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Glycogen has been carefully isolated from rabbit brain tissue and found to be of significantly greater molecular size (up to approx. 100 MDa) and heterogeneity than previously reported. The incorporation of radioisotope from glucose, pyruvate or acetate precursor has been shown to be non-uniform, being similar to the metabolic inhomogeneity observed in other tissues. Physicochemical studies have shown the gross hydrodynamic structure of the glycogen to be inhomogeneous and to differ significantly from that of liver glycogen.

Because of the critical need for such data in the development of mathematical models, it is appropriate to begin this discussion by emphasizing the importance of working with specifically labeled precursors when attempting to chemically dissect the metabolic heterogeneity of brain tissue, especially for the operation of the Krebs tricarboxylic acid cycle. Most of the early work on brain metabolism—as well as on other organs—was done using uniformly labeled glucose. This is the most readily available precursor and it can be obtained at much higher specific activities than specifically labeled glucose, thus allowing maximum incorporation into the molecules of interest to the investigator. Geiger’s laboratory did some of the earliest studies of this type in brain (Barkulis et al., 1960; Allwis and Magnes, 1958). These investigators seemed to have been surprised at the slowness with which [14 C] -CO2 was produced and at the extent of labeling of those amino acids that are related to the tricarboxylic acid cycle, viz. glutamate and aspartate. After Schonheimer (1942) had established the dynamic state of body constituents, primarily using stable isotopes, this observation should not have been surprising. However, even today there seem to be investigators who are surprised by such results.

The incorporation of [2-3H]glycerol and lysolecithin labeled with [2-3H]glycerol into lecithin and its subspecies was investigated in epithelial and muscular layers of rat small intestine. The labeled compounds were administered in two wways: the intraduodenal injection and the injection into femoral vein. The incorporation of glycerol into lecithin was distinctly higher in epithelial layer than in muscular layer in both administration routes, but the incorporation of lysolecithin into lecithin showed no marked differences between both layers. Among lecithin species, dienoic and monoenoic species were highly labeled with the injection of labeled glycerol, and dienoic as well as tetraenoic specied were markedly labeled with the injecttion of labeled lysolecithin. Anyhow, no marked differences were found on the incorporation pattern of any labeled compounds into lecithin between both layers and between both administration routes.

Cell heterogeneity may be expressed in many ways such as variability in morphology, genetics, growth rate, cell cycle distribution, membrane antigen expression, clonogeni-city, metabolic and biochemical activity, and therapeutic sensitivity. Virtually all forms of functional heterogeneity must ultimately be expressed as some difference in biochemical, metabolic or physiological patterns of activity. Not surprisingly, this may be clinically significant since growth rate, for example, can influence drug sensitivity [1]. However, quantifying metaboUc heterogeneity in tumour cells, and assessing its significance in a dosimetric sense, requires the capability either to measure the relevant biochemical pathways in each cell or to find a suitable measurement from which differences may be inferred. Since the precise pattern of metabolic activity that determines sensitivity or resistance to cytotoxic therapy is largely unknown, and since biochemical techniques preclude measurements on individual cells, a flow cytometric approach is indicated.

In vertebrates proteochondroitin sulfates represent the main component of the ground substance of connective tissues. They participate in growth, aging and in many pathological changes. Up to this day many details of structure and biosynthesis of chondroitin sulfate proteins are still unknown. Difficulties arising during the investigation of this macromolecule are caused by its complexity as well as by its chemical and metabolic heterogeneity.

Cerebral ischemia causes metabolic alterations that vary greatly in different regions of the brain. Even in the most uniform of ischemic episodes, i.e., complete cessation of flow, metabolic changes are regionally inhomogeneous. Further, the patchy per­ fusion that characterizes incomplete ischemia ac­ centuates the metabolic heterogeneity. F inally, in focal ischemia, metabolic perturbations in the isch­ emic focus are qualitatively different from those in adjacent tissue. Therefore, it is imperative that bio­ chemical studies of cerebral ischemia employ methods with appropriate spatial resolution.

Mammalian arterial tissue is known to contain hyaluronate (HA), chondroitin 4(6)-sulfate (CS) dermatan sulfate (DS) heparan sulfate (HS) (Kaplan and Meyer, 1960; Antonopoulos et al., 1965; Dunstone, 1967; Nakamura et al., 1968; Buddecke and Kresse, 1960; Kresse and Buddecke, 1970) and their protein complexes respectively (Jacobs and Muir, 1963; Buddecke et al., 1963; Fransson and Havsmark, 1970) in a total amount of 1 – 2% of the dry weight of tissue.

Publisher Summary This chapter discusses the role of vesicle recycling in vesicular storage and release of acetylcholine (ACh) in Torpedo electroplaque synapses. Vesicle turnover and acetylcholine (ACh) metabolism have been compared in isolated blocks of Torpedo electric tissue under conditions selected to produce (a) maximum conservation of synaptic vesicle numbers and maximum metabolic heterogeneity (b) maximum depletion of synaptic vesicles and maximum metabolic homogeneity. The former involved: crossed circuit perfusion, stimulation at 1 Hz and a 3 h recovery period, the latter open circuit perfusion, and stimulation at 1 Hz and up to 20 h recovery. In experiments designed to create maximum vesicle heterogeneity with minimum depletion of vesicle numbers, blocks of electric tissue were perfused in a closed circuit and vesicles isolated essentially except that the stimulus frequency was 1 Hz instead of 0.1 Hz and blocks were allowed to recover for 3 h after stimulation before analysis or restimulation. In experiments designed to cause maximum vesicle depletion and thus, after recovery, minimum vesicle heterogeneity, blocks were perfused with a choline-free medium in open circuit; stimulation was again at 1 Hz. The results confirm the pattern of vesicle exocytosis and thus the morphology of the presynaptic terminal can be profoundly modified by the conditions of stimulation in a manner consistent with eventual recovery.

A 20-month-old boy presented with multiple fractures and respiratory failure. He was found to have vitamin D-dependent rickets. The rickets did not improve with phosphate, calcium and calciferol. The rickets healed, however, with large doses of l-alpha-hydroxycholecalci-ferol. The presentation is unusual and the response to therapy suggests metabolic heterogeneity in vitamin D-dependent rickets.

On sequential extraction of bovine corneas with 0.155 M NaCl and 1 M CaCl2 two macromolecular fractions were obtained in a ratio of 0.7–1.5, both containing glycosa-minoglycans and a hexosamine containing non-glycosaminoglycan subfraction.

Lung and liver slices were incubated with 2-3H-glycerol and U-14C-palmitate and the incorporation of radioactivities into various lipid classes and their subfractions with both precursors were examined. (1) The incorporation of both precursors into phosphatidic acid and diglyceride was much smaller in lung than in liver, but the incorporation into phosphatidylcholine and triglyceride was exactly the opposite. (2) The incorporation of 3H-glycerol into various subfractions was highest in the oligoenoic fraction both in phosphatidic acid and diglyceride, in dienoic subfraction in phosphatidylcholine, and in the polyenoic subfraction in phosphatidylethanolamine and phosphatidylinositol in both liver and lung. (3) The ratios of 14C/3H were higher in phosphatidylcholine than in phosphatidic acid and diglyceride, both in lung and liver. The highest ratio was found in the saturated species of phosphatidylcholine among these lipids in lung. (4) Some discussions were made concerning the formation pathways of dipalmitoyl species in lung.

Intratumoral genetic heterogeneity and the role of metabolic reprogramming in renal cell carcinoma have been extensively documented. However, the distribution of these metabolic changes within the tissue has not been explored. We report on the first-in-human in vivo non-invasive metabolic interrogation of renal cell carcinoma using hyperpolarized carbon-13 (13C) MRI and describe the validation of in vivo lactate metabolic heterogeneity against multi regional ex vivo mass spectrometry. hyperpolarized carbon-13 (13C)-MRI provides an in vivo assessment of metabolism and provides a novel opportunity to safely and non-invasively assess cancer heterogeneity.

Proton magnetic resonance spectroscopy (1H-MRS) delivers information about the non-invasive metabolic landscape of brain pathologies. 1H-MRS is used in clinical setting in addition to MRI for diagnostic, prognostic and treatment response assessments, but the use of this radiological tool is not entirely widespread. The importance of developing automated analysis tools for 1H-MRS lies in the possibility of a straightforward application and simplified interpretation of metabolic and genetic data that allow for incorporation into the daily practice of a broad audience. Here, we report a prospective clinical imaging trial (DRKS00019855) which aimed to develop a novel MR-spectroscopy-based algorithm for in-depth characterization of brain lesions and prediction of molecular traits. Dimensional reduction of metabolic profiles demonstrated distinct patterns throughout pathologies. We combined a deep autoencoder and multi-layer linear discriminant models for voxel-wise prediction of the molecular profile based on MRS imaging. Molecular subtypes were predicted by an overall accuracy of 91.2% using a classifier score. Our study indicates a first step into combining the metabolic and molecular traits of lesions for advancing the pre-operative diagnostic workup of brain tumors and improve personalized tumor treatment.

The ability of the liver to simultaneously carry out multiple functions is dependent on the metabolic heterogeneity of hepatocytes spatially located within a liver lobule spanning from the portal triad to the central vein. This complex zonal architecture of the liver, however, makes accurate in vitro modeling a challenge and often standard culture systems assume a homogenous model which may lead to inaccurate translatability of results. Here, we use a combination of mathematical modeling and experimental data to demonstrate a readily constructible in vitro flow system capable of liver zonation in primary rat hepatocytes. We show the differential expression of zonation markers, enhanced functionality when compared to standard static cultures and zone-specific metabolism and cell damage in the presence of paracetamol, a known zone-specific toxin. This type of advanced system provides a more in-depth and essential understanding of liver physiology and pathophysiology as well as the accurate evaluation of pharmacological interventions at a zone-specific level.

As our knowledge of cancer metabolism has increased, it has become apparent that cancer metabolic processes are extremely heterogeneous. The reasons behind this heterogeneity include genetic diversity, the existence of multiple and redundant metabolic pathways, altered microenvironmental conditions, and so on. As a result, methods in the clinic and beyond have been developed in order to image and study tumor metabolism in the in vivo and in vitro regimes. Both regimes provide unique advantages and challenges, and may be used to provide a picture of tumor metabolic heterogeneity that is spatially and temporally comprehensive. Taken together, these methods may hold the key to appropriate cancer diagnoses and treatments in the future.

THE problem of ageing of protein molecules has been considered by several authors. Kunkel1 in man, Ranney2 in the rabbit, have attempted to demonstrate the ageing of haemoglobin, taking advantage of the metabolic heterogeneity of haemoglobins described by us in 19503. They observe, indeed, during the life of the red cells, an equalization of the specific activities of haemoglobin fractions which were unequal initially. These authors were using iron-59, and it is known that iron is re-utilized after the death of the red cells : this prevents observation of an eventual crossing of the specific activity curves of different fractions in the course of the ageing of the red cells. Therefore they cannot decide between the two following hypotheses : (1) there are metabolic exchanges between the fractions, contrary to the theory of the metabolic inertness of haemoglobin ; (2) there is ageing of part of the haemoglobin, which during this process changes its electric charge and becomes concentrated in one of the fractions.

Molecular signatures have identified several subsets of diffuse large B cell lymphoma (DLBCL) and rational targets within the B cell receptor (BCR) signaling axis. The OxPhos-DLBCL subset, which harbors the signature of genes involved in mitochondrial metabolism, is insensitive to inhibition of BCR survival signaling but is functionally undefined. We show that, compared with BCR-DLBCLs, OxPhos-DLBCLs display enhanced mitochondrial energy transduction, greater incorporation of nutrient-derived carbons into the tricarboxylic acid cycle, and increased glutathione levels. Moreover, perturbation of the fatty acid oxidation program and glutathione synthesis proved selectively toxic to this tumor subset. Our analysis provides evidence for distinct metabolic fingerprints and associated survival mechanisms in DLBCL and may have therapeutic implications.

Although metabolic reprogramming is a hallmark of oncogenic transformation and growth of primary tumor cells, little is known about how metabolic alterations impact metastasis. In this issue of Cell Metabolism, Dupuy et al. (2015) show that primary breast cancer cells display metabolic heterogeneity, and that their distinct metabolic programs define their sites of metastasis.