Dietary PUFAs reduce atherosclerosis and macrophage inflammation, but how nucleotide-binding oligomerization domain leucine-rich repeat-containing receptor protein (NLRP3) inflammasome activation and autophagy influence PUFA-mediated atheroprotection is poorly understood. We fed Ldlr−/− mice diets containing 10% (calories) palm oil (PO) and 0.2% cholesterol, supplemented with an additional 10% of calories as PO, fish oil (FO), echium oil (EO, containing 18:4 n-3), or borage oil (BO, containing 18:3 n-6). Inflammasome activation, autophagic flux, and mitochondrial function were measured in peritoneal macrophages, blood monocytes, or liver from diet-fed mice. Compared with PO, dietary PUFAs (FO, EO, or BO) markedly inhibited inflammasome activation, shown by 1) less macrophage IL-1β secretion and caspase-1 cleavage in response to NLRP3 inflammasome activators, 2) less IL-1β secretion and caspase-1 cleavage from liver or hepatocytes in response to lipopolysaccharide (LPS), and 3) attenuated caspase-1 activity in blood monocytes. Furthermore, PUFA-enriched diets increased LC3-II expression in macrophage, aorta, and liver samples and reduced numbers of dysfunctional mitochondria in macrophages in response to LPS and palmitate, suggesting enhanced autophagic activation. Dietary PUFAs did not attenuate NLRP3 inflammasome activation in atg5-deficient macrophages, indicating that autophagic activation is critical for the PUFA-mediated inflammasome inactivation. In conclusion, dietary PUFAs reduce atherosclerosis, in part, by activation of macrophage autophagy and attenuation of NLRP3 inflammasome activation.

Over 650 million adults are obese (body mass index ≥ 30 kg/m2) worldwide. Obesity is commonly associated with several comorbidities, including cardiovascular disease and type II diabetes. However, compiled estimates suggest that from 5 to 40% of obese individuals do not experience metabolic or cardiovascular complications. The existence of the metabolically unhealthy obese (MUO) and the metabolically healthy obese (MHO) phenotypes suggests that underlying differences exist in both tissues and overall systemic function. Macrophage accumulation in white adipose tissue (AT) in obesity is typically associated with insulin resistance. However, as plastic cells, macrophages respond to stimuli in their microenvironments, altering their polarization between pro- and anti-inflammatory phenotypes, depending on the state of their surroundings. The dichotomous nature of MHO and MUO clinical phenotypes suggests that differences in white AT function dictate local inflammatory responses by driving changes in macrophage subtypes. As obesity requires extensive AT expansion, we posit that remodeling capacity with adipose expansion potentiates favorable macrophage profiles in MHO as compared with MUO individuals. In this review, we discuss how differences in adipogenesis, AT extracellular matrix deposition and breakdown, and AT angiogenesis perpetuate altered AT macrophage profiles in MUO compared with MHO. We discuss how non-autonomous effects of remote organ systems, including the liver, gastrointestinal tract, and cardiovascular system, interact with white adipose favorably in MHO. Preferential AT macrophage profiles in MHO stem from sustained AT function and improved overall fitness and systemic health.

Metabolic reprogramming between resistance and tolerance occurs within the immune system in response to sepsis. While metabolic tissues such as the liver are subject to damage during sepsis, how their metabolic and energy reprogramming ensures survival is unclear. Employing comprehensive metabolomic, lipidomic, and transcriptional profiling in a mouse model of sepsis, we show that hepatocyte lipid metabolism, mitochondrial TCA energetics, and redox balance are significantly reprogramed after cecal ligation and puncture (CLP). We identify increases in TCA cycle metabolites citrate, cis-aconitate, and itaconate with reduced fumarate and triglyceride accumulation in septic hepatocytes. Transcriptomic analysis of liver tissue supports and extends the hepatocyte findings. Strikingly, the administration of the pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate (DCA) reverses dysregulated hepatocyte metabolism and mitochondrial dysfunction. In summary, our data indicate sepsis promotes hepatic metabolic dysfunction and that targeting the mitochondrial PDC/PDK energy homeostat rebalances transcriptional and metabolic manifestations of sepsis within the liver.

42Dramatic metabolic reprogramming between an anabolic resistance and catabolic toler-43 ance occurs within the immune system in response to systemic infection with the sepsis 44 syndrome. While metabolic tissues such as the liver are subject to end-organ damage 45 during sepsis and are the primary cause of sepsis death, how their metabolic and energy 46 reprogramming during sepsis state ensures survival is unclear. Employing comprehen-47 sive metabolomic screening, targeted lipidomic screening, and transcriptional profiling in 48 a mouse model of septic shock, we show that hepatocyte lipid metabolism, mitochondrial 49 TCA energetics, and redox balance are significantly reprogramed after cecal ligation and 50 puncture (CLP). We identify increases in TCA cycle metabolites citrate, cis-aconitate, 51 and itaconate with reduced fumarate, elevated triglyceride synthesis, and lipid droplet 52 accumulation in the septic hepatocytes. Transcription analysis of liver tissue supports and 53 extends the hepatocyte findings. Plasma metabolomics show systemic hypoglycemia and 54 increased concentrations of free fatty acids, ketones and corticosterone in parallel with 55 liver reprogramming. Strikingly, the administration of the pyruvate dehydrogenase kinase 56 (PDK) inhibitor dichloroacetate (DCA) reverses dysregulated hepatocyte and systemic 57 metabolism and mitochondrial dysfunction. DCA administered during sepsis arrests ano-58 rexia and weight loss, restores V02 levels as an index of increased carbohydrate oxida-59 tion and promotes physical activity. We suggest that sepsis inflicts an energy demand 60 and supply crisis with distinct shifts in hepatocyte and systemic mitochondrial function.61 Targeting the mitochondrial PDC/PDK energy homeostat rebalances life-threatening en-62 ergy deregulation caused by bacterial sepsis.63 64conserving "hibernation-like" state as a protective mechanism to lower the metabolic de-86 mands of the cell and help with its recovery 6,12,13 . However, staying in this hypometabolic 87 state for a prolonged period can lead to organ dysfunction and failure 12,13 . 88Of particular interest is that, during the hyper-inflammatory anabolic phase of sep-89 sis, an increase in the expression and activity of pyruvate dehydrogenase kinase 1 90 (PDK1) consistently occurs 4 . This enzyme is one of four PDK isoforms that reversibly 91 phosphorylates serine residues on pyruvate dehydrogenase complex (PDC) E1a subunit, 92 inhibiting the conversion of pyruvate to acetyl coenzyme A (acetyl CoA) 14 . Inhibition of 93 this important enzymatic activity that connects glycolysis to tricarboxylic cycle (TCA), ox-94 idative phosphorylation (OXPHOS) and the lipogenic pathway is thought to be one of the 95 main mechanisms that is driving dysfunction of mitochondrial respiration and cell bioen-96 ergetics observed during sepsis 15,16 , suggesting that PDK may be a novel, druggable 97 target for treatment of sepsis.. 98 There a few reports that indicate changes in hepatic metabolism during sepsis but 99 these stud...

Increased flux of glucose through glycolysis is a hallmark of inflammatory macrophages and is essential for optimal effector functions. Solute carrier (SLC) 37A2 is an endoplasmic reticulum-anchored phosphate-linked glucose-6-phosphate transporter that is highly expressed in macrophages and neutrophils. We demonstrate that SLC37A2 plays a pivotal role in murine macrophage inflammatory activation and cellular metabolic rewiring. Toll-like receptor (TLR) 4 stimulation by lipopolysaccharide (LPS) rapidly increases macrophage SLC37A2 protein expression. SLC37A2 deletion reprograms macrophages to a hyper-glycolytic process and accelerates LPS-induced inflammatory cytokine production, which partially depends on nicotinamide adenine dinucleotide (NAD + ) biosynthesis. Blockade of glycolysis normalizes the differential expression of pro-inflammatory cytokines between control and SLC37A2 deficient macrophages. Conversely, overexpression of SLC37A2 lowers macrophage glycolysis and significantly reduces LPS-induced pro-inflammatory cytokine expression. In conclusion, our study suggests that SLC37A2 dampens murine macrophage inflammation by down-regulating glycolytic reprogramming as a part of macrophage negative feedback system to curtail acute innate activation.