Studies of metabolic compartmentation and glucose transport using in vivo MRS

Abstract

Organs consist of several types of cells with specialized functions. This cellular localization of function is often referred to as compartmentation. Due to the intrinsic low sensitivity of MR methods it is generally not possible in vivo to obtain images or spectra of single cells. Instead the MRS signal is the sum of the signal from millions of cells and multiple cell types. A major challenge in using MRS to study biological processes such as metabolism and transport is to devise measurements that provide cell-specific information from this mix. Fortunately nature has helped the MR scientist by in several cases nearly completely localizing metabolic pathways and their associated metabolites in specific cell types. The chemical specificity of MRS allows the concentrations and synthesis rates of these metabolites to be measured, providing information about the compartmentation of metabolism and function. In this review examples are presented from MRS studies of metabolic trafficking between neurons and astrocytes in the brain, brain glucose transport, and the role of muscle glucose transport in insulin resistance and diabetes. The concepts and approaches used in these studies are generally applicable for studying cellular metabolic compartmentation in a wide range of systems.

Regulation of glial metabolism studied by 13C‐NMR

“…In particular, the label incorporation into specific carbon positions of a given metabolite provides important information about metabolic pathways and may reveal unexpected metabolic phenomena. 13 C-NMR investigations combined with systemically administered 13 C-labelled precursors in human and experimental animals 7,8,10,11,[44][45][46] have confirmed and extended the concept of metabolic compartmentation in the brain. However, various ambiguities remain as the intact brain consists of metabolically different brain regions and cell types.…”

“…In vivo, ex vivo and in vitro 13 C-NMR spectroscopy has been widely used to follow up the metabolism of glucose in human and animal brain as well as primary brain cell cultures. The most commonly used glucose isotopomers are [1][2][3][4][5][6][7][8][9][10][11][12][13] C 1 ]-, [2][3][4][5][6][7][8][9][10][11][12][13] C 1 ]-and [U- 13 C 6 ]glucose, which lead to differently labelled metabolic isotopomers, such as pyruvate and TCA cycle intermediates, depending on the enzymatic pathways involved (Table 1).…”

“…After the first turn, -ketoglutarate is monolabelled at C-4. During the second PDH turn, [4][5][6][7][8][9][10][11][12][13] C 1 ]-ketoglutarate is transformed into C-3 or alternatively C-2 labelled (dashed squares) oxaloacetate passing the symmetrical succinate. Note, the same labelling pattern in oxaloacetate is seen through PC-mediated entry of pyruvate into the TCA cycle.…”

“…In the course of the first PC turn, the labels reach C-2 or C-3 in -ketoglutarate, which is subsequently scrambled in fumarate between 1 or 4 as well as 2 or 3, leading to -ketoglutarate labelled at C-1 or again at C-2 and C-3 during the second TCA cycle turn via PC (Table 1). In the oxidative pathway, pyruvate enters the TCA cycle as [2][3][4][5][6][7][8][9][10][11][12][13] C 1 ]acetyl-CoA via PDH (closed squares). After the first turn, -ketoglutarate is monolabelled at C-4.…”

“…However, the brain contains metabolically different compartments [5][6][7][8][9][10][11] with at least two kinetically different TCA cycles, i.e. neuronal and glial compartments, which are connected by the exchange of metabolites.…”