Characteristic of FFARs.
\r\n\tThe major pathogenetic mechanisms resulting from RAAS overactivity include activation of the sympathetic nervous system, endothelial dysfunction, proinflammatory, and procoagulant states.
\r\n\tEmerging from basic science evidence, major clinical trials established the beneficial effects of inhibitors of the different components of RAAS such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), aldosterone antagonists. These effects range from treatment of hypertension, diabetic nephropathy, CHF, as well as improvement of outcomes after myocardial infarction and improvement in glucose homeostasis and prevention of type 2 diabetes with some agents.
\r\n\tIn this book, written by a world-renowned scholar, we will address the major concepts and topics related to RAAS activation including the pathogenetic mechanisms underlying the deleterious effects of activated RAAS and the role of local tissue RAAS in various organ systems such as the heart and vasculature, the skeletal muscle, adipose tissues, pancreas and the angiotensinergic pathways in the brain. Cutting-edge information is provided that will address the need for a wide range of readers including a medical student, clinical practitioner, and basic science investigators alike. This book will be bridging the gap between basic science and clinical practice regarding the RAAS system, which is imminently critical and highly relevant to the practice of medicine.
\r\n\r\n\tFinally, with data emerging from the COVID-19 pandemic indicating overrepresentation of people with diseases associated with RAAS activation such as hypertension, chronic kidney disease, and diabetes, the role of RAAS activation and RAAS inhibition in the pathogenesis and clinical outcomes in COVID-19 has garnered a great deal of interest. In this book, we will dedicate a chapter addressing this topical and highly critical subject.
\r\n\t
Obesity-driven type II diabetes mellitus has become a major crisis in modern societies. In the United States, over 80% of type II diabetic patients are obese [1]. In the case of Chinese adult diabetic patients, diabetes is also significantly associated with obesity [2]. Previous investigations have focused on looking for obesity-related factors that cause insulin resistance, the failure of the body to respond to insulin, which is the hallmark of type II diabetes. The abnormal plasma fatty acid metabolism associated with diabetes mellitus [3], and the high level of obesity-related plasma free fatty acids (FFAs, also known as non-esterified fatty acids, NEFA) have been identified since the 1950s as major risk factors for insulin resistance.
Natural fatty acids are carboxylic acids with saturated or unsaturated aliphatic tails which have an even number of carbon atoms from 4 to 28. When they are not incorporated into other compounds, like triglyceride or phospholipids, they are known as "free" fatty acids. When metabolized, fatty acids yield a large quantity of ATP, and thus represent an important fuel for the body, particularly for heart and skeletal muscle. They are not only essential dietary nutrients, but also function in many cellular events by activating nuclear receptors, such as the peroxisome proliferator-activated receptors (PPARs), and fatty acid binding proteins (FABPs).
How FFAs induce insulin resistance is not a novel topic in pathological studies on obesity-associated type II diabetes. Many efforts have been made to uncover the underlying molecular mechanisms, but they remain elusive. It seems that FFA-induced insulin resistance occurs not via a single pathway but rather via a complicated network of pathways in organs, tissues, and cells.
Major investigatons of the mechanisms of extra FFA-induced insulin resistance have focused on the chronic effects of FFAs. However, plasma FFA concentrations are not consistent and vary widely from hour to hour, displaying waves according to nutritional state and the presence of regulators including hormones (Figure 1). The normal level of postprandial plasma FFAs is about 0.1- 0.4 mmol/L, while in obese individuals this value can reach to 0.2 - 0.6 mmol/L [4]. In healthy people the level of plasma FFAs decreases during the 2 h after a meal until it drops to nearly 0.1 mmol/L, and then rises to a concentration of about 0.3-0.4 mmol/L before the next meal. Such plasma FFA fluctuations also occur in people with metabolic disorders, but display a different pattern. In mild essential hypertensive patients, the plasma FFA concentrations at 3 and 4 h after a meal are significantly higher than that in healthy people (Figure 1, lower panel) [5]. The response of the body to acute variation in plasma FFA concentration is probably associated with the energy balance of the whole body, and requires further investigation to obtain a more in-depth understanding of the pathology of obesity-related metabolic diseases.
Variation in free fatty acids (●) and insulin (○) concentrations in response to meals in healthy people (upper panel, reprinted from Frayn KN, 1998) [6] and fatty acid levels in mild essential hypertensive patients (---) and normotensive control subjects (——) (lower panel, reprinted from Singer P et al. 1985) [5].
Previous works have reported that FFAs are able to acutely induce several cellular events in various tissues. For example, FFAs can stimulate insulin secretion in pancreatic β-cells [7, 8], leptin secretion in adipocytes [9], and glucose uptake in adipocytes and skeletal muscle cells [10, 11]. All these happen within a short interval after FFA treatment, implying that the FFAs may work as signaling molecules such as hormones, to trigger signal transduction and subsequent physiological events.
During signal transduction, many intracellular signaling proteins work as molecular switches and are activated by GTP binding or phosphorylation. That FFAs acutely stimulate protein phosphorylation suggests that FFAs are able to evoke signal transduction. One study reports that arachidonic acid is able to stimulate the phosphorylation of tyrosine-containing proteins in cultured vascular endothelial and smooth muscle cells [12]; arachidonic acid-induced phosphorylation was rapid and transient, reaching a peak 0.5 min after the addition of arachidonic acid and returning to baseline by 8 min. When cyclooxygenase, lipoxygenase, and epoxygenase pathways were inhibited, phosphorylation was still detected, suggesting it was fatty acid, not its metabolites that triggered the phosphorylation. In addition, increased protein tyrosine phosphorylation was also observed after treatment with oleic, linolenic and γ-linoleic acid. In another work it was reported that unsaturated fatty acids are able to stimulate protein phosphorylation by activating protein kinase C in intact hippocampal slices [13]. Oleic acid stimulated phosphorylation of several proteins of molecular weights 92,000, 58,000, 50,000, 47,000 and 44,000 Da. The 44,000 and 47,000 Da proteins were particularly sensitive to fatty acids and were phosphorylated in a dose- and time-dependent manner. Increased 32P incorporation into the 44,000 Da protein was apparent after 1 min and reached a maximum at 5 min. Phosphorylation of the 47,000 Da protein followed a similar pattern. Studies on fatty acid-stimulated protein phosphorylation have shed light on the role of fatty acids as signal molecules.
During the last decade, a series of free fatty acid receptors (FFARs) has been identified, indicating that like other extracellular signal molecules, FFAs bind to their receptors on the plasma membrane to trigger signal transduction. The FFARs identified belong to a large protein family, the G protein-coupled receptors (GPCRs), which are integral membrane proteins with seven trans-membrane domains. The extracellular parts of the receptors sense external signals and activate heterotrimeric G proteins to transduce signals to downstream molecules. GPCRs are activated by various types of ligands, including ions, nucleotides, amino acids, lipids, peptides, and proteins. It is estimated that more than half of modern drugs target these receptors [14]. The known FFARs include FFAR1 (GPR40), FFAR2 (GPR43), FFAR3 (GPR41), GPR84, GPR119 and GPR120 (Table 1).
Protein | Tissue Expression | Ligand | Function | Synthetic Agonist | G protein-coupling |
GPR 40 (FFAR1) | Pancreatic β -cell [15, 16], intestinal tract [17], muscle[16], brain, monocytes [18] | Medium- and long- C8-C22 [18, 15] | Insulin secretion [15]; incretin secretion [17] | Thiazolidinedione [16], GW9508, MEDICA16 [18] | Gq/11, Gi [15, 16] |
GPR 41 (FFAR3) | Adipose tissue [9], sympathetic ganglia [19], enteroendocrine cells [20] | Short C2-C4 [9] | Leptin secretion [9]; PYY secretion [20] | / | Gi/o [19, 21] |
GPR 43 (FFAR2) | Leukocyte, spleen, bone marrow, adipose tissue [22] | Short C2-C4 [21] | 5-HT secretion; PYY secretion [23]; inhibition of lipolysis [24] | / | Gq/11, Gi/o [21] |
GPR 84 | Immune cell, bone marrow, leukocyte, lung, lymph node, spleen [25, 26] | Medium C9-14C [26] | Amplify IL-12 p40 [27] | / | Gi/o [26] |
GPR 119 | Brain, gastrointestinal tract, pancreas [28] | Ethanolamide [28], Lysophosphatidyl choline [29] | Insulin secretion [29]; food intake; body weight [28] | PSN632408, PSN37569 [30], AR23145 [31] | Gs [29] |
GPR 120 | Intestinal tract, Macrophage, lung, adipose tissue [32, 33] | Medium- and long- C10-C22 [32] | GLP-1 secretion [32] | NCG21 [34], GW9508 [35] | Gq/11 [32] |
Characteristic of FFARs.
It has been reported that GPR40 is activated by medium- and long-chain FFAs [18, 15, 16]. GPR40 is abundantly expressed in the pancreas, and is especially enriched in pancreatic β-cells. When activated by FFAs, GPR40 activates G-protein, which transduces the signal leading to stimulation of insulin secretion. Using Chinese hamster ovary (CHO) cells in which GPR40 is stably expressed, Itoh et al. found that free fatty acids are able to stimulate the formation of inositol 1,4,5-trisphosphate, intracellular Ca2+ mobilization, and the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 [15]. Furthermore, in 2006 Feng et al. reported that fatty acids, especially linoleic acid, are able to stimulate insulin secretion in rat β-cells by reducing the voltage-gated K+ current via GPR40 and the cAMP-protein kinase A system [36].
Unlike GPR40, the physiological ligands of GPR41 and GPR43 are short chain fatty acids (SCFAs), including acetate (C2), propionate (C3), butyrate (C4), and valerate (C5). SCFAs are generated by bacterial fermentation of undigested carbohydrates from ingested dietary fiber in the gut. Subsequently SCFAs are released in the bloodstream and accumulate to micromolar concentrations.
GPR41 is expressed abundantly in adipose tissue, enteroendocrine cells, and sympathetic ganglia. SCFAs activate GPR41 and stimulate leptin expression in mouse adipocytes and mouse primary-cultured adipocytes. Acute oral administration of propionate increases circulating leptin levels in mice [9]. Overexpression of exogenous GPR41 and knockdown of GPR41 by RNAi regulates leptin production positively and negatively. Given that leptin is a potent anorexigenic hormone that reduces food intake, propionate may inhibit food intake by increasing leptin release. The analysis of GPR41-deficient mice showed that GPR41 is expressed in enteroendocrine cells, and GPR41 deficiency is associated with reduced expression of PYY [20]. GPR41 is also abundantly expressed in sympathetic ganglia in mice and humans [19]. Studies using GPR41-/- mice and co-culturing of fetal-isolated cardiomyocytes with primary-cultured sympathetic neurons have shown that propionate promotes sympathetic outflow via GPR41, reduces intracellular cAMP concentrations and promotes ERK1/2 phosphorylation, phenomena which were not observed in sympathetic neurons from GPR41−/− mice. GPR41-mediated rise in beat rate was effectively blocked by Gallein (Gβγ blocker) and pertussis toxin (PTX) treatments, whereas NF023 (Gα(i/o) blocker) had no inhibitory effects. Knockdown of PLCβ 2/3 or ERK1/2 by RNAi significantly inhibits the propionate-induced rise in the beat rate of cardiomyocytes. These results indicate that GPR41 activation of sympathetic neurons may involve Gβγ, PLCβ, and MAPK.
GPR43 is highly expressed in immune cells, spleen, and bone marrow, and is also detected at low levels in the placenta, lung, liver, and adipose tissues [22]. A study on adipocytes showed that acetate and propionate can reduce lipolytic activity and thus plasma FFA level in a mouse in vivo model. This inhibition of lipolysis is abolished in adipocytes isolated from GPR43 knockout animals [24]. Similar to GPR41, GPR43 activation is also coupled to intracellular Ca2+ release, ERK1/2 activation, and a reduction in cAMP accumulation. Unlike GPR41, however, which signals via the Gi/o family, GPR43 signals via both the Gi/o and Gq pathways [21].
GPR84 mRNA is expressed mainly in bone marrow, leukocytes, the spleen and lung [25, 26]. GPR84 functions as a receptor for medium-chain FFAs with carbon chain lengths of 9–14. Capric acid (C10:0), undecanoic acid (C11:0), and lauric acid (C12:0) are the most potent agonists of GPR84. A functional study conducted in GPR84-/- mice revealed that primary stimulation of T cells with anti-CD3 results in increased IL-4, but not IL-2 or IFN-γ production, compared to wild-type mice [27]. Wang et al. reported that medium-chain FFAs act through GPR84 to amplify the stimulation of IL-12 p40 production by lipopolysaccharides in monocytes/macrophages [26]. Medium-chain FFAs induce Ca2+ mobilization and inhibit cAMP production. The activation of GPR84 by medium-chain FFAs is primarily coupled to a PTX-sensitive Gi/o pathway [26].
GPR119 in humans and rodents is expressed predominantly in the pancreas and gastrointestinal tract and also in the rodent brain [28]. The lipid signaling agent oleoylethanolamide (OEA) is an endogenous ligand of GPR119. OEA is a peripherally acting agent that reduces food intake and body weight gain in rat feeding models, suggesting that GPR119 might mediate the OEA-induced reduction of food intake [28]. Lysophosphatidyl choline (LPC) is another bioactive lipid mediator that activates GPR119 to stimulate insulin release from pancreatic islets, via Gs activation which leads to cAMP production [29].
GPR120 is highly expressed in the human and mouse intestinal tract, as well as in adipocytes, taste buds, and lungs [32, 33]. GRP120 activation by saturated FFAs with a carbon chain length of 14–18, and by unsaturated FFAs with a chain length of 16–22 has been detected [32]. Activated by medium- and long- chain fatty acids, GPR120 increases insulin secretion indirectly by stimulating the secretion of glucagon-like peptide-1 (GLP-1), the most potent insulinotropic incretin, which is coupled to the elevation of Ca2+ and activation of the ERK cascade [32]. In addition, GPR120 is also reported to function as an ω-3 FA receptor in proinflammatory macrophages and mature adipocytes that mediates the potent anti-inflammatory effects of DHA and EPA by inhibiting both the TLR and TNF- inflammatory signaling pathways [37]. Chronic tissue inflammation is another important mechanism causing insulin resistance, so the effect of GPR120 on insulin sensitivity as well as on the stimulation of insulin-secretion will make it an attractive drug target for diabetes-therapeutic agents.
The discovery of FFARs developed our understanding of the role of FFAs as signal molecules. Cells expressing FFARs, such as pancreatic β-cells, adipocytes, and macrophages sense FFAs and make various corresponding responses to control metabolic homeostasis (Figure 2). FFARs have thus attracted considerable attention due to their potential as valuable drug targets.
Roles of GPR40 and GPR120 in nutritional regulation. Free fatty acid receptors control metabolism through promoting the secretion or production of peptide hormones (Reprinted from Hara et al., 2011) [38].
In addition to the functions described above, FFAs are also able to acutely stimulate glucose uptake in adipocytes and skeletal muscle cells, which is directly associated with metabolic homeostasis. A few reports indicate that fatty acids have acute effects on glucose uptake, but conclusions have been inconsistent and the underlying molecular mechanisms controlling these responses are still elusive. For example, alpha-lipoic acid has been shown to enhance basal glucose uptake both in normal and ob/ob mice [10], while palmitic acid (PA) treatment was reported to inhibit insulin-stimulated but not basal glucose uptake [11].
Although both adipocytes and skeletal muscle cells are able to ingest glucose by stimulation of FFAs, skeletal muscle consumes more than 70% of the plasma glucose, suggesting that whole body plasma glucose concentration is tightly associated to the sensitivity of muscle tissue to insulin [39, 40]. We therefore focused on the molecular mechanism of fatty acid-induced glucose uptake in skeletal muscle cells [41].
A rat skeletal muscle cell line L6 with stable expression of myc-tagged GLUT4 (L6) was used to study the acute effects of fatty acids. When L6 cells were treated with palmitic acid (PA), the most abundant free fatty acid in the blood, glucose uptake increased rapidly in a time-dependent manner, beginning from 5 min, and reaching a peak at 20 min (Figure 3, lower panel). By incubating intact PA-treated L6-GLUT4myc cells with myc antibody to detect plasma membrane-located GLUT4, we found that PA stimulates GLUT4 translocation from the cytosol to the plasma membrane (Figure 3, upper panel). The stimulatory effects of PA on glucose uptake and GLUT4 translocation are similar to those of insulin.
Fluorescence imaging shows GLUT4 translocation to the cell surface after L6-GLUT4myc (L6) cells are treated with (upper right panel) or without (upper left panel) PA or insulin (upper middle panel). The lower panel shows that glucose uptake increases in a time-dependent manner when L6 cells are treated with PA.
Akt plays an important role in insulin-stimulated GLUT4 translocation and glucose uptake. Akt, also known as protein kinase B (PKB), is a serine/threonine-specific protein kinase. Akt possesses a protein domain known as the PH domain, which binds to phosphoinositides. Binding to PIP3, and phosphorylated from PIP2 by PI3 Kinase (PI3K) via its PH domain, Akt can be phosphorylated by phosphoinositide dependent kinase 1 (PDK1) at threonine 308 and/or the mammalian target of rapamycin complex 2 (mTORC2) at serine 473. In the insulin signaling pathway, the insulin receptor (IR) is activated and tyrosine is phosphorylated after binding to insulin, subsequently activating hte IRS-1/PI3K/PDK/Akt cascade, and finally increasing the level of GLUT4 in the plasma membrane (Figure 4).
Palmitate stimulates GLUT4 translocation and glucose uptake [41].
Insulin signaling pathway for glucose uptake stimulation (Reprinted from Frøsig and Richter, 2009) [42].
In our study, PA stimulated Akt phosphorylation at serine 473 in a time- and dose-dependent manner (Figure 5). During PA treatment, Akt phosphorylation was detected after 10 min, peaked at 45 min, then decreased dramatically after 1 h, and became nondetectable after 3 h. When treated with different concentrations of PA, Akt phosphorylation increased with PA concentration, beginning from 0.2 mM. Such time- and dose-dependent responses to PA treatment in cells match the characteristics of signal transduction, and so it is possible that a signal transduction cascade initiated by PA leads to the activation of Akt. To further verify the stimulatory effect of PA on Akt activation, we treated rat skeletal muscle tissue with PA. Rats were anesthetized and perfused with 2 mM PA. Skeletal muscle strips were collected and then incubated in vitro with PA. Similar to the results from cells, Akt phosphorylation also increased in PA-treated skeletal muscle tissue, suggesting that this acute response of PA may be physiologically relevant.
Palmitate acutely stimulates AMPK and Akt phosphorylation in a time- and dose-dependent manner [41].
To investigate the putative PA-mediated signaling pathway, we tested the activity of other molecules and found that AMP-activated protein kinase (AMPK) and extracellular signal-related kinase (ERK1/2) can also be activated by acute PA treatment. AMPK is a heterotrimeric complex composed of a catalytic α subunit and regulatory β and γ subunits, which together make a functional enzyme that plays a role in cellular energy homeostasis [43]. AMPK is activated by an elevated AMP/ATP ratio and undergoes a conformational change of its γ subunit to expose the active site (Thr172) on the catalytic subunit α that is phosphorylated by the upstream kinase AMPK kinase (AMPKK) [44]. Upon activation, AMPK decreases energy consumption by inhibiting fatty acid and protein synthesis and enhances energy production by stimulating fatty acid oxidation and glucose transport to increase cellular energy levels. While it is known that AMPKα is phosphorylated at Thr258 and Ser485, its upstream kinases still need further study [45]. ERK1/2 belongs to the mitogen-activated protein kinase (MAPK) family, a widely conserved family of serine/threonine protein kinases. The ERK1/2 (p44/42 MAPK) signaling pathway responds to various extracellular stimuli including mitogens, growth factors, and cytokines [46]. Upon activation by MEK1 and MEK2 by phosphorylation of its Thr202 and Tyr204 residues, respectively, ERK1/2 phosphorylates downstream targets, forming a signal cascade.
Similar to Akt, AMPK in L6 cells is also activated acutely by PA. AMPK phosphorylation (Thr172) starts as early as 5 min after PA treatment and reaches a peak at 20 min. After 1 h, the signal cannot be detected (Figure 5, upper panel). In addition, PA-induced phosphorylation of AMPK is also dose-dependent. Unlike Akt and AMPK, ERK1/2 is phosphorylated for a shorter duration, increasing after 5 min and returning to basal level after 15 min (Figure 6).
Palmitate acutely stimulates ERK1/2 phosphorylation in a time-dependent manner [41].
To test if Akt, AMPK, and ERK1/2 are involved in PA-stimulated glucose uptake, tools such as inhibitors, dominant negative constructs, and short interference RNA (siRNA) were used to inhibit their protein activity or expression levels. Western blotting and glucose uptake assay results showed that all of these proteins participate in signal transduction.
We applied API-2, an Akt selective inhibitor, to block Akt activity. As a result, API-2 abolished Akt phosphorylation as well as significantly decreasing PA-induced glucose uptake (Figure 7, left panel). In addition, siRNA duplexes were nucleofected into L6 cells; compared to the negative control (N.C.), total Akt expression level was efficiently down-regulated. Glucose uptake assays showed that PA-induced glucose uptake decreased when Akt expression decreased due to RNAi (Figure 7, right panel). Together, these data suggest that PA induces glucose uptake in skeletal muscle cells via Akt activation.
To study the role of AMPK in PA-induced glucose uptake, we used AMPK inhibitor Compound C, an myc-tagged AMPK dominant negative (AMPK-DN) plasmid, and siRNA targeting AMPK catalytic subunits α1 and α2. Since AMPK and Akt activation was observed sequentially in PA-treated cells, we also examined the relationship between AMPK and Akt. AMPK inhibitor Compound C suppressed AMPK activity and decreased PA-induced Akt phosphorylation and glucose uptake (Figure 8, left panel). Similar results were obtained when AMPK-DN was nucleofected into L6 cells. Furthermore, an siRNA duplex mixture targeting AMPK α decreases PA-stimulated Akt phosphorylation in L6 cells (Figure 8, right panel), consistent with the inhibitor and AMPK-DN experiments.
In contrast, when AMPK agonist AICAR was used to stimulate AMPK phosphorylation, Akt was also stimulated rapidly in a time-dependent manner (Figure 9), suggesting that it is possible to stimulate Akt via AMPK activation in L6 cells. These data suggest that PA-stimulated AMPK phosphorylation may contribute to regulating Akt activity and is involved in PA-induced glucose uptake.
PA-induced glucose uptake is decreased when Akt activity is blocked by an Akt inhibitor (left panel) or RNAi (right panel) [41].
PA-induced glucose uptake and Akt phosphorylation is decreased when AMPK activity is reduced by an AMPK inhibitor (left panel) or AMPK dominant-negative construct (right panel) [41].
AMPK agonist AICAR stimulates Akt phosphorylation in a time-dependent manner [41].
The role of ERK1/2 in PA-stimulated signal transduction was examined by using the MEK1/2 inhibitors PD98056 and U0126. While both inhibitors decreased basal and PA-induced ERK1/2 phosphorylation, U0126 was more potent (Figure 10, upper left). When ERK1/2 activity was inhibited by U0126, PA-induced glucose uptake was reduced significantly (Figure 10, upper right). These data suggest that PA-stimulated ERK1/2 phosphorylation may contribute to PA-induced glucose uptake. To determine the relationship between ERK1/2 and the AMPK/Akt pathway, AMPK α1/α2 siRNA transfected cells were used to test ERK1/2 activity; ERK1/2 phosphorylation increased at the same rate as in N.C. cells after PA treatment (Figure 10, lower left). In addition, the Akt inhibitor API-2 did not affect PA-induced ERK1/2 phosphorylation, and MEK1/2 inhibitors PD98056 and U0126 did not affect PA-induced Akt phosphorylation (Figure 10, lower right). These data suggest that ERK1/2 contributes to PA-stimulated signal transduction independently from the AMPK/Akt pathway, consistent with the partial decrease in PA-induced glucose uptake by inhibition of either Akt, AMPK, or ERK1/2.
MEK1/2 inhibitors decrease PA-induced ERK1/2 phosphorylation and glucose uptake, but do not affect Akt activity; AMPK and Akt activity inhibition does not affect ERK1/2, while PI3K inhibitor does [41].
Having shown that the two pathways work independently in PA-induced glucose uptake in L6 cells, we investigated signaling molecules upstream of the intersection. When we used PI3 Kinase (PI3K) -specific inhibitor LY294002 to treat L6 cells, PA-induced glucose uptake was totally abolished (Figure 11, upper panel), suggesting that PI3K may control these two pathways. Indeed, LY294002 could abolish PA-stimulated AMPK, Akt, and ERK1/2 phosphorylation (Figure 10, lower right and Figure 11, lower panel). Results from the above experiments indicate that, in skeletal muscle cell lines and tissues, acute PA-stimulated glucose uptake occurs via activation of the PI3K/AMPK/Akt and PI3K/ERK1/2 pathways leading to GLUT4 translocation (Figure 12).
PI3K-specific inhibition abolishes PA-induced glucose uptake and phosphorylation of Akt and AMPK [41].
Schematic diagram of PA-induced signal pathway stimulation of acute glucose uptake in skeletal muscle cells [41].
As shown in Figure 12, how PA activates PI3K is still unknown. According to our current understanding of signal transduction, we speculate that PA may bind to a protein on the cell plasma membrane to trigger signal transduction. We performed fatty acid binding assays to test this hypothesis.
L6 cells were incubated with PA at low temperature (4°C) to facilitate PA binding to the cell surface while preventing its internalization, then washed with buffer to remove unbound PA, or with BSA solution to remove not only unbound but also some membrane-bound PA by competitive binding, Cells were then transferred to 37°C to recover cellular activity. The amount of PA which binds to the cell surface was measured by adding trace amounts of 3H-labeled PA to the solution. Results showed that after washing, with either buffer or BSA solution, very little PA remained (Figure 13, upper panel). When these cells were transferred to 37°C, Western blot results showed that Akt phosphorylation took place at a similar level to that in cells kept at 37°C, and increased in a time-dependent manner in buffer-washed cells, while p-Akt was not detectable in BSA solution-washed cells (Figure 13, lower panel). These results suggest that the amount of cell surface-bound PA was sufficient to activate Akt; intracellular PA accumulation was not required. Moreover, based on lipid analysis by TLC, fatty acids were the main component of total lipids during cell treatment with fatty acid and the 10 min incubation at 37°C. These results indicate that it is fatty acids rather than their metabolites that trigger signal transduction.
Cell plasma-bound PA stimulates Akt phosphorylation [41].
Could the postulated cell membrane protein which binds to FFAs and triggers signal transduction to stimulate glucose uptake in skeletal muscle cells be a G-protein coupled receptor? FFA binding assays suggest that PA initiates signal transduction via a protein(s) on the cell surface, and meanwhile in the FFA-stimulated signal cascade ERK1/2 pathways were involved, which also appeared in some known FFAR signal pathways. Therefore, a GPCR on the plasma membrane of skeletal muscle cells may be the FFA receptor we have postulated.
PA is a long-chain fatty acid with 16 carbons. We tested other long-chain fatty acids such as C18:1 (oleic acid), C18:2 (Linoleic acid), and C18:0 (Stearic acid) in addition to PA to examine their effects of stimulating AMPK and Akt phosphorylation. All of these fatty acids activated AMPK and Akt in a time- and dose-dependent manner. It is thus likely that our postulated FFAR may function using long-chain FFAs as its ligands.
The known long-chain FFARs include GPR40 and GPR120, both of which are related to insulin secretion. Oh et al. found that GPR120 agonists DHA and GW9508 enhance glucose uptake by activating the PI3K-Akt pathway and GLUT4 translocation in 3T3-L1 adipocytes. The stimulatory effect of DHA and GW9508 was blocked when GPR120 or Gαq/11 was depleted by siRNA knockdown [37], indicating that FFAs stimulate glucose uptake in adipocytes via the FFA receptor GPR120. However, neither GPR120 nor GPR40 is expressed in muscles. In the Oh et al. study, DHA and GW9508 did not enhance glucose uptake in L6 skeletal muscle cells. We therefore conclude that known long-chain FFARs GPR40 and GPR120 are not our postulated FFA receptor. In 2005, Gaël Jean-Baptiste et al. described the GPCRs expressed in skeletal muscle tissue, but none of them are FFA receptors [47]. Our postulated receptor might therefore be a novel FFAR whose function is to stimulate glucose uptake in skeletal muscle tissue. Like GPR40 and GPR120, our postulated FFAR is also related to metabolic homeostasis, and so it is likely to be a potential drug target for the treatment of diabetes. Identification of this FFAR is one of our goals.
Another significant implication of our results is that PA plays two opposing roles in skeletal muscle. Under chronic treatment it inhibits insulin-stimulated glucose uptake by blocking Akt phosphorylation, while it enhances glucose uptake by activating Akt when cells are exposed to PA for a short time. What is the relationship between the long-term and short-term effects of FFAs on glucose uptake? Our results show that phosphorylation of Akt is only stimulated when the concentration of PA reached a certain level (at or above 0.2 mmol/L in C2C12 cells). We thus conclude that phosphorylation of Akt may require high concentrations of fatty acids under physiological situations. Akt phosphorylation is not detectable 3 h after fatty acid treatment (Figure 5, upper panel). In addition, when fatty acids are withdrawn, the Akt phosphorylation signal disappears after 3 h in C2C12 cells (data not shown), suggesting that fatty acid-induced phosphorylation and dephosphorylation of Akt can be completed within one cycle of a postprandial FFA wave. It is therefore possible that Akt phosphorylation and dephosphorylation occur again and again as the concentration of FFA increases and decreases. Plasma FFA concentration starts to rise from 2 h after a meal (Figure 1) and continues to rise until the next meal due to the release of FFA from adipocytes during fasting. Based on our findings, when increasing plasma FFA reaches a certain level it stimulates Akt phosphorylation and glucose uptake. In obesity patients, elevated plasma FFA probably reaches the FFA level triggering Akt phosphorylation earlier during a plasma FFA wave, leading to abnormal glucose uptake. Many abnormal fatty acid cycles may contribute to the development of insulin resistance by disturbing glucose homeostasis. This Yin-Yang balance of PA in skeletal muscle is likely to be physiologically significant, and the possibility of its involvement in the development of insulin resistance needs to be investigated further.
Free fatty acids (FFAs) function as signal molecules by activating their receptors in the cell plasma membrane to evoke signal transduction by a series of protein phosphorylation events, eventually leading to physiological events. Some of the known cell responses to FFAs are directly or indirectly related to metabolic homeostasis, so the study of FFA-triggered signal transduction will help us to understand the development of metabolic disorders and to design strategies for therapy. FFA receptors have become attractive drug targets for metabolic diseases. We have investigated the mechanism of long-chain fatty acid palmitate-induced glucose uptake in skeletal muscle cells and found that the two independent PI3K/AMPK/Akt and PI3K/ERK1/2 pathways are responsible for this process. Our results also provide supporting evidence that palmitate triggers signal transduction via a cell surface protein(s) that is probably a novel FFA receptor whose identity still remains to be determined.
This work was supported by grants from the Ministry of Science and Technology of China (2006CB911001 and 2009CB919003), and the National Natural Science Foundation of China (30871229).
The research on carbonaceous mesophase can be traced back to the 1960s, when Books and Taylor found there was liquid-crystalline phase (i.e., mesophase spheres) in the thermal conversion of carbonaceous feedstocks, which opens a new era in the research of liquid-phase carbonization and the development of carbon material industry [1]. Up to now, carbonaceous mesophase has been studied for more than 50 years and has always been the research hotspot and focus in the field of carbon materials [2, 3, 4, 5]. Mesophase pitch has long been recognized as a liquid crystal in a defined temperature range (e.g., 200–400°C) and exhibits both lyotropic and thermotropic nature, which is different from ordinary polymers and isotropic pitch [2]. It is well known that the mesophase pitch with a nematic liquid crystal structure possesses an easily graphitizable characteristic and can be preferentially aligned under mechanical force shearing after melting; thereby it is regarded as a basic raw material for preparing high-performance carbon and graphite materials with controllable structure of forming an ordered graphite, which provides a feasible route to prepare graphite-like materials [2]. In addition to the high carbon yield and potential price advantage (owing to the relatively low cost of carbonaceous raw materials) of mesophase pitch, it has become a high-quality precursor material for fabricating high-performance and multifunctional carbon materials as shown in Figure 1, such as mesophase pitch-based coke, needle coke, high-power graphite electrodes, mesocarbon microbeads (MCMBs), mesophase pitch-based carbon foam, mesophase pitch-based carbon fibers with high modulus and thermal conductivity, good binder and impregnating agent for high-thermal conductivity carbon-based composites, etc. Therefore, there is no doubt that mesophase pitch occupies a pivotal and irreplaceable position in various fields, such as defense, military, aerospace, cutting-edge technology, high-end industrial manufacturing, etc. [2, 3, 5].
\nMain promising applications of carbonaceous mesophase as an excellent precursor for making a wide variety of industrial and engineering carbon products.
The formation of mesophase pitch is a phase inversion process (transformed from isotropic to anisotropic), which is a result in which the pitch precursor undergoes thermal decomposition and thermal polycondensation to a certain extent. Nowadays, either thermal polycondensation of commercial coal-tar pitch and petroleum pitch (or even their certain soluble fractions) or catalytic polymerization of some aromatic substances is commonly used to prepare the carbonaceous mesophase [5]. It needs to be emphasized that carbonaceous precursors for the preparation of high-performance mesophase pitch are very crucial. Although commercial coal-tar pitch or petroleum pitch or heavy oil is very cheap and easy to obtain, these feedstocks are normally a complex mixture including with some heteroatoms and inorganic ash (~0.2 wt.%), which makes a spinnable mesophase pitch difficult to prepare [6, 7, 8]. So far, it is still very hard to massively produce cheap mesophase pitch with high quality, especially for continuously melt spinning high-performance carbon fibers. In recent 30 years, small model aromatic compounds (such as naphthalene, methylnaphthalene, anthracene, etc.) have been widely used to synthesize spinnable mesophase pitch by catalyzing with superacid, HF-BF3. The obtained naphthalene-derived mesophase pitch possesses characteristics of high purity, controllable molecular structure, and ideal physical property [3, 9, 10, 11]. However, the severe corrosion problem and potential operating risk of using HF-BF3 as a catalyst will unfortunately limit its widespread use (and such a mesophase pitch product named “AR” as shown in Figure 2(a) is now no longer available from, e.g., Mitsubishi Gas Chemical Company).
\nOptical photographs of (a) pellet and (b) block-shaped carbonaceous mesophase pitch derived from naphthalene.
In the meantime, a mild catalyst AlCl3 has been selectively used to prepare the mesophase pitch from the simple molecules and achieve the anticipated catalytic polymerization effect in spite of a trace of residual catalyst (e.g., 300–1000 ppm) inevitably intermingled in the mesophase pitch [3, 12, 13, 14]. Figure 3 shows the flow diagram of catalytic thermal polymerization of naphthalene molecule to prepare carbonaceous mesophase pitch as shown in Figure 2(b) by a two-step reaction process at a liquid-phase carbonization temperature of 350–450°C for a certain period of time. It could be concluded that some carbonaceous precursors (e.g., naphthalene) have undergone four stages of liquid-crystalline sphere development and transformation and finally formed a bulk liquid-crystalline mesophase from an isotropic matrix as illustrated in Figure 4 under a suitable reaction condition (i.e., reaction temperature and time) [2, 15, 16]. The general four-stage conversion of liquid crystals during the whole process is diagramed as follows: (I) generation of optically anisotropic spheres in isotropic matrix, (II) growth of anisotropic spheres in isotropic matrix, (III) coalescence of anisotropic spheres in isotropic matrix, and (IV) deformation and disintegration of anisotropic coalesced spheres to form bulk liquid-crystalline mesophase.
\nFlow diagram of catalytic thermal polymerization of naphthalene molecule to form carbonaceous mesophase pitch ((LT) a low temperature of ~200°C and (MT) a mid temperature of ~430°C).
Schematic illustration of the formation and development process of bulk liquid-crystalline mesophase under a suitable reaction condition (scale bar in PLM micrographs is 100 μm).
However, it has been demonstrated that the formation, development, and transformation of liquid-crystalline anisotropic spheres (i.e., nucleation, growth, coalescence and deformation and orientation) in an isotropic pitch matrix are unconcerted and inhomogeneous during the process of liquid-phase carbonization as shown in Figure 5 [16]. Furthermore, it is not easy to obtain a 100 vol.% anisotropic mesophase pitch (i.e., bulk mesophase) both with a fine flow optical texture and an acceptable softening point less than 300°C for subsequent fiber spinning. This mainly depends on the carbonaceous precursors (e.g., molecular unit size, the flatness of molecules and the chemical reactivity, etc.) and the suitable thermal reaction conditions adopted [2, 15, 16].
\n(a) Polarized light microscope (PLM) micrograph of the naphthalene-based synthetic pitch and (b) SEM image of broken surface of the pitch-derived coke showing an unsynchronized and inhomogeneous conversion of liquid-crystalline anisotropic spheres.
Mesophase pitch consists of a large variety of polycyclic aromatic hydrocarbons and maintains the molecular ordering (i.e., optical anisotropy), which is an important precursor for high-performance industrial carbon materials. Characterizing the structures and properties of carbonaceous mesophase plays a significant role in its quality control, process optimization, and applications [5, 17, 18]. Only through effective measurement of the molecular weight distribution and quantitative description of the structural characteristic as well as the multi-scale evaluation of the thermophysical nature will the understanding, controllable preparation, and applications of carbonaceous mesophase be updated. The common instruments used for characterizing carbonaceous mesophase are as follows: Fourier-transform infrared spectrometer (FTIR), elemental analyzer, nuclear magnetic resonance (NMR), flight mass spectrometer (MS), polarized light microscope, capillary rheometer, X-ray diffractometer, Raman spectrum, thermogravimetric, differential scanning calorimetry, etc.
\nThe carbonaceous mesophase pitch prepared by AlCl3 catalytic thermal polymerization of naphthalene has a relatively high aromaticity (the aromatic index is about 0.70) and a regular planar molecular structure constructed by a number of naphthenic structure, as well as a relatively large molecular weight of ~2600 g/mol, consisting of mesogen units (a ladder-shaped molecular structure) formed by ~20 naphthalene molecules through thermally induced aromatic growth [3, 10, 11] according to the analyses of Figures 6–8. The suitable softening point (260–280°C) and appropriate H/C mol ratio (0.52–0.60), as well as high liquid-crystalline mesophase content (100 vol.%) and ideal fine flow texture as displayed in Figures 9 and 11, are the significant characteristics of such carbonaceous mesophase. The analysis results of other characterizations are not shown here (refer to previous work [2, 3, 10, 11, 15, 18]).
\nFTIR patterns of (a) naphthalene pitch and (b) its derived mesophase pitch.
\n1H-NMR spectra of the soluble fractions from (a) naphthalene pitch and (b) its derived mesophase pitch.
MS spectra of (a) naphthalene pitch and (b) its derived mesophase pitch.
Typical PLM micrographs of the (a, b) as-received, (c) melted, and (d) melt-stirred naphthalene-based AR mesophase pitch.
The as-received liquid-crystalline AR mesophase pitch as shown in Figure 9(a,b) possesses a streamline “fibrous” texture with highly preferred orientation visible via orthogonal observation by rotating the object stage of the PLM. Following melting and melt-stirred treatments at 320°C as shown in Figure 9(c,d), respectively, the optical texture of the melting pitch is nearly maintained, and the conformation and orientation of the macromolecules in the melt-stirred pitch are disrupted to become partially disordered or turbulent (severely deformed) depending upon the degree of stirring [19]. The purpose of this thermo-stirring treatment is to investigate the influence of liquid-crystalline texture of mesophase pitch precursors on the morphology, microstructure, and physical properties of resulting carbon fibers as shown in Figure 10.
\nSchematic of the microstructure evolution from mesophase pitch precursor to transverse texture-controlled carbon fibers as degree of melt-stirring increases.
It can be found that the as-prepared naphthalene-based mesophase pitch as being transmitted from the reaction autoclave to a metal plate at a molten status exhibits good wire-drawing performance and ideal viscoelastic property and the unwittingly drawn wires (i.e., large-diameter pitch fibers) possess an orderly liquid-crystalline texture as shown in Figure 11, which is closely related to its plastic flowing behavior and low apparent viscosity upon melting as shown in Figure 12. This is favorable for pitch melt spinning and other rheology applications [5].
\n(a) Optical photograph of a naphthalene-based synthetic pitch with good wire-drawing performance and (b) PLM micrograph of the drawn pitch fiber.
Typical (a) molten flow curve of distance-temperature and (b) viscosity-temperature curve of naphthalene-based AR mesophase pitch.
It is well known that pitch-derived coke is mainly used to make carbon and graphite electrodes equipped within electric arc furnaces for steelmaking, and mesophase pitch-derived coke (or needle coke) has an overwhelming advantage to produce graphite electrodes with high and ultrahigh power [5, 20].
\nIt can be clearly seen that mesophase pitch-derived coke exhibits a well-oriented texture as shown in Figure 13(a,b), which is closely related to the formation and development of flow-type liquid crystalline in carbonaceous mesophase products during the process of delayed coking [5]. In contrast, coarse-grained mosaic texture is presented in the coke derived from commercial coal-tar pitch as shown in Figure 13(c,d) [16, 20]. Thus it can be concluded that the carbonaceous feedstocks have a significant influence on the optical texture and microstructure of resulting coke, which depends on the development and evolution of carbonaceous mesophase during the liquid-phase carbonization process.
\n(a, c) Optical photographs and (b, d) PLM micrographs of mesophase pitch-derived coke (a, b) and coal-tar pitch-derived coke (c, d).
As a special type of carbon material, MCMB has some outstanding physical and chemical properties that other carbon materials do not have due to its unique spherical morphology and lamellar structure. Therefore, MCMB can be widely applied to various fields, such as high-performance liquid chromatography column materials, high-specific surface area activated carbon materials, high-efficiency lithium ion battery anodes, high-density and high-strength graphite materials, etc. [5, 21].
\nUnder suitable thermal reaction conditions, homogeneous liquid-crystalline spheres with an identical diameter of ~10 μm which appeared in the optically isotropic pitch matrix can be achieved as shown in Figure 14(a), which is closely related to the effective control of the polymerization degree of naphthalene molecules. Through subsequent separation, infusibilization, and carbonization treatments, uniform-sized MCMBs as shown in Figure 14(b) can be easily obtained by starting with a simple naphthalene molecule.
\n(a) PLM micrograph of anisotropic liquid-crystalline carbonaceous spheres generated from naphthalene-based synthetic pitch and (b) SEM image of homogeneous MCMBs derived from the spherical liquid crystals.
Recently, many researchers have used mesophase pitch as a raw material to prepare porous carbon materials (e.g., ultrahigh surface area activated carbon, mesoporous carbon, and hierarchical porous carbon) with controlled microstructure and morphology [22, 23]. The large specific surface area, rich pore structure and excellent adsorption performance of porous carbon materials provide excellent supporting characteristics for various transition metal and precious metal catalysts. Porous carbon support can resist the severe corrosion in harsh environments such as acid, alkali and salts, and greatly improve the adsorption performance and catalytic efficiency, and thus has broad applications [24].
\nMesophase pitch-based carbon foam is a new type of porous carbon material prepared by foaming mesophase pitch as shown in Figure 15. Owing to its low density, high thermal and electrical conductivity, fire resistance, microwave absorption, noise reduction, low thermal expansion coefficient, chemical resistance, etc., carbon foam is extremely suitable for heat transfer systems, such as aerospace vehicles and satellites, rocket launching platforms, large heat exchangers, and computers in chemical plants [25, 26, 27]; therefore, such carbon foam sees promising application prospects.
\n(a) Optical photograph and (b) PLM micrograph of carbon foam derived from naphthalene-based mesophase pitch.
Mesophase pitch-based carbon fibers firstly reported by Singer in 1978 are the most successful high-end product for the development and application of carbonaceous mesophase, which are derived from spinnable mesophase pitch by melt spinning, oxidative stabilization, and carbonization and graphitization treatments [28]. The inherent alignment structure of liquid crystal molecules is preserved within the as-spun pitch fibers. Upon high-temperature graphitization, the graphite crystals are preferentially oriented along the fiber axis, so the final fibers have super high Young’s modulus (up to a theoretical value of graphite, 1000 GPa) and excellent axial electrical (as low as 1.0 μΩ m in electrical resistivity) and thermal conductivity (exceeding 1000 W/m K). Thus they are now being widely used in aviation, aerospace, nuclear, and other high-tech fields, in which polyacrylonitrile-based carbon fibers have a certain limitation [3, 5, 29, 30, 31, 32, 33]. At present, only the United States (Cytec Industries Incorporated) and Japan (Mitsubishi Chemical Corporation and Nippon Graphite Fiber Corporation) have mature manufacturing technology ranging from the precursor materials to the final products (i.e., mesophase pitch, high-performance carbon fiber continuous filaments, and carbon fiber composites). The morphology of commercial carbon fibers usually includes three types of forms, i.e., continuous filament, chopped fiber, and ground fiber powder.
\nThe round-shaped carbon fibers with different diameters and large-sized ribbon-shaped carbon fibers (sectional width ~2 mm, thickness ~10 μm) as shown in Figure 16 can been successfully prepared from the AR mesophase pitch owing to its good spinnability. It is worthy to point out that most large-diameter carbon fibers with a radial transverse texture are inclined to spit in the subsequent high-temperature heat treatment. The ribbon-shaped carbon fibers can efficiently solve the crack problem and maintain their shape and structure without any damage. The carbon crystalline structure and layered orientation parallel to the ribbon main surface are obviously better than those of round fibers. The axial electrical resistivity and thermal conductivity of the round and ribbon fibers graphitized at 3000°C are measured to be as low as 1.1–1.30 μΩ m and about 900–1000 W/m K at room temperature [19, 34, 35, 36].
\n(a, c) Optical photographs and (b, d) SEM micrographs of round- (a, b) and ribbon-shaped carbon fibers (c, d) derived from naphthalene-based AR mesophase pitch.
Mesophase pitch-based carbon (graphite) fibers are often used as ideal functional fillers for preparing various carbon-based composites with high thermal conductivity [5, 37, 38, 39, 40, 41], which can be widely utilized in the field of thermal management [32, 33]. The thermal conductivity of these carbon-based composites depends not only on the conduction performance of carbon fibers themselves and their loading amount, as well as laying or weaving architecture in the composites, but also on the physical properties of matrix materials involved (i.e., the resin, mesophase pitch, or pyrolytic carbon).
\nIn the previous work, the mesophase pitch-based graphite fiber (long filament) reinforced one-dimensional (as shown in Figure 17(a)–(c)) and two-dimensional ABS resin composites with a large size of 10 cm × 10 cm x 0.3–2 cm can reach a high thermal conductivity of ~500 W/m K [37, 38]. However, the thermal conductivity of composites reinforced by shortcut carbon fibers and milled fiber powders as shown in Figure 17(d,e) is only 10–20 W/m K, which can be used as heat paste or thermal grease for interfacial heat dissipation. Using various mesophase pitch-based graphite fibers (i.e., round-shaped and ribbon-shaped fibers) as a reinforcing filler and the same mesophase pitch as a binder, ultrahigh thermal conductivity (700–900 W/m K) of the one-dimensional C/C composites as shown in Figures 18 and 19 could be realized [39, 40]. However, it is disadvantage to use phenolic resin as a binder to prepare high-thermal-conductivity materials owing to its non-graphitizable nature (i.e., a typical hard carbon) as shown in Figure 20. By comparison, the mesophase pitch-derived carbon after high-temperature treatment exhibits good crystallinity, high graphitization degree, and orderly stacked graphene sheets as shown in Figure 18(d), which is very important to improve the directional thermal conductivity performance. It is worth noting that the pyrolytic carbon with a highly oriented texture deposited on the mesophase pitch-based graphite fibers as shown in Figure 21 is also found to markedly increase the thermal conductivity of C/C composites [41].
\n(a) Optical photograph, (b–d) PLM micrographs, and (e) SEM image of ABS resin composites reinforced by unidirectional (b, c) and disordered (d, e) mesophase pitch-based carbon fibers ((b, c) are, respectively, imaged perpendicular and parallel to the fiber axis).
(a) Optical photograph, (b) PLM micrograph, and (c)–(e) SEM images of unidirectional carbon/carbon composites reinforced by mesophase pitch-based carbon fibers using mesophase pitch as a binder ((b)–(d) are imaged perpendicular to the fiber axis, and (e) is imaged parallel to the fiber axis).
(a) Optical photograph, (b, c) PLM orthogonal micrographs, and (d) SEM image of unidirectional carbon/carbon composites reinforced by mesophase pitch-based ribbon fibers using mesophase pitch as a binder.
(a) PLM micrograph and (b) SEM image of unidirectional carbon/carbon composites reinforced by mesophase pitch-based carbon fibers using phenolic resin as a binder.
(a) Optical photograph, (b) PLM micrograph, and (c) SEM image of unidirectional carbon/carbon composites reinforced by mesophase pitch-based carbon fibers using pyrolytic carbon as a “binder.”
It is interesting to note that mesophase pitch is a promising binder (due to its good flow orientation performance in the molten state, easily graphitizable characteristic, etc.) for large-scale fabricating natural flake graphite-molded blocks by using the cheap and available natural graphite flakes as a raw material. The prepared graphite blocks with a high bulk density of 1.9 g/cm3 possess a highly preferred structural orientation perpendicular to the hot-pressing direction as shown in Figure 22 and a high thermal conductivity of 500–600 W/m K in plane two-dimensional direction [42, 43].
\n(a) Optical photograph, (b) PLM micrograph, and (c) SEM image of natural flake graphite-molded blocks perpendicular to the hot-pressing direction using mesophase pitch as a binder.
It is well known that carbon materials are important materials for the preparation of various batteries. From ancient dry batteries to today’s high-efficiency fuel cells, as well as new high-energy storage batteries being developed, pitch-based carbon materials are playing an increasingly important role. Mesophase pitch is an easily graphitizable carbonaceous precursor. After high-temperature heat treatment, its three-dimensional stack structure is very regular, and mesophase pitch can be transformed into a high-crystalline graphite. The necessary energy of intercalating lithium ions into the carbon layers is relatively low, and thus such material has a large lithium insertion depth and reversible capacity [44, 45], especially carbonaceous mesophase-derived coke after spheroidizing and coating treatments as shown in Figure 23(a) which can significantly improve the cycle stability and service life of the battery.
\nTypical (a) SEM image of carbonaceous mesophase-derived spherical coke used as Li-ion battery anodes and (b) TEM image of carbonaceous mesophase-derived graphene with a relatively large size.
By the same token, using the easily graphitized mesophase pitch-derived carbon as a raw material, a large-sized graphene (or a few layers of graphene sheets) with uniform thickness and good transparency as shown in Figure 23(b) can be successfully prepared through a special technique (i.e., molten salt ion intercalation stripping), which can realize the size and thickness control of carbon layers. The preparation method seems to be very simple and easy to operate and thus will have a good prospect.
\nIn addition to being used as a high-quality raw material for the above-mentioned carbon materials, carbonaceous mesophase can also be used to prepare some novel and value-added carbon materials such as miracle graphene [46], carbon quantum dots [47], good binder for high-performance magnesia carbon bricks [48], fluorinated pitch [49], etc.
\nIn this chapter, the preparation, characterization, and applications of naphthalene-based carbonaceous mesophase are reviewed. With the continuous advancement of preparation techniques and characterization methods, the understanding of the molecular structure, molecular weight, molecular weight distribution, aggregation texture, and rheology property of mesophase liquid crystals will be deepened, and finally the comprehensive understanding of the carbonaceous mesophase (including the formation mechanism, molecular dynamic law and high-efficiency control) from molecular and micro and macro scales could be realized, which will maximize the performance of carbonaceous mesophase-derived carbon products with desirable performance, multi-versatility, and high added value, thus to promote the theoretical foundation of carbonaceous mesophase and accelerate its broad applications in various fields.
\nThe authors would like to thank professor Xuanke Li for his good suggestion and professional advice. This work was supported by the National Natural Science Foundation of China (Grant Nos. 91016003 and 51372177), the Hubei Provincial Department of Education Science Research Project (Grant No. Q20141104), the Key Laboratory of Hubei Province for Coal Conversion and New Carbon Materials (Grant No. WKDM201701), and the China Scholarship Council Fund (201808420114).
\nThe authors declare no conflict of interest.
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