The carrying capacity for free fatty acids in plasma is exceedingly high in mammals, and this may be a liability for human metabolic health

As the need to mobilize fuel from adipose tissue changes across a day, such as during the transition from the postprandial to postabsorptive state, the rate of lipolysis is accelerated to mobilize triacylglycerol from adipose tissue in the form of free fatty acids (FFAs) and glycerol. Following export of FFAs from the cell, these hydrophobic molecules face an aqueous environment in blood, where FFA carrier proteins promote their solubility. Plasma FFA carrier proteins, such as albumin, play an important role in the ability of the body to mobilize and utilize fat. Albumin is the most abundant plasma protein in mammals (Abdollahi et al., 2022), and FFAs are its primary ligand (Petitpas et al., 2001). Each albumin molecule has seven FFA binding sites. All seven sites exhibit hydrophobic interactions with FFAs, and the five sites with the highest affinity also exhibit ionic interactions with the FFA carboxylate group to orient the FFA further within the binding site (Bhattacharya et al., 2000; Petitpas et al., 2001). It is not understood definitively why natural selection led to very high albumin expression with so many binding sites for FFAs, ultimately creating the very high binding capacity for FFAs in plasma. The normal reference range for serum albumin in humans is ∼3.5–5 g/dl (Albumin reference range citations; Quest Diagnostics, Labcorp), which equates to a molar concentration of ∼0.5–0.75 mm. When multiplying that albumin concentration range by seven (because of seven FFA binding sites), it becomes apparent that the total FFA binding capacity of serum albumin would be ∼3.5–5.25 mm in humans, well beyond the typical physiological range for plasma FFA. It seems that this high albumin expression would not limit plasma FFA abundance. Reducing albumin expression by approximately half by knocking out one copy of the gene in heterozygous albumin knockout (Alb+/−) mice has no significant impact on the plasma FFA concentration (Abdollahi et al., 2024), because the FFA binding capacity of albumin is not recruited fully in wild-type mice. However, homozygous albumin knockout (Alb−/−) mice, expressing essentially zero albumin, exhibit substantially suppressed plasma FFA concentration and flux (Abdollahi et al., 2022, 2023, 2024; Tomoo et al., 2024). In the absence of albumin, the appearance and disappearance rate of FFAs (i.e. FFA flux) in blood is reduced in mice (Tomoo et al., 2024), suggesting that albumin deficiency might slow the release of FFAs from adipose tissue, ultimately impacting the supply of FFAs for uptake into various tissues in the body. This is in agreement with a study of cultured adipocytes, in which omission of albumin from the medium drastically reduced the release of FFAs from the cells (Paar et al., 2012). At first glance, the observation of low FFA flux in the bloodstream of Alb−/− mice might seem at odds with the known biochemical relationship between albumin and FFA uptake; when albumin concentration is reduced while keeping the same total FFA concentration in the medium, this promotes uptake of FFAs by cultured cells, probably because albumin holds FFA in a bound state, whereas it is unbound FFAs that can cross the plasma membrane (Abumrad et al., 1981). Thus, a perspective from biochemical studies could be that albumin might slow FFA uptake into cells, because in certain controlled experimental conditions this is the case. However, under in vivo physiological conditions, with multiple organs and an intact circulation, albumin appears to promote the movement of FFAs between tissues, such as from adipose tissue to elsewhere, as evidenced further by the low ectopic lipid deposition in Alb−/− mice (Abdollahi et al., 2022, 2023). While the albumin-mediated potential for FFA dissolution in plasma is built to be beyond the needs of the body, it is clear that albumin would become rate limiting for FFA trafficking if its expression were much lower or if it had far fewer FFA binding sites. Although the serum albumin expression is extremely high in humans, and high in mammals in general, this is not a universal design characteristic in the animal kingdom; serum albumin concentration is notably lower in some bird species than in humans and rodents, and albumin expression is extremely low or completely absent in numerous fish species (Badawy Green et al., 2010, 2011; Hammer et al., 2008), even if the individuals have performed challenging daily exercise during the starvation (Green et al., 2011). During this extreme physiological challenge, still only approximately half of the FFA binding sites, at most, would be occupied (Fig. 1). Even if, hypothetically, only the five highest-affinity FFA binding sites could be used in albumin, the FFA binding capacity would still be in excess of the physiological range for plasma FFA concentration. Thus, in humans the plasma proteome does not seem to restrict the ability of adipose tissue to release FFAs into the bloodstream, thus allowing plasma FFA abundance to reach the high levels that can cause metabolic dysfunction (Henderson, 2021). Individuals with insulin resistance often exhibit elevated plasma FFA concentration (Henderson, 2021). High plasma FFA levels lead to increased lipid uptake, steatosis and lipotoxicity in liver and muscle, causing insulin resistance and promoting type 2 diabetes risk (Henderson, 2021). To understand the role of albumin in permitting this pathophysiological process, it was of interest to understand what would happen if serum albumin abundance became a limiting factor for plasma FFA concentration. Despite the fact that inducing obesity in mice with a high-fat diet drastically worsens glucoregulation in wild-type mice, Alb−/− mice were protected from dysregulation of glucose metabolism even when challenged with a high-fat diet (Abdollahi et al., 2022, 2023). Through these studies of Alb−/− mice, it became apparent that a high carrying capacity for plasma FFA might be limiting insulin sensitivity in wild-type animals. The apparently excessive capacity for FFA transport via FFA carrier proteins in plasma might be a liability for metabolic health. It is not known conclusively why we evolved this characteristic, but it is likely that in our evolutionary past there had been a physiological benefit from having an extremely high capacity for plasma proteins to bind FFAs in the circulation for tolerance of factors such as exercise, starvation or a combination of these and other stressors (Henderson, 2025). The ability to tolerate fasting with intermittent food availability would be important in various animals, with the ability to tolerate such fasts being on the order of days for small mammals, such as mice, and substantially longer in larger mammals, such as humans. With FFAs being an alternative fuel to spare blood glucose and to support ketone body production, a restriction on plasma FFA concentration might have been a disadvantage. Furthermore, in our evolutionary past, the ability to exercise for very long durations, such as during persistence hunting (Liebenberg, 2006), might have benefitted from the expression of plasma FFA carriers being overbuilt by a safe margin to allow for abundant release of FFAs from adipose tissue. As discussed above, the capacity of albumin for FFA dissolution in plasma is very high. Furthermore, the FFA carrying capacity in blood is even higher than this, as we recently discovered that there are numerous other FFA carrier proteins in plasma (Tomoo Tomoo et al., 2025), many of which might have multiple FFA binding sites and a binding affinity for FFA that is similar to albumin (Tomoo et al., 2025). Although one can reason that albumin promotes high plasma FFA concentration, which is a factor driving insulin resistance, there are also other FFA carriers that might further amplify the capacity for FFA dissolution in plasma. It is clear that elevating the total plasma FFA concentration in resting, well-nourished individuals worsens insulin resistance, and blunting the plasma FFA level improves insulin sensitivity (Henderson, 2021). However, there are also instances in which elevation of the plasma FFA concentration is physiologically appropriate, as occurs as part of the counterregulatory response during starvation and exercise to spare blood glucose, and thus it would be an exaggeration to state that higher plasma FFA concentration is always problematic. FFA mobilization into the bloodstream is both a friend and a foe, depending upon the energy needs and nutritional status of the body. Next, it is important to consider whether all FFA species in excess lead to metabolic problems or whether there are specific classes of FFAs that drive the relationship between the total plasma FFA concentration and insulin resistance. Saturated, monounsaturated and n-6 polyunsaturated fatty acids are major contributors to the total FFA concentration. There are also minor components, such as the n-3 polyunsaturated fatty acids. In contrast to fatty acid classes known to impair metabolic function (e.g. saturated fatty acids), n-3 polyunsaturated fatty acids tend to have beneficial properties (Lanza et al., 2013). There is still much to learn about this topic, but it is safe to assume that different fatty acid species impact health differently from one another, although metabolic health improves when the total plasma FFA concentration is suppressed. High total plasma FFA concentration overall in resting individuals can cause metabolic harm, but it is also noteworthy that the circulating FFA pool contains some potentially beneficial FFAs. Thus, the circulating FFA pool contains some beneficial molecules but as a whole can exert negative influences on metabolic health. Although having some non-zero level of circulating FFAs is important, suppressing the total plasma FFA concentration to lower levels would likely be beneficial for metabolic health. If clinical approaches for suppressing plasma FFA concentration become available, this could potentially improve insulin sensitivity. Previously, high-dose niacin (and its analogue, acipimox) has been used to inhibit lipolysis as a means of decreasing plasma FFA concentration, but this is effective only transiently, until the body compensates and raises the plasma FFA concentration (Henderson, 2021). Other possible approaches, aside from inhibiting lipolysis, could be to trap FFAs in adipose tissue while allowing lipolysis to proceed. This phenotype occurs in Alb−/− mice, and adipose tissue seems to remain healthy without abnormal expansion of this lipid storage depot (Zhang et al., 2025). In Alb−/− mice, adipose tissue increases its expression of adiponectin (a health-promoting hormone), while upregulating enzymes of FFA re-esterification (Abdollahi et al., 2022, 2023) and increasing uncoupling protein-1 expression (Zhang et al., 2025) alongside improved insulin sensitivity (Abdollahi et al., 2022, 2023). As a potential reaction to this fatty acid sequestration in white adipose tissue, the liver show signs of decreased glycogen, decreased levels of steatosis and inflammation, and increased expression of β-oxidation enzymes (Abdollahi et al., 2022, 2023). Work on this animal model suggests that albumin-bound FFAs in circulation act to spare liver glycogen, dampen insulin sensitivity and promote tissue steatosis and inflammation (Fig. 2). It appears that decreasing the efficiency of FFA release from adipose tissue could be a potential therapeutic goal in the future, perhaps through the development of inhibitors of FFA transporters or inhibitors of the FFA–albumin interaction. In contrast to the very low albumin expression in some other animal groups, the high albumin expression in humans and other mammals does not limit plasma FFA abundance. In modern times, with a high incidence of obesity, insulin resistance and diabetes, this physiological design characteristic in humans is a metabolic liability because it allows plasma FFA levels to be unrestrained by the plasma proteome. This is a concern because higher plasma FFA levels promote insulin resistance and metabolic dysfunction. In the future, it might be a therapeutic goal to reduce plasma FFA concentration chronically. FFA export from adipose tissue and the acceptance of those FFAs by FFA carrier proteins in plasma might represent intervention points. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The author declares no competing interests. Sole author. None. I thank Keigo Tomoo and Yi Zhang for input on the figure designs.