for future study, this observation adds a critical layer of complexity to our understanding of adipose tissue biology and systemic metabolic regulation.
The discovery of haem biosynthesis as a central regulator linking mitochondrial function, BCAA catabolism, and thermogenesis has broad implications extending beyond fundamental cellular physiology. Given the rising global incidence of metabolic disorders such as obesity and type 2 diabetes, where BAT activity and BCAA metabolism are often dysregulated, these findings open new avenues for therapeutic intervention. Manipulating haem biosynthetic pathways could potentially restore or enhance BAT thermogenic capacity and improve systemic amino acid metabolism, thereby offering innovative strategies to combat metabolic disease.
Furthermore, the intricate metabolon involving BCAA-derived carbons channels into haem production, delineated in this study, challenges existing metabolic models by revealing a tightly integrated enzymatic assembly that coordinates amino acid catabolism and heme synthesis. This spatial and functional integration ensures metabolic efficiency and finely tuned energy homeostasis in brown adipocytes. The concept of metabolons has gained traction as a means by which cells achieve substrate channeling and metabolic regulation; here, the identification of a haem-associated metabolon adds a new member to this emerging class of metabolic complexes.
Beyond cellular metabolism, the epigenetic consequences of propionyl-CoA accumulation draw attention to the broader theme of how mitochondrial metabolites can influence nuclear gene expression through chromatin modifications. The reversible nature of histone propionylation and its impact on UCP1 expression points to a sophisticated feedback loop wherein metabolic flux governs epigenetic states, which in turn dictate thermogenic gene programs. Such metabolic-epigenetic crosstalk represents a frontier in metabolic biology, with potential relevance to other tissues and disease contexts.
Importantly, the persistence of UCP1 downregulation despite restored haem levels upon exogenous supplementation reveals that simple replenishment of haem is insufficient to reverse the epigenetic landscape altered by prior metabolic stress. This finding underscores the temporal dynamics and potential irreversibility of metabolite-induced chromatin remodeling, emphasizing the need for timely intervention. It also raises questions about the mechanisms by which propionyl-CoA-mediated histone modifications are established and whether they can be therapeutically targeted or reversed.
Investigating the physiological relevance in vivo, the observed cold intolerance and disrupted BCAA clearance confirm that haem biosynthesis in brown adipocytes is essential not only for local mitochondrial function but also for systemic metabolic homeostasis. As BCAAs have garnered interest due to their association with insulin resistance and obesity, the finding that BAT serves as a sex-hormone-dependent regulator of BCAA clearance offers a nuanced perspective on gender disparities in metabolic disease susceptibility and progression.
This study’s multidisciplinary approach, combining genetics, metabolomics, mitochondrial physiology, and epigenetic analysis, provides a comprehensive framework for understanding how haem biosynthesis acts as a metabolic hub within BAT. The identification of sex-specific metabolic phenotypes also encourages future research to consider hormonal influences when developing BAT-targeted metabolic therapies.
In summary, this groundbreaking research reveals haem biosynthesis as a pivotal control point that orchestrates branched-chain amino acid catabolism, mitochondrial respiration, epigenetic regulation, and ultimately thermogenic capacity in brown adipose tissue. The discovery of a haem-associated metabolon integrating amino acid metabolism with heme production, coupled with insights into propionyl-CoA-mediated histone propionylation suppressing UCP1, transforms our understanding of BAT function. Moreover, the demonstrated sex differences in metabolic response provide a critical lens for personalized medicine approaches targeting BAT for metabolic health. These revelations pave the way for innovative strategies to enhance energy expenditure and address metabolic disease burden, representing a leap forward in adipose tissue biology and systemic metabolism.
Subject of Research: Regulation of haem biosynthesis, BCAA catabolism, and thermogenesis in brown adipose tissue.
Article Title: Haem biosynthesis regulates BCAA catabolism and thermogenesis in brown adipose tissue.
Article References:
Duerre, D.J., Hansen, J.K., John, S.V. et al. Haem biosynthesis regulates BCAA catabolism and thermogenesis in brown adipose tissue. Nat Metab (2025). https://doi.org/10.1038/s42255-025-01253-6
Image Credits: AI Generated
