Atypical monocyte dynamics in healthy humans in response to fasting and refeeding are distinguished by fasting HDL and postprandial cortisol

Authors: Snodgrass, Ryan; Stephensen, Charles; Laugero, Kevin

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/25/2024
Publication Date: 7/3/2024
Citation: Snodgrass, R.G., Stephensen, C.B., Laugero, K.D. 2024. Atypical monocyte dynamics in healthy humans in response to fasting and refeeding are distinguished by fasting HDL and postprandial cortisol. American Journal of Physiology - Endocrinology and Metabolism. https://doi.org/10.1152/ajpendo.00158.2024.
DOI: https://doi.org/10.1152/ajpendo.00158.2024

Interpretive Summary: Monocytes are a versatile population of immune cells that are continuously produced in bone marrow which enter and circulate in blood. While monocytes are important for maintaining health, elevated numbers in blood are associated with progression of chronic disease including atherosclerosis and cardiovascular disease. In response to nutrient scarcity, such as during an overnight fast, blood monocytes migrate back to bone marrow where upon refeeding (e.g. breakfast or the first meal of the day) they are re-released back into the bloodstream to replenish the circulation. While the movement of monocyte between blood and bone marrow is well described in animals, it is not well characterized in healthy humans. To better understand the movement of monocytes in humans we measured blood monocyte fluctuations in 346 clinically healthy individuals after a 12-hour overnight fast and at 3- and 6-hours after consuming a mixed macronutrient challenge meal. Using statistical analysis, we identified three groups each with a distinct monocyte behavior in response to fasting and refeeding. Group 1 comprised 34% of study subjects and was characterized by relatively low fasting blood monocyte counts that markedly increased at 3 hours after consuming the test meal and remained elevated at 6 hours. Group 2, which comprised 17% of study subjects, was characterized by relatively high fasting blood monocyte counts which decreased at 3 hours after meal consumption and changed little between 3 and 6 hours. Group 3 comprised 49% of study subjects and, like Group 1, was characterized by lower fasting blood monocytes. However, Group 3 monocyte numbers did not change at the 3-hour postprandial time point but moderately increased at 6 hours. While the monocyte fluctuations observed in Groups 1 and 3 align well with previously published results, the atypical dynamic observed in Group 2 does not. While generally younger in age, Group 2 subjects burned lower amounts of carbohydrate to fuel whole-body processes, had lower HDL-cholesterol levels (sometimes called “good” cholesterol because it removes cholesterol from the bloodstream and carries it to the liver), exhibited delayed postprandial declines in salivary cortisol, and displayed lower levels of endothelial function which is important for keeping blood flowing smoothly and maintaining a healthy vascular system. These unique characteristics were not explained by group differences in age, gender, or body mass index (BMI). Taken together these results in clinically healthy subjects highlight distinct patterns of monocyte responsiveness to natural changes in dietary energy availability.

Technical Abstract: Background: Monocytes are innate immune cells that are continuously produced from myeloid precursor cells in bone marrow which enter and circulate the vasculature. In response to nutrient scarcity peripheral monocytes migrate back to bone marrow where upon refeeding they are re-released back into the bloodstream to replenish the circulation. While monocyte dynamics in animals is well described, the individual variability in monocyte behavior in response to fasting and refeeding in healthy humans has not been characterized. Objective: To investigate monocyte dynamics in humans we measured blood monocyte fluctuations in a cohort of 346 clinically healthy individuals after a 12-hour overnight fast and at 3- and 6-hours after consuming a mixed macronutrient challenge meal. Results: Using cluster analysis, we identified three distinct monocyte behaviors in response to fasting and refeeding. Group 1 comprised 34% of study subjects and was characterized by relatively low fasting blood monocyte counts that markedly increased at 3 hours after consuming the test meal and remained elevated at 6 hours. Group 2, which comprised 17% of study subjects, was characterized by relatively high fasting blood monocyte counts which decreased at 3 hours after meal consumption and changed little between 3 and 6 hours. Group 3 comprised 49% of study subjects and, like Group 1, was characterized by lower fasting peripheral monocyte counts. However, Group 3 monocyte counts did not change at the 3-hour postprandial time point but moderately increased at 6 hours. While monocyte fluctuations observed in Groups 1 and 3 align well with the current paradigm of monocyte dynamics in response to fasting and refeeding, the atypical dynamic observed in Group 2 does not. While generally younger in age, Group 2 subjects had lower whole-body carbohydrate oxidation rates, lower HDL-cholesterol levels, delayed postprandial declines in salivary cortisol, and reduced postprandial peripheral microvascular endothelial function as assessed by reactive hyperemia. These unique characteristics were not explained by group differences in age, sex, or BMI. Taken together these results in clinically healthy subjects highlight distinct patterns of monocyte responsiveness to natural fluctuations in dietary fuel availability.