Myo-inositol is a key regulator of hummingbird fuel selection

Naturally hyperglycemic, birds maintain twice the plasma-glucose concentration of mammals at equivalent size and are relatively insensitive to insulin. Most avian species possess mechanisms to enhance fatty acid (FA) transport and oxidation using pathways comparable to those in diabetic humans. Recent evidence suggests that perturbation of myo-inositol (MI), a carbocyclic sugar derived from glucose-6-phosphate, plays a role in mammalian hyperglycemic regulation. While MI is not typically utilized for energy, it serves as a mediator in signal transduction, regulating multiple metabolic processes. We hypothesized that MI plays a key role in regulating avian metabolism and body mass regulations. We investigated this at two levels. At the organismal level, Anna’s Hummingbirds (Calypte anna) were supplemented with either control nectar (Nektar plus) or MI enhanced nectar (5% MI), to explore the role of dietary MI in body mass regulation. Hummingbirds body masses were continuously monitored for 7 days. Additionally, we designed a choice experiment, presenting the birds with 2 feeders (control and either 1%, 3% or 5% MI enhanced), to explore hummingbirds MI preferences. We recorded hummingbirds body masses before and after a 2-hour trial, as well as their nectar consumption. At the cellular level, we assessed MI's effect on mitochondrial fuel utilization using fibroblast cells from Japanese Quail (Coturnix japonica), incubated for 2 hours with control media or MI enhanced media (5% MI), and assayed utilizing extracellular flux assays. Results: For the chronic exposure experiment, a split plot ANOVA with treatment as the between-subject factor; day as a within-subject factor and initial body mass as a covariate, revealed that MI significantly decreased evening body mass (F 1,6 =12.862, p=0.012). For the choice experiments, split plot ANOVAs with either treatment or body mass change as the between-subject factor and trial number as a within-subject factor, revealed that Ingested MI significantly and negatively affected changes in body mass. (F 1,18 4 =5.768, p=0.017). We also found a significant effect of seasonality on the birds’ choice (F 2,3 =60.392, p=0.004), and that birds avoid higher MI concentrations (F 2,8 =5.754, p=0.028) in most seasons, except for post-migration season, when they arrive at higher body mass to the wintering grounds. Cellular assays showed a significantly higher external FA oxidation (t 3 = -3.42, p = 0.042), and lower Pyruvate dehydrogenase (PDH) activity (t 2 =17.96, P < 0.001) for MI treated cells. Our findings show that dietary MI reduces fat accumulation in Anna’s Hummingbirds. MI consumption by hummingbirds varies with seasonal changes in body mass, consistent with a regulatory role. Furthermore, MI enhances FA oxidation in avian cells, via effects on PDH complexes. Adi Domer is supported by a long term Human Frontiers Science Program Postdoctoral fellowship This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.