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Scholarly Works (11 results)

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UC Berkeley Electronic Theses and Dissertations (2024)

Aging-related decrements in metabolic flexibility have been reported during supraphysiological conditions, but responses to physiological perturbations are less studied. The purpose of this research was to assess metabolic flexibility by determining changes in the rates of whole-body lipolysis, fatty acid (FA) oxidation, carbohydrate (CHO) oxidation, and FA reesterification in the postprandial period. Further, we sought to examine how lactate controls energy substrate partitioning in the postprandial period. After a 12-hr overnight fast, 15 young (21-35 yr; 7 men and 8 women) and 14 older (60-80 yr; 7 men and 7 women) participants had the forearm vein catheterized for primed, continuous infusion of [1,1,2,3,3-2H]glycerol. A contralateral warmed hand vein was catheterized for arterialized blood sampling. Indirect calorimetry was performed simultaneously to determine total FA and CHO oxidation rates (Rox). Total FA reesterification rates (Rs) were estimated from tracer-measured lipolytic and FA oxidation rates. After a 90-min equilibration period, participants underwent a 120-min, 75-g oral glucose tolerance test (OGTT).

In young participants, glycerol rate of appearance (Ra) (an index of lipolysis) decreased from baseline 5 min post-challenge (p = 0.03), remained steady until 15 min, decreased until 30 min (p < 0.001), and then continuously declined until the end of observation at 120 min (P < 0.001). In older participants, Ra decreased 30 min post-challenge (p = 0.002) and then remained low until 120 min (p ≤ 0.003). There were no differences in glycerol Ra between groups at any time (p ≥ 0.14). Blood lactate concentrations were inversely correlated with glycerol Ra in both groups, but the correlation was higher in older participants (r = -0.93 vs. r = -0.71).

At 60 min post-challenge, FA Rox decreased from baseline in both groups (p < 0.001), but FA Rox was higher in older participants (p = 0.04). In young participants, CHO Rox increased 5 min post-challenge (p = 0.02) and then remained elevated until 120 min (p ≤ 0.01). In older participants, CHO Rox increased 30 min post-challenge (p = 0.02) and then continuously rose until 120 min (p < 0.001). In both groups, FA Rs decreased between 5–30 min post-challenge (p ≤ 0.002) and then increased, but FA Rs was lower in older participants at 60 min (p = 0.02) and 90 min (p = 0.03). The AUC for FA Rox was greater than that for FA Rs in older (p = 0.008), but not young participants (p = 0.34). Blood lactate concentrations and lactate oxidation rates were inversely correlated with FA Rox in both groups, but the correlations were higher in older participants (r ≥ -0.83 vs. r ≤ 0.73).

In young participants, plasma insulin concentrations increased from baseline 5 min post-challenge (p = 0.01), continuously rose until 30 min (p = 0.001), and then remained elevated until 120 min (p < 0.001). In older participants, [Insulin] increased 15 min post-challenge (p < 0.001) and then remained elevated until 120 min (p < 0.001). Further, [Insulin] was higher in young participants at 5 min (p = 0.05) and 30 min (p = 0.01) post-challenge. Plasma [Insulin] was inversely correlated with glycerol Ra in both groups, but the correlation was higher in older participants (r = -0.98 vs. r = -0.78). Further, the correlations between [Lactate], [Insulin], glycerol Ra, and FA Rox were more significant in older participants (p ≤ 0.02 vs. p ≥ 0.04).

Our results indicate that metabolic flexibility to oral glucose consumption is delayed in “healthy” aging. Specifically, we report the following: (1) the suppression of lipolysis was delayed, (2) the fall in FA oxidation and rise in CHO oxidation rates were delayed; (3) the suppression of FA oxidation was attenuated such that FA oxidation was favored over CHO oxidation and FA reesterification, and (4) lactate is involved in the suppression of lipid metabolism in aging.

    Cover page: Metabolic Flexibility in the Postprandial Period is Attenuated in Healthy Aging
    • Article
    • Peer Reviewed
    UC Berkeley Previously Published Works (2024)
    Dietary glucose in excess is stored in the liver in the form of glycogen. As opposed to direct conversion of glucose into glycogen, the hypothesis of the postprandial lactate shuttle (PLS) proposes that dietary glucose uptake is metabolized to lactate in the gut, thereby being transferred to the liver for glycogen storage. In the present study, we provide evidence of a PLS in young healthy men and women. Overnight fasted participants underwent an oral glucose tolerance test, and arterialized lactate concentration and rate of appearance were determined. The concentration of lactate in the blood rose before the concentration of glucose, thus providing evidence of an enteric PLS. Secondary increments in the concentration of lactate in the blood and its rate of appearance coincided with those of glucose, which indicates the presence of a larger, secondary, systemic PLS phase driven by hepatic glucose release. The present study challenges the notion that lactate production is the result of hypoxia in skeletal muscles, because our work indicates that glycolysis proceeds to lactate in fully aerobic tissues and dietary carbohydrate is processed via lactate shuttling. Our study proposes that, in humans, lactate is a major vehicle for carbohydrate carbon distribution and metabolism.
      Cover page: Enteric and systemic postprandial lactate shuttle phases and dietary carbohydrate carbon flow in humans.
      • Article
      • Peer Reviewed
      UC Berkeley Previously Published Works (2022)
      Isotope tracer infusion studies employing lactate, glucose, glycerol, and fatty acid isotope tracers were central to the deduction and demonstration of the Lactate Shuttle at the whole-body level. In concert with the ability to perform tissue metabolite concentration measurements, as well as determinations of unidirectional and net metabolite exchanges by means of arterial-venous difference (a-v) and blood flow measurements across tissue beds including skeletal muscle, the heart and the brain, lactate shuttling within organs and tissues was made evident. From an extensive body of work on men and women, resting or exercising, before or after endurance training, at sea level or high altitude, we now know that Organ-Organ, Cell-Cell, and Intracellular Lactate Shuttles operate continuously. By means of lactate shuttling, fuel-energy substrates can be exchanged between producer (driver) cells, such as those in skeletal muscle, and consumer (recipient) cells, such as those in the brain, heart, muscle, liver and kidneys. Within tissues, lactate can be exchanged between white and red fibers within a muscle bed and between astrocytes and neurons in the brain. Within cells, lactate can be exchanged between the cytosol and mitochondria and between the cytosol and peroxisomes. Lactate shuttling between driver and recipient cells depends on concentration gradients created by the mitochondrial respiratory apparatus in recipient cells for oxidative disposal of lactate.
        Cover page: Tracing the lactate shuttle to the mitochondrial reticulum
        • Article
        • Peer Reviewed
        UC Berkeley Previously Published Works (2022)
        After a century, it's time to turn the page on understanding of lactate metabolism and appreciate that lactate shuttling is an important component of intermediary metabolism in vivo. Cell-cell and intracellular lactate shuttles fulfil purposes of energy substrate production and distribution, as well as cell signalling under fully aerobic conditions. Recognition of lactate shuttling came first in studies of physical exercise where the roles of driver (producer) and recipient (consumer) cells and tissues were obvious. Moreover, the presence of lactate shuttling as part of postprandial glucose disposal and satiety signalling has been recognized. Mitochondrial respiration creates the physiological sink for lactate disposal in vivo. Repeated lactate exposure from regular exercise results in adaptive processes such as mitochondrial biogenesis and other healthful circulatory and neurological characteristics such as improved physical work capacity, metabolic flexibility, learning, and memory. The importance of lactate and lactate shuttling in healthful living is further emphasized when lactate signalling and shuttling are dysregulated as occurs in particular illnesses and injuries. Like a phoenix, lactate has risen to major importance in 21st century biology.
          Cover page: Lactate in contemporary biology: a phoenix risen
          • Article
          • Peer Reviewed
          UC Berkeley Previously Published Works (2023)
          Brain injuries (BI) are highly disruptive, often having long lasting effects. Inadequate standard of care (SOC) energy support in the hospital leads to dietary energy deficiencies in BI patients. However, it is unclear how underfeeding (UF) affects protein synthesis post-BI. Therefore, in a rat model, we addressed the issue of UF on the protein fractional synthesis rate (fSR) post-BI. Compared to ad libitum (AL)-fed animals, we found that UF decreased protein synthesis in hind-limb skeletal muscle and cortical mitochondrial and structural proteins (p ≤ 0.05). BI significantly increased protein synthesis in the left and right cortices (p ≤ 0.05), but suppressed protein synthesis in the cerebellum (p ≤ 0.05) as compared to non-injured sham animals. Compared to underfeeding alone, UF in conjunction with BI (UF+BI) caused increased protein synthesis rates in mitochondrial, cytosolic, and whole-tissue proteins of the cortical brain regions. The increased rates of protein synthesis found in the UF+BI group were mitigated by AL feeding, demonstrating that caloric adequacy alleviates the effects of BI on protein dynamics in cortical and cerebellar brain regions. This research provides evidence that underfeeding has a negative impact on brain healing post-BI and that protein reserves in uninjured tissues are mobilized to support cortical tissue repair following BI.
            Cover page: Underfeeding Alters Brain Tissue Synthesis Rate in a Rat Brain Injury Model.
            • Article
            • Peer Reviewed
            UC Berkeley Previously Published Works (2022)
            The Lactate Shuttle hypothesis is supported by a variety of techniques including mass spectrometry analytics following infusion of carbon-labeled isotopic tracers. However, there has been controversy over whether lactate tracers measure lactate (L) or pyruvate (P) turnover. Here, we review the analytical errors, use of inappropriate tissue and animal models, failure to consider L and P pool sizes in modeling results, inappropriate tracer and blood sampling sites, and failure to anticipate roles of heart and lung parenchyma on L⇔P interactions. With support from magnetic resonance spectroscopy (MRS) and immunocytochemistry, we conclude that carbon-labeled lactate tracers can be used to quantitate lactate fluxes.
              Cover page: The blood lactate/pyruvate equilibrium affair
              • Article
              • Peer Reviewed
              UC Berkeley Previously Published Works (2023)
              No longer viewed as a metabolic waste product and cause of muscle fatigue, a contemporary view incorporates the roles of lactate in metabolism, sensing and signaling in normal as well as pathophysiological conditions. Lactate exists in millimolar concentrations in muscle, blood, and other tissues and can rise more than an order of magnitude as the result of increased production and clearance limitations. Lactate exerts its powerful driver-like influence by mass action, redox change, allosteric binding, and other mechanisms described in this article. Depending on the condition, such as during rest and exercise, following carbohydrate nutrition, injury, or pathology, lactate can serve as a myokine or exerkine with autocrine-, paracrine-, and endocrine-like functions that have important basic and translational implications. For instance, lactate signaling is: involved in reproductive biology, fueling the heart, muscle adaptation, and brain executive function, growth and development, and a treatment for inflammatory conditions. Lactate also works with many other mechanisms and factors in controlling cardiac output and pulmonary ventilation during exercise. Ironically, lactate can be disruptive of normal processes such as insulin secretion when insertion of lactate transporters into pancreatic β-cell membranes is not suppressed, and in carcinogenesis when factors that suppress carcinogenesis are inhibited, whereas factors that promote carcinogenesis are upregulated. Lactate signaling is important in areas of intermediary metabolism, redox biology, mitochondrial biogenesis, neurobiology, gut physiology, appetite regulation, nutrition, and overall health and vigor. The various roles of lactate as a myokine and exerkine are reviewed.NEW & NOTEWORTHY Lactate sensing and signaling is a relatively new and rapidly changing field. As a physiological signal lactate works both independently and in concert with other signals. Lactate operates via covalent binding and canonical signaling, redox change, and lactylation of DNA. Lactate can also serve as an element of feedback loops in cardiopulmonary regulation. From conception through aging lactate is not the only a myokine or exerkine, but it certainly deserves consideration as a physiological signal.
                Cover page: Lactate as a myokine and exerkine: drivers and signals of physiology and metabolism
                • Article
                • Peer Reviewed
                UC Berkeley Previously Published Works (2022)
                  Cover page: Lactate as a major myokine and exerkine
                  • Article
                  • Peer Reviewed
                  UC Berkeley Previously Published Works (2022)
                  Patients treated for traumatic brain injury (TBI) are in metabolic crises because of the trauma and underfeeding. We utilized fractional gluconeogenesis (fGNG) to assess nutritional adequacy in ad libitum-fed and calorically-restricted rats following TBI. Male Sprague-Dawley individually housed rats 49 days of age were randomly assigned into four groups: ad libitum (AL) fed control (AL-Con, sham), AL plus TBI (AL+TBI), caloric restriction (CR) control (CR-Con, sham), and CR plus TBI (CR+TBI). From days 1-7 animals were given AL access to food and water containing 6% deuterium oxide (D2O). On day 8, a pre-intervention blood sample was drawn from each animal, and TBI, sham injury, and CR protocols were initiated. On day 22, the animals were euthanized, and blood was collected to measure fGNG. Pre-intervention, there was no significant difference in fGNG among groups (p ≥ 0.05). There was a significant increase in fGNG due to caloric restriction, independent of TBI (p ≤ 0.05). In addition, fGNG may provide a real-time, personalized biomarker for assessing patient dietary caloric needs.
                    Cover page: Fractional Gluconeogenesis: A Biomarker of Dietary Energy Adequacy in a Rat Brain Injury Model
                    • Article
                    • Peer Reviewed
                    UC Berkeley Previously Published Works (2024)
                    Lactate, a product of glycolysis, is formed under aerobic conditions. Extensive work has shown lactate flux in young and exercising humans; however, the effect of age is not known. We tested the hypothesis that postprandial lactate shuttling (PLS) would be diminished in older adults. We used [3-13C]lactate and [6,6-2H]glucose tracers, an oral glucose tolerance test (OGTT), and arterialized blood sampling to determine postprandial lactate rates of appearance (Ra), disappearance (Rd), and oxidation (Rox) in 15 young (28.1 ± 1.4 yr) and 13 older (70.6 ± 2.4 yr) healthy men and women. In young participants, fasting blood [lactate] (≈0.5 mM) rose after the glucose challenge, peaked at 15 min, dipped to a nadir at 30 min, and rose again peaking at 60 min (≈1.0 mM). Initial responses in lactate Ra of older participants were delayed and diminished until 90 min rising by 0.83 mg·kg-1·min-1. Lactate Rox was higher throughout the entire trial in young participants by a difference of ∼0.5 mg·kg-1·min-1. Initial peaks in lactate Ra and concentration in all volunteers demonstrated the presence of an enteric PLS following an OGTT. Notably, in the systemic, but not enteric, PLS phase, lactate Ra correlated highly with glucose Rd (r2 = 0.92). Correspondence of second peaks in lactate Ra and concentration and glucose Rd shows dependence of lactate Ra on glucose Rd. Although results show both enteric and systemic PLS phases in young and older study cohorts, metabolic responses were delayed and diminished in healthy older individuals.NEW & NOTEWORTHY We used isotope tracers, an oral glucose tolerance test, and arterialized blood sampling to determine postprandial lactate flux rates in healthy young and older men and women. Lactate rates of appearance and oxidation and the lactate-pyruvate exchange were delayed and diminished in both enteric and systemic postprandial lactate shuttle phases in older participants.
                      Cover page: Delayed and diminished postprandial lactate shuttling in healthy older men and women
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