Branched-chain fatty acids fire up the peroxisome

In their recent Nature publication, Liu et al. demonstrate an important role for the synthesis and catabolism of long-chain monomethyl branched-chain fatty acids (mmBCFAs) in supporting thermogenesis in mouse brown adipose tissue. Through the elegant use of genetic mouse models, metabolic tracing, and genetically-encoded temperature sensors, they describe a thermogenic pathway involving fatty acid synthase-mediated mmBCFA synthesis and catabolism within peroxisomes by acyl-CoA oxidase 2.

In mammals, monomethyl branched-chain fatty acids (mmBCFAs) were long thought to be derived primarily from the diet or microbiome. Indeed, they are highly enriched in dairy products¹ while being important lipid components of many microbes.² However, mmBCFAs are actively synthesized de novo in mammalian adipose tissues, the skin, and meibomian glands,^3,4 and they may be important biologically active components of human milk.^5,6 Since fatty acid synthase (FASN) does not discriminate against different initiating substrates, mmBCFAs as well as odd-chain fatty acids are readily produced when short, branched-chain acyl-CoAs or propionyl-CoA are abundant in the cytosol. This pathway is highly active in germ-free mice and strongly influenced by dietary fat intake and tissue hypoxia, which strongly downregulate adipocyte branched-chain amino acid catabolic and lipogenic fluxes.³ Many factors can therefore influence the synthesis and breakdown of these fatty acid species. In a recent Nature paper, Liu et al.⁷ demonstrate a functional role for this pathway in mice by targeting FASN in brown adipocytes and observing impacts on mmBCFA abundance, energy expenditure, and thermogenesis in response to cold exposure. These data directly implicate brown adipose tissue (BAT) lipogenesis in thermoregulation and energy homeostasis.

Perhaps more importantly, Liu et al. define a role for peroxisomal mmBCFA catabolism in BAT-mediated thermogenesis. Multi-branched-chain lipid species like phytanic acid are specifically processed in the peroxisome via α-oxidation before being further degraded via β-oxidation. Here, the authors identify acyl-CoA oxidase 2 (Acox2) as highly upregulated in thermogenic BAT tissue, and deletion of this peroxisomal enzyme leads to a selective accumulation of mmBCFAs. In turn, targeting Acox2 in adipose tissue compromises thermogenesis in mice while influencing diet-induced obesity and insulin sensitivity. On the other hand, Acox2 overexpression has the opposite effects: reducing weight gain, BAT lipid accumulation, and insulin resistance in mice fed a high-fat diet (HFD). Furthermore, the authors performed these interventions in uncoupling protein 1 (Ucp1) knockout mice, and demonstrated that this process is independent of Ucp1-mediated thermogenesis. To examine mmBCFA-mediated thermogenesis at the cellular level, the authors expressed a fluorescent, ratiometric temperature sensor in the peroxisome. Using this approach, they demonstrated that mmBCFA treatment stimulates temperature changes in the peroxisome of Acox2-overexpressing brown adipocytes. These data identify a potential functionality of mmBCFA synthesis and peroxisomal catabolism in thermogenesis that leverages this organelle’s ability to metabolize structurally diverse and/or transiently abundant fatty acids.

One caveat with this study is the use of HFD feeding to elucidate thermogenic effects, since mmBCFA synthesis is generally low under these conditions. However, these data generally highlight the importance of peroxisomal fatty acid catabolism in supporting thermogenesis, as this organelle represents an important “overflow” pathway through which cells and tissues can manage and metabolize diverse fatty acids.⁸ By way of localized synthesis and selective transport, mmBCFAs may play an active role in thermoregulation.

Nevertheless, mmBCFAs may have other functions that influence cell behavior. Despite the focus on peroxisomal mmBCFA catabolism in this study, these fatty acids can readily be oxidized via mitochondrial β-oxidation. Carnitine O-acetyl-transferase is involved in transfer of branched-CoAs in/out of these organelles and likely contributes to such coordination. However, mmBCFAs are also incorporated into membrane lipids where they can endow structural changes and curvature in organelles and vesicles without increasing the potential for toxic lipid oxidation. Indeed, polyunsaturated fatty acids are effective at modulating membrane fluidity but may be a liability for cells with high respiratory rates (e.g., BAT). Finally, mmBCFAs may serve as signaling ligands that provide a readout of tissue health or infections. Some BCFA species like phytanic acid can act as ligands for peroxisomal proliferating activator receptor α, and thus mmBCFAs could act as endogenous signals to regulate metabolic processes. On the other hand, mmBCFAs are highly enriched in the membranes of some microbial species. As such, when incorporated into α-galactosylceramide, mmBCFAs alter the presentation of this microbial lipid via CD1d to natural killer T cells and enhance IL-2 production.⁹ Similar findings have been made for phospholipids containing mmBCFAs, which influence toll-like receptor binding that correlates with microbiome composition.¹⁰ These results demonstrate that the mmBCFA structure alters binding of lipids to receptors involved in immune signaling.

Ultimately, organisms are constantly exposed to diverse fatty acids from their environment (e.g., diet, commensal microbes, pathogens). This diversity is also shaped by endogenous metabolic pathways. As a result, there is likely no perfect or idealized lipidome, and animals must constantly negotiate fluctuations in their palette of fatty acids as a function of their environment, disease status, and age. Here, Liu et al. highlight an important role for both mmBCFA synthesis and peroxisomal fatty acid catabolism in leveraging acyl-chain diversity to support thermogenesis.