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Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity.

Germinal center B cells (GCBCs) are critical for generating long-lived humoral immunity. How GCBCs meet the energetic challenge of rapid proliferation is poorly understood. Dividing lymphocytes typically rely on aerobic glycolysis over oxidative phosphorylation for energy. Here we report that GCBCs are exceptional among proliferating B and T cells, as they actively oxidize fatty acids (FAs) and conduct minimal glycolysis. In vitro, GCBCs had a very low glycolytic extracellular acidification rate but consumed oxygen in response to FAs. [ 13 C 6 ]-glucose feeding revealed that GCBCs generate significantly less phosphorylated glucose and little lactate. Further, GCBCs did not metabolize glucose into tricarboxylic acid (TCA) cycle intermediates. Conversely, [ 13 C 16 ]-palmitic acid labeling demonstrated that GCBCs generate most of their acetyl-CoA and acetylcarnitine from FAs. FA oxidation was functionally important, as drug-mediated and genetic dampening of FA oxidation resulted in a selective reduction of GCBCs. Hence, GCBCs appear to uncouple rapid proliferation from aerobic glycolysis. Germinal center B cells can undergo rapid proliferation. Shlomchik and colleagues show that germinal center B cells, unlike other rapidly proliferating cells, do not depend on glycolysis, but rather increase their peroxisome content and rewire their cellular metabolism to exclusively utilize fatty acid oxidation for their energetic needs.

Microbes have already been engineered to produce diesel fuels, and now the microbial production of components of petrol (gasoline) including short-chain alkanes has been achieved using Escherichia coli strains metabolically engineered with components of fatty acid biosynthesis pathways. Engineering bacteria to pump gasoline High oil prices and the depletion of fossil resources have fuelled extensive research on the production of sustainable biofuels from renewable resources. Engineered microbes are one option, but until now microbes have not produced gasoline, a mixture of lighter liquid hydrocarbons in the range C4 to C12, in part because cellular metabolism favours the production of mainly long-chain fatty acids and their derivatives. Here Yong Jun Choi and Sang Yup Lee describe Escherichia coli strains engineered to produce short-chain alkanes, free fatty acids, fatty esters and fatty alcohols. The final engineered strain produced as much as 580.8 milligrams per litre of short-chain alkanes, primarily nonane and decane. The metabolic engineering strategies described here should be useful in designing microorganisms for the production of short-chain fatty acids and derivatives as many useful industrial fuels and chemicals. Increasing concerns about limited fossil fuels and global environmental problems have focused attention on the need to develop sustainable biofuels from renewable resources. Although microbial production of diesel has been reported, production of another much in demand transport fuel, petrol (gasoline), has not yet been demonstrated. Here we report the development of platform Escherichia coli strains that are capable of producing short-chain alkanes (SCAs; petrol), free fatty acids (FFAs), fatty esters and fatty alcohols through the fatty acyl (acyl carrier protein (ACP)) to fatty acid to fatty acyl-CoA pathway. First, the β-oxidation pathway was blocked by deleting the fadE gene to prevent the degradation of fatty acyl-CoAs generated in vivo . To increase the formation of short-chain fatty acids suitable for subsequent conversion to SCAs in vivo , the activity of 3-oxoacyl-ACP synthase (FabH) 1 , which is inhibited by unsaturated fatty acyl-ACPs 2 , was enhanced to promote the initiation of fatty acid biosynthesis by deleting the fadR gene; deletion of the fadR gene prevents upregulation of the fabA and fabB genes responsible for unsaturated fatty acids biosynthesis 3 . A modified thioesterase 4 was used to convert short-chain fatty acyl-ACPs to the corresponding FFAs, which were then converted to SCAs by the sequential reactions of E. coli fatty acyl-CoA synthetase, Clostridium acetobutylicum fatty acyl-CoA reductase and Arabidopsis thaliana fatty aldehyde decarbonylase. The final engineered strain produced up to 580.8 mg l −1 of SCAs consisting of nonane (327.8 mg l −1 ), dodecane (136.5 mg l −1 ), tridecane (64.8 mg l −1 ), 2-methyl-dodecane (42.8 mg l −1 ) and tetradecane (8.9 mg l −1 ), together with small amounts of other hydrocarbons. Furthermore, this platform strain could produce short-chain FFAs using a fadD -deleted strain, and short-chain fatty esters by introducing the Acinetobacter sp. ADP1 wax ester synthase ( atfA ) 5 and the E. coli mutant alcohol dehydrogenase ( adhE mut ) 6 .

Weight loss by ketogenic diet (KD) has gained popularity in management of nonalcoholic fatty liver disease (NAFLD). KD rapidly reverses NAFLD and insulin resistance despite increasing circulating nonesterified fatty acids (NEFA), the main substrate for synthesis of intrahepatic triglycerides (IHTG). To explore the underlying mechanism, we quantified hepatic mitochondrial fluxes and their regulators in humans by using positional isotopomer NMR tracer analysis. Ten overweight/obese subjects received stable isotope infusions of: [D₇]glucose, [13C₄]β-hydroxybutyrate and [3-13C]lactate before and after a 6-d KD. IHTG was determined by proton magnetic resonance spectroscopy (¹H-MRS). The KD diet decreased IHTG by 31% in the face of a 3% decrease in body weight and decreased hepatic insulin resistance (−58%) despite an increase in NEFA concentrations (+35%). These changes were attributed to increased net hydrolysis of IHTG and partitioning of the resulting fatty acids toward ketogenesis (+232%) due to reductions in serum insulin concentrations (−53%) and hepatic citrate synthase flux (−38%), respectively. The former was attributed to decreased hepatic insulin resistance and the latter to increased hepatic mitochondrial redox state (+167%) and decreased plasma leptin (−45%) and triiodothyronine (−21%) concentrations. These data demonstrate heretofore undescribed adaptations underlying the reversal of NAFLD by KD: That is, markedly altered hepatic mitochondrial fluxes and redox state to promote ketogenesis rather than synthesis of IHTG.

FABP4 and FABP5 are important for the maintenance, longevity and function of CD8 + tissue-resident memory T cells, which use oxidative metabolism of exogenous free fatty acids to persist in tissues and to mediate protective immunity. Lipid uptake in tissue-resident memory T cells Tissue-resident memory T (T RM ) cells are found in the skin, where they protect the host against pathogens, but it has not been clear how they manage to survive long-term. Thomas Kupper and colleagues now report that these cells are more dependent on exogenous free fatty acid uptake than are central memory and effector memory T cells. They show that T RM cells express high levels of several molecules that mediate the uptake and intracellular transport of lipids, including fatty-acid-binding proteins 4 and 5 (FABP4 and FABP5), and implicate Fabp4 and Fabp5 as critical mediators of exogenous fatty acid uptake in murine and human T RM cells. Tissue-resident memory T (T RM ) cells persist indefinitely in epithelial barrier tissues and protect the host against pathogens 1 , 2 , 3 , 4 . However, the biological pathways that enable the long-term survival of T RM cells are obscure 4 , 5 . Here we show that mouse CD8 + T RM cells generated by viral infection of the skin differentially express high levels of several molecules that mediate lipid uptake and intracellular transport, including fatty-acid-binding proteins 4 and 5 (FABP4 and FABP5). We further show that T-cell-specific deficiency of Fabp4 and Fabp5 ( Fabp4 / Fabp5 ) impairs exogenous free fatty acid (FFA) uptake by CD8 + T RM cells and greatly reduces their long-term survival in vivo, while having no effect on the survival of central memory T (T CM ) cells in lymph nodes. In vitro , CD8 + T RM cells, but not CD8 + T CM cells, demonstrated increased mitochondrial oxidative metabolism in the presence of exogenous FFAs; this increase was not seen in Fabp4 / Fabp5 double-knockout CD8 + T RM cells. The persistence of CD8 + T RM cells in the skin was strongly diminished by inhibition of mitochondrial FFA β-oxidation in vivo . Moreover, skin CD8 + T RM cells that lacked Fabp4 / Fabp5 were less effective at protecting mice from cutaneous viral infection, and lung Fabp4 / Fabp5 double-knockout CD8 + T RM cells generated by skin vaccinia virus (VACV) infection were less effective at protecting mice from a lethal pulmonary challenge with VACV. Consistent with the mouse data, increased FABP4 and FABP5 expression and enhanced extracellular FFA uptake were also demonstrated in human CD8 + T RM cells in normal and psoriatic skin. These results suggest that FABP4 and FABP5 have a critical role in the maintenance, longevity and function of CD8 + T RM cells, and suggest that CD8 + T RM cells use exogenous FFAs and their oxidative metabolism to persist in tissue and to mediate protective immunity.

Key Points This Review focuses on the pathways that catabolize cellular triacylglycerol ('fat'), namely, neutral lipolysis, acid lipolysis and lipophagy. Neutral lipolysis of triglycerides in cytosolic lipid droplets relies on three lipid hydrolases (lipases): adipose triglyceride lipase, hormone-sensitive lipase and monoacylglycerol lipase. The consecutive action of these enzymes provides free fatty acids and glycerol for energy production and other metabolic pathways during fasting. The regulation of neutral lipolysis is complex and involves numerous proteins, hormones, growth factors and cytokines. Conversely, products and intermediates of neutral lipolysis regulate key metabolic pathways by transcriptional and post-transcriptional mechanisms. Lipophagy is a subtype of macroautophagy. Portions of cytosolic lipid droplets are engulfed by lipoautophagosomes and transported to lysosomes, where triacylglycerols and other lipids undergo acid lipolysis by lysosomal acid lipase. The regulation of acid lipolysis is less complex than the regulation of neutral lipolysis, but again, the products and intermediates of triacylglycerol hydrolysis exit lysosomes and regulate multiple key processes in energy metabolism. Neutral lipolysis, acid lipolysis and lipophagy cooperate mechanistically. Rare mutations in the genes coding for adipose triglyceride lipase; its co-activator, lipid droplet-binding protein CGI-58; hormone-sensitive lipase; and lysosomal acid lipase cause distinct metabolic disorders in humans. Recent insights led to a better understanding of how cellular triacylglycerol catabolism affects the pathogenesis of metabolic diseases, cancer and cancer-associated cachexia and highlighted potential treatment strategies for lipid-associated disorders. Lipolysis degrades triacylglycerols to supply cells with free fatty acids, which are essential components of membrane lipids and substrates for energy production. Recent discoveries transformed our understanding of the functions of and crosstalk between 'neutral' lipolysis, which occurs in the cytosol, and lipophagy and 'acid' lipolysis, which occur in lysosomes, and how dysfunction in these processes contributes to metabolic diseases. Fatty acids are the most efficient substrates for energy production in vertebrates and are essential components of the lipids that form biological membranes. Synthesis of triacylglycerols from non-esterified free fatty acids (FFAs) combined with triacylglycerol storage represents a highly efficient strategy to stockpile FFAs in cells and prevent FFA-induced lipotoxicity. Although essentially all vertebrate cells have some capacity to store and utilize triacylglycerols, white adipose tissue is by far the largest triacylglycerol depot and is uniquely able to supply FFAs to other tissues. The release of FFAs from triacylglycerols requires their enzymatic hydrolysis by a process called lipolysis. Recent discoveries thoroughly altered and extended our understanding of lipolysis. This Review discusses how cytosolic 'neutral' lipolysis and lipophagy, which utilizes 'acid' lipolysis in lysosomes, degrade cellular triacylglycerols as well as how these pathways communicate, how they affect lipid metabolism and energy homeostasis and how their dysfunction affects the pathogenesis of metabolic diseases. Answers to these questions will likely uncover novel strategies for the treatment of prevalent metabolic diseases.

BACKGROUNDReprogramming of host metabolism supports viral pathogenesis by fueling viral proliferation, by providing, for example, free amino acids and fatty acids as building blocks.METHODSTo investigate metabolic effects of SARS-CoV-2 infection, we evaluated serum metabolites of patients with COVID-19 (n = 33; diagnosed by nucleic acid testing), as compared with COVID-19-negative controls (n = 16).RESULTSTargeted and untargeted metabolomics analyses identified altered tryptophan metabolism into the kynurenine pathway, which regulates inflammation and immunity. Indeed, these changes in tryptophan metabolism correlated with interleukin-6 (IL-6) levels. Widespread dysregulation of nitrogen metabolism was also seen in infected patients, with altered levels of most amino acids, along with increased markers of oxidant stress (e.g., methionine sulfoxide, cystine), proteolysis, and renal dysfunction (e.g., creatine, creatinine, polyamines). Increased circulating levels of glucose and free fatty acids were also observed, consistent with altered carbon homeostasis. Interestingly, metabolite levels in these pathways correlated with clinical laboratory markers of inflammation (i.e., IL-6 and C-reactive protein) and renal function (i.e., blood urea nitrogen).CONCLUSIONIn conclusion, this initial observational study identified amino acid and fatty acid metabolism as correlates of COVID-19, providing mechanistic insights, potential markers of clinical severity, and potential therapeutic targets.FUNDINGBoettcher Foundation Webb-Waring Biomedical Research Award; National Institute of General and Medical Sciences, NIH; and National Heart, Lung, and Blood Institute, NIH.

Abstract Context Consuming calories later in the day is associated with obesity and metabolic syndrome. We hypothesized that eating a late dinner alters substrate metabolism during sleep in a manner that promotes obesity. Objective The objective of this work is to examine the impact of late dinner on nocturnal metabolism in healthy volunteers. Design and Setting This is a randomized crossover trial of late dinner (LD, 22:00) vs routine dinner (RD, 18:00), with a fixed sleep period (23:00-07:00) in a laboratory setting. Participants Participants comprised 20 healthy volunteers (10 male, 10 female), age 26.0 ± 0.6 years, body mass index 23.2 ± 0.7 kg/m2, accustomed to a bedtime between 22:00 and 01:00. Interventions An isocaloric macronutrient diet was administered on both visits. Dinner (35% daily kcal, 50% carbohydrate, 35% fat) with an oral lipid tracer ([2H31] palmitate, 15 mg/kg) was given at 18:00 with RD and 22:00 with LD. Main Outcome Measures Measurements included nocturnal and next-morning hourly plasma glucose, insulin, triglycerides, free fatty acids (FFAs), cortisol, dietary fatty acid oxidation, and overnight polysomnography. Results LD caused a 4-hour shift in the postprandial period, overlapping with the sleep phase. Independent of this shift, the postprandial period following LD was characterized by higher glucose, a triglyceride peak delay, and lower FFA and dietary fatty acid oxidation. LD did not affect sleep architecture, but increased plasma cortisol. These metabolic changes were most pronounced in habitual earlier sleepers determined by actigraphy monitoring. Conclusion LD induces nocturnal glucose intolerance, and reduces fatty acid oxidation and mobilization, particularly in earlier sleepers. These effects might promote obesity if they recur chronically.

Aging women experience hormonal changes, such as decreased estrogen and increased circulating androgen, due to natural or surgical menopause. These hormonal changes make postmenopausal women vulnerable to body composition changes, muscle loss, and abdominal obesity; with a sedentary lifestyle, these changes affect overall energy expenditure and basal metabolic rate. In addition, fat redistribution due to hormonal changes leads to changes in body shape. In particular, increased bone marrow-derived adipocytes due to estrogen loss contribute to increased visceral fat in postmenopausal women. Enhanced visceral fat lipolysis by adipose tissue lipoprotein lipase triggers the production of excessive free fatty acids, causing insulin resistance and metabolic diseases. Because genes involved in β-oxidation are downregulated by estradiol loss, excess free fatty acids produced by lipolysis of visceral fat cannot be used appropriately as an energy source through β-oxidation. Moreover, aged women show increased adipogenesis due to upregulated expression of genes related to fat accumulation. As a result, the catabolism of ATP production associated with β-oxidation decreases, and metabolism associated with lipid synthesis increases. This review describes the changes in energy metabolism and lipid metabolic abnormalities that are the background of weight gain in postmenopausal women.

Visceral adipose tissue plays a critical role in numerous diseases. Although imaging studies often show adipose involvement in abdominal diseases, their outcomes may vary from being a mild self-limited illness to one with systemic inflammation and organ failure. We therefore compared the pattern of visceral adipose injury during acute pancreatitis and acute diverticulitis to determine its role in organ failure. Acute pancreatitis-associated adipose tissue had ongoing lipolysis in the absence of adipocyte triglyceride lipase (ATGL). Pancreatic lipase injected into mouse visceral adipose tissue hydrolyzed adipose triglyceride and generated excess nonesterified fatty acids (NEFAs), which caused organ failure in the absence of acute pancreatitis. Pancreatic triglyceride lipase (PNLIP) increased in adipose tissue during pancreatitis and entered adipocytes by multiple mechanisms, hydrolyzing adipose triglyceride and generating excess NEFAs. During pancreatitis, obese PNLIP-knockout mice, unlike obese adipocyte-specific ATGL knockouts, had lower visceral adipose tissue lipolysis, milder inflammation, less severe organ failure, and improved survival. PNLIP-knockout mice, unlike ATGL knockouts, were protected from adipocyte-induced pancreatic acinar injury without affecting NEFA signaling or acute pancreatitis induction. Therefore, during pancreatitis, unlike diverticulitis, PNLIP leaking into visceral adipose tissue can cause excessive visceral adipose tissue lipolysis independently of adipocyte-autonomous ATGL, and thereby worsen organ failure.