Adipocyte fatty acid-binding protein (A-FABP), which is also known as ap2 or FABP4, is a fatty acid chaperone that has been further defined as a fat-derived hormone. It regulates lipid homeostasis ...and is a key mediator of inflammation. Circulating levels of A-FABP are closely associated with metabolic syndrome and cardiometabolic diseases with imminent diagnostic and prognostic significance. Numerous animal studies have elucidated the potential underlying mechanisms involving A-FABP in these diseases. Recent studies demonstrated its physiological role in the regulation of adaptive thermogenesis and its pathological roles in ischemic stroke and liver fibrosis. Due to its implication in various diseases, A-FABP has become a promising target for the development of small molecule inhibitors and neutralizing antibodies for disease treatment. This review summarizes the clinical and animal findings of A-FABP in the pathogenesis of cardio-metabolic diseases in recent years. The underlying mechanism and its therapeutic implications are also highlighted.
Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19), with macrophages as one of the main cell types involved. It is urgent to understand the ...interactions among permissive cells, macrophages, and the SARS-CoV-2 virus, thereby offering important insights into effective therapeutic strategies. Here, we establish a lung and macrophage co-culture system derived from human pluripotent stem cells (hPSCs), modeling the host-pathogen interaction in SARS-CoV-2 infection. We find that both classically polarized macrophages (M1) and alternatively polarized macrophages (M2) have inhibitory effects on SARS-CoV-2 infection. However, M1 and non-activated (M0) macrophages, but not M2 macrophages, significantly up-regulate inflammatory factors upon viral infection. Moreover, M1 macrophages suppress the growth and enhance apoptosis of lung cells. Inhibition of viral entry using an ACE2 blocking antibody substantially enhances the activity of M2 macrophages. Our studies indicate differential immune response patterns in distinct macrophage phenotypes, which could lead to a range of COVID-19 disease severity.
Although obesity occurs in most of the patients with type 2 diabetes (T2D), a fraction of patients with T2D are underweight or have normal weight. Several studies have linked the gut microbiome to ...obesity and T2D, but the role of gut microbiota in lean individuals with T2D having unique clinical characteristics remains unclear. A metagenomic and targeted metabolomic analysis is conducted in 182 lean and abdominally obese individuals with and without newly diagnosed T2D. The abundance of Akkermansia muciniphila (A. muciniphila) significantly decreases in lean individuals with T2D than without T2D, but not in the comparison of obese individuals with and without T2D. Its abundance correlates inversely with serum 3β‐chenodeoxycholic acid (βCDCA) levels and positively with insulin secretion and fibroblast growth factor 15/19 (FGF15/19) concentrations. The supplementation with A. muciniphila is sufficient to protect mice against high sucrose‐induced impairment of glucose intolerance by decreasing βCDCA and increasing insulin secretion and FGF15/19. Furthermore, βCDCA inhibits insulin secretion and FGF15/19 expression. These findings suggest that decreased abundance of A. muciniphila is linked to the impairment of insulin secretion and glucose homeostasis in lean T2D, paving the way for new therapeutic options for the prevention or treatment of diabetes.
Intestinal Akkermansia muciniphila is depleted in lean individuals with type 2 diabetes, who have increased 3β‐chenodeoxycholic acid (βCDCA), reduced insulin secretion and fibroblast growth factor 19 (FGF19) expression. A. muciniphila treatment in mice modulates βCDCA levels, stimulates insulin secretion and FGF19 expression, leading to improved glucose metabolism. The way is paved fornew therapeutic options for diabetes prevention or treatment.
OBJECTIVE—To analyze the role of toll-like receptor 4 in modulating metabolism and endothelial function.
APPROACH AND RESULTS—Type 2 diabetic mice with mutated toll-like receptor 4 (DWM) were ...protected from hyperglycemia and hypertension, despite an increased body weight. Isometric tension was measured in arterial rings with endothelium. Relaxations to acetylcholine were blunted in aortae and mesenteric arteries of Lepr mice, but not in DWM mice; the endothelial NO synthase dimer/monomer ratio and endothelial NO synthase phosphorylation levels were higher in DWM preparations. These differences were abolished by apocynin. Contractions to acetylcholine (in the presence of L-NAME) were larger in carotid arteries from Lepr mice than from DWM mice and were inhibited by indomethacin and SC560, demonstrating involvement of cyclooxygenase-1. The release of 6-ketoprostaglandin F1α was lower in DWM mice arteries, implying lower cyclooxygenase-1 activity. Apocynin, manganese(III) tetrakis(1-methyl-4-pyridyl) porphyrin, catalase, and diethyldithiocarbamate inhibited endothelium-dependent contractions. The mRNA and protein levels of NADPH oxidase isoforms NOX1 and NOX4 were downregulated in DWM mice arteries. The in vivo and in vitro administration of lipopolysaccharide caused endothelial dysfunction in the arteries of wild-type, but not toll-like receptor 4–mutated mice.
CONCLUSIONS—Toll-like receptor 4 plays a key role in obesity and diabetes-associated endothelial dysfunction by increasing oxidative stress.
Mesenchymal stem cells (MSCs) can donate mitochondria and rescue anthracycline-induced cardiomyocyte (CM) damage, although the underlying mechanisms remain elusive. We determined that the superior ...efficiency of mitochondrial transfer by human induced-pluripotent-stem-cell-derived MSCs (iPSC-MSCs) compared with bone marrow-derived MSCs (BM-MSCs) is due to high expression of intrinsic Rho GTPase 1 (MIRO1). Further, due to a higher level of TNFαIP2 expression, iPSC-MSCs are more responsive to tumor necrosis factor alpha (TNF-α)-induced tunneling nanotube (TNT) formation for mitochondrial transfer to CMs, which is regulated via the TNF-α/NF-κB/TNFαIP2 signaling pathway. Inhibition of TNFαIP2 or MIRO1 in iPSC-MSCs reduced the efficiency of mitochondrial transfer and decreased CMs protection. Compared with BM-MSCs, transplantation of iPSC-MSCs into a mouse model of anthracycline-induced cardiomyopathy resulted in more human mitochondrial retention and bioenergetic preservation in heart tissue. Efficacious transfer of mitochondria from iPSC-MSCs to CMs, due to higher MIRO1 expression and responsiveness to TNF-α-induced nanotube formation, effectively attenuates anthracycline-induced CM damage.
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•Functional mitochondrial transfer of iPSC-MSCs attenuates Dox-induced cardiomyopathy•High intrinsic Miro1 in iPSC-MSCs contributes to efficacious mitochondrial transfer•iPSC-MSCs are highly responsive to TNF-α-induced tunneling nanotube formation
Lian, Tse, and colleagues reveal the protective effects of iPSC-MSCs against Dox-induced cardiomyopathy by efficacious mitochondrial transfer from iPSC-MSCs to injured cardiomyocytes, independently of MSC paracrine effects, and show that augmentation of Dox-induced cardiomyopathy with iPSC-MSCs is attributed to an intrinsically high level of Miro1 and high sensitivity to TNF-α-induced TNT formation.
Abstract
Aims
Aged arteries are characterized by attenuated vasodilator and enhanced vasoconstrictor responses, which contribute to the development of diseases such as arterial hypertension, ...atherosclerosis, and heart failure. SIRT1 is a longevity regulator exerting protective functions against vascular ageing, although the underlying mechanisms remain largely unknown. This study was designed to elucidate the signalling pathways involved in endothelial SIRT1-mediated vasodilator responses in the arteries of young and old mice. In particular, the contributions of nitric oxide (NO), endothelial NO synthase (eNOS), cyclooxygenase (COX), and/or soluble guanylyl cyclase (sGC) were examined.
Methods and results
Wild type (WT) or eNOS knockout (eKO) mice were cross-bred with those overexpressing human SIRT1 selectively in the vascular endothelium (EC-SIRT1). Arteries were collected from the four groups of mice (WT, EC-SIRT1, eKO, and eKO-SIRT1) to measure isometric relaxations/contractions in response to various pharmacological agents. Reduction of NO bioavailability, hyper-activation of COX signalling, and down-regulation of sGC collectively contributed to the decreased vasodilator and increased vasoconstrictor responses in arteries of old WT mice. Overexpression of endothelial SIRT1 did not block the reduction in NO bioavailability but attenuated the hyper-activation of COX-2, thus protecting mice from age-induced vasoconstrictor responses in arteries of EC-SIRT1 mice. Deficiency of eNOS did not affect endothelial SIRT1-mediated anti-contractile activities in arteries of eKO-SIRT1 mice. Mechanistic studies revealed that overexpression of endothelial SIRT1 enhanced Notch signalling to up-regulate sGCβ1 in smooth muscle cells. Increased expression and activity of sGC prevented age-induced hyper-activation of COX-2 as well as the conversion of endothelium-dependent relaxations to contractions in arteries of EC-SIRT1 mice.
Conclusion
Age-induced down-regulation of sGC and up-regulation of COX-2 in arteries are at least partly attributable to the loss-of-endothelial SIRT1 function. Enhancing the endothelial expression and function of SIRT1 prevents early vascular ageing and maintains vasodilator responses, thus representing promising drug targets for cardiovascular diseases.
The gut microbiota has the potential to influence the efficacy of cancer therapy. Here, we investigated the contribution of the intestinal microbiome on treatment outcomes in a heterogeneous cohort ...that included multiple cancer types to identify microbes with a global impact on immune response. Human gut metagenomic analysis revealed that responder patients had significantly higher microbial diversity and different microbiota compositions compared to non-responders. A machine-learning model was developed and validated in an independent cohort to predict treatment outcomes based on gut microbiota composition and functional repertoires of responders and non-responders. Specific species, Bacteroides ovatus and Bacteroides xylanisolvens, were positively correlated with treatment outcomes. Oral gavage of these responder bacteria significantly increased the efficacy of erlotinib and induced the expression of CXCL9 and IFN-γ in a murine lung cancer model. These data suggest a predictable impact of specific constituents of the microbiota on tumor growth and cancer treatment outcomes with implications for both prognosis and therapy.
The adipokine adipocyte fatty acid-binding protein (A-FABP) has been implicated in obesity-related cardio-metabolic complications. Here we show that A-FABP increases thermogenesis by promoting the ...conversion of T4 to T3 in brown adipocytes. We find that A-FABP levels are increased in both white (WAT) and brown (BAT) adipose tissues and the bloodstream in response to thermogenic stimuli. A-FABP knockout mice have reduced thermogenesis and whole-body energy expenditure after cold stress or after feeding a high-fat diet, which can be reversed by infusion of recombinant A-FABP. Mechanistically, A-FABP induces the expression of type-II iodothyronine deiodinase in BAT via inhibition of the nuclear receptor liver X receptor α, thereby leading to the conversion of thyroid hormone from its inactive form T4 to active T3. The thermogenic responses to T4 are abrogated in A-FABP KO mice, but enhanced by A-FABP. Thus, A-FABP acts as a physiological stimulator of BAT-mediated adaptive thermogenesis.
Fibroblast growth factor (FGF) 21 belongs to the FGF superfamily that is involved in cell proliferation and differentiation, neural development, angiogenesis, and metabolism. FGF21 requires β-Klotho ...as a co-receptor. Tissues involved in metabolism such as the liver, adipose tissues, skeletal muscle, and pancreas express FGF21. Starvation increases hepatic expression of FGF21, which then acts centrally to increase hepatic gluconeogenesis. FGF21 also increases fatty acid oxidation. This may be relevant in cold exposure, when expression of FGF21 is induced. Chronic treatment with recombinant FGF21 reduces serum and hepatic triglyceride levels and ameliorates fatty liver in obese mice, through the suppression of the lipogenic gene,
Srebp-1
. FGF21 reduces hepatic cholesterol production by inhibiting
Srebp-2
, a transactivator of proprotein convertase subtilisin/kexin type 9 (PCSK9). LY2045319, an FGF21 analog, reduces LDL-C and triglycerides and increases HDL-C in obese human subjects with type 2 diabetes. FGF21 does not seem to lower blood pressure acutely. In rats fed with high-fructose water to induce mild hypertension, 4-week treatment with recombinant FGF21 led to normalization of systolic blood pressure and improved serum lipid profile. FGF receptors and β-Klotho are expressed on the nucleus tractus solitarii and nodose ganglion in the baroreflex afferent pathway. Moreover, FGF21 acts on the hypothalamus to release corticosterone and induces in adipocytes the production of adiponectin, an adipokine with antihypertensive activities. Therefore, FGF21 may decrease blood pressure indirectly, through its actions in the liver, brain, and adipose tissues.
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