The aqueous intracellular environment is subdivided into functional domains (organelles) by hydrophobic lipid membranes. Assembly of these lipid barriers requires shuttling of precursor lipids from their sites of synthesis or uptake to sites of oxidation or membrane assembly. Free fatty acids and their coenzyme A (CoA) esters are potent emulsifiers and can damage the cellular environment through generation of reactive oxygen species. Accordingly, the free intracellular concentrations of reactive oxygen species are tightly controlled by binding to carrier proteins, which traffic fatty acids to sites of utilization or storage reservoirs such as lipid droplets. Against this backdrop, the recent report by Faergeman and colleagues in Acta Physiologica is surprising 1. The authors show that adipocyte function and homeostasis in mice in vivo are unaffected by the knockout of acyl-CoA binding protein (ACBP) specifically in adipocytes. ACBP binds medium-, long-, and very-long-chain fatty acyl-CoA esters, and its deletion might therefore have been expected to disrupt lipid handling. Indeed, global knockout of ACBP has dramatic effects on systemic metabolism, including the adaptation of liver function to weaning and pronounced alterations in skin-associated epithelial cells—keratinocytes and sebocytes—leading to marked changes in skin function and energetics 2. Given these findings, it would have been reasonable to predict that adipocytes—the ultimate specialists in lipid storage and mobilization—would also depend on ACBP. To test this, Faergeman and colleagues employed two distinct Cre drivers to delete Acbp either selectively in brown adipose tissue, or across all adipose depots. These depots differ profoundly in morphology, regulation, and function (Figure 1). Yet, neither knock-out model displayed changes in systemic energy expenditure, food intake, adipose mass, lipid composition, mitochondrial respiration, or gene expression in white or brown adipose tissue. This lack of phenotype is particularly striking in brown adipose tissue (BAT), a highly dynamic depot that repeatedly assembles and dismantles multilocular lipid droplets to fuel mitochondrial heat production. Defects in lipid metabolism often manifest prominently in BAT 3, whether due to impaired endothelial or adipocyte lipid handling 4, 5, or defects in the peripheral tissues that supply substrates for thermogenesis 6. Such perturbations commonly result in impaired maintenance of body temperature during acute cold exposure. Nevertheless, even under cold stress—when acyl-CoA flux and oxidation rates are maximal—ACBP-deficient adipose tissue showed little evidence of dysfunction. Why, then, is ACBP essential for lipid handling in skin but dispensable in adipose tissue? One key distinction lies in lipid storage capacity. The epithelial compartment of skin produces two lipid pools with overlapping barrier functions: keratinocytes generate the ceramide-rich stratum corneum, while sebocytes synthesize wax esters that coat hair and skin 7, 8. Unlike adipocytes, however, keratinocytes lack a large neutral lipid reservoir that might buffer disruptions in acyl-CoA handling. Moreover, ceramide synthesis requires abundant long-chain fatty acids, and ACBP functions as a component of ceramide synthase activity 9, providing a plausible mechanistic explanation for its essential role in epidermis. In prior work, this group demonstrated that both global and skin-specific ACBP knockout mice are resistant to diet-induced obesity. Perhaps because loss of ACBP in skin alone is sufficient to confer this phenotype 10, dietary stress was not examined in the current adipose-specific models. Besides skin, where might ACBP prove essential? Known functions of long-chain acyl-CoA species suggest likely sites of action for their binding proteins, including processes such as plasma membrane curvature, myelin formation, eicosanoid biosynthesis, endoplasmic reticulum expansion during high secretory demand, regulation of mitochondrial enzyme activity, and synthesis of mitochondrial lipids such as cardiolipin. These predictions provide a roadmap for future studies aimed at finding out where acyl-CoA buffering is truly indispensable. The author declares no conflicts of interest. This article is linked to Nørremark et al. papers. To view this article, visit https://doi.org/10.1111/apha.70159.
C. Bruce Alexander (Thu,) studied this question.