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Fatty acid mobilization from adipose tissue is mediated by CD36 posttranslational modifications and intracellular trafficking.

ABSTRACT: The mechanism controlling long-chain fatty acid (LCFA) mobilization from adipose tissue is not well understood. Here, we investigated how the LCFA transporter CD36 regulates this process. By using tissue-specific KO mouse models, we showed that CD36 in adipocytes and endothelial cells mediated both LCFA deposition into and release from adipose tissue. We demonstrated the role of adipocytic and endothelial CD36 in promoting tumor growth and chemoresistance conferred by adipose tissue-derived LCFAs. We showed that dynamic cysteine S-acylation of CD36 in adipocytes, endothelial cells, and cancer cells mediated intercellular LCFA transport. We demonstrated that lipolysis induction in adipocytes triggered CD36 deacylation and deglycosylation, as well as its dissociation from interacting proteins, prohibitin-1 (PHB) and annexin 2 (ANX2). Our data indicate that lipolysis triggers caveolar endocytosis and translocation of CD36 from the cell membrane to lipid droplets. This study suggests a mechanism for both outside-in and inside-out cellular LCFA transport regulated by CD36 S-acylation and its interactions with PHB and ANX2.

SUBMITTER: Daquinag AC

PROVIDER: S-EPMC8492349 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Endothelial cell CD36 optimizes tissue fatty acid uptake.

Project description:Movement of circulating fatty acids (FAs) to parenchymal cells requires their transfer across the endothelial cell (EC) barrier. The multiligand receptor cluster of differentiation 36 (CD36) facilitates tissue FA uptake and is expressed in ECs and parenchymal cells such as myocytes and adipocytes. Whether tissue uptake of FAs is dependent on EC or parenchymal cell CD36, or both, is unknown. Using a cell-specific deletion approach, we show that EC, but not parenchymal cell, CD36 deletion increased fasting plasma FAs and postprandial triglycerides. EC-Cd36-KO mice had reduced uptake of radiolabeled long-chain FAs into heart, skeletal muscle, and brown adipose tissue; these uptake studies were replicated using [11C]palmitate PET scans. High-fat diet-fed EC-CD36-deficient mice had improved glucose tolerance and insulin sensitivity. Both EC and cardiomyocyte (CM) deletion of CD36 reduced heart lipid droplet accumulation after fasting, but CM deletion did not affect heart glucose or FA uptake. Expression in the heart of several genes modulating glucose metabolism and insulin action increased with EC-CD36 deletion but decreased with CM deletion. In conclusion, EC CD36 acts as a gatekeeper for parenchymal cell FA uptake, with important downstream effects on glucose utilization and insulin action.

| S-EPMC6159965 | biostudies-literature

UCP1 deficiency increases adipose tissue monounsaturated fatty acid synthesis and trafficking to the liver.

Project description:Uncoupling protein-1 (UCP1) facilitates thermogenesis in brown and beige adipocytes and can promote energy expenditure by decreasing mitochondrial respiratory efficiency. Defects in UCP1 and brown adipose tissue thermogenesis subject animals to chronic cold stress and elicit compensatory responses to generate heat. How UCP1 regulates white adipose tissue (WAT) lipid biology and tissue crosstalk is not completely understood. Here, we probed the effect of UCP1 deficiency on FA metabolism in inguinal and epididymal WAT and investigated how these metabolic perturbations influence hepatic lipid homeostasis. We report that at standard housing temperature (21°C), loss of UCP1 induces inguinal WAT de novo lipogenesis through transcriptional activation of the lipogenic gene program and elevated GLUT4. Inguinal adipocyte hyperplasia and depot expansion accompany the increase in lipid synthesis. We also found that UCP1 deficiency elevates adipose stearoyl-CoA desaturase gene expression, and increased inguinal WAT lipolysis supports the transport of adipose-derived palmitoleate (16:1n7) to the liver and hepatic triglyceride accumulation. The observed WAT and liver phenotypes were resolved by housing animals at thermoneutral housing (30°C). These data illustrate depot-specific responses to impaired BAT thermogenesis and communication between WAT and liver in UCP1-/- mice.

| S-EPMC5794418 | biostudies-literature

Keap1-knockdown decreases fasting-induced fatty liver via altered lipid metabolism and decreased fatty acid mobilization from adipose tissue.

Project description:AimsThe purpose of this study was to determine whether Nrf2 activation, via Keap1-knockdown (Keap1-KD), regulates lipid metabolism and mobilization induced by food deprivation (e.g. fasting).Methods and resultsMale C57BL/6 (WT) and Keap1-KD mice were either fed ad libitum or food deprived for 24 hours. After fasting, WT mice exhibited a marked increase in hepatic lipid accumulation, but Keap1-KD mice had an attenuated increase of lipid accumulation, along with reduced expression of lipogenic genes (acetyl-coA carboxylase, stearoyl-CoA desaturase-1, and fatty acid synthase) and reduced expression of genes related to fatty acid transport, such as fatty acid translocase/CD36 (CD36) and Fatty acid transport protein (FATP) 2, which may attribute to the reduced induction of Peroxisome proliferator-activated receptor (Ppar) ? signaling in the liver. Additionally, enhanced Nrf2 activity by Keap1-KD increased AMP-activated protein kinase (AMPK) phosphorylation in liver. In white adipose tissue, enhanced Nrf2 activity did not change the lipolysis rate by fasting, but reduced expression of fatty acid transporters--CD36 and FATP1, via a PPAR?-dependent mechanism, which impaired fatty acid transport from white adipose tissue to periphery circulation system, and resulted in increased white adipose tissue fatty acid content. Moreover, enhanced Nrf2 activity increased glucose tolerance and Akt phosphorylation levels upon insulin administration, suggesting Nrf2 signaling pathway plays a key role in regulating insulin signaling and enhanced insulin sensitivity in skeletal muscle.ConclusionEnhanced Nrf2 activity via Keap1-KD decreased fasting-induced steatosis, pointing to an important function of Nrf2 on lipid metabolism under the condition of nutrient deprivation.

| S-EPMC3817107 | biostudies-literature

Endothelial Cell CD36 Optimizes Tissue Fatty Acid Uptake

Project description:Movement of circulating fatty acids (FAs) to parenchymal cells requires their transfer across the endothelial cell (EC) barrier. The multi-ligand receptor cluster of differentiation 36 (CD36) facilitates tissue FA uptake and is expressed in ECs and parenchymal cells such as myocytes and adipocytes. Whether tissue uptake of FAs is dependent on EC or parenchymal cell CD36, or both, is unknown. Using a cell-specific deletion approach, we show that CD36-mediated FA transport across ECs rate-limits tissue FA uptake, and its loss leads to metabolic effects in parenchymal cells.

2018-06-28 | GSE116350 | GEO

Adipose and muscle tissue profile of CD36 transcripts in obese subjects highlights the role of CD36 in fatty acid homeostasis and insulin resistance.

Project description:Fatty acid (FA) metabolism is tightly regulated across several tissues and impacts insulin sensitivity. CD36 facilitates cellular FA uptake, and CD36 genetic variants associate with lipid abnormalities and susceptibility to metabolic syndrome. The objective of this study was to gain insight regarding the in vivo metabolic influence of muscle and adipose tissue CD36. For this, we determined the relationships between CD36 alternative transcripts, which can reflect tissue-specific CD36 regulation, and measures of FA metabolism and insulin resistance.The relative abundance of alternative CD36 transcripts in adipose tissue and skeletal muscle from 53 nondiabetic obese subjects was measured and related to insulin sensitivity and FA metabolism assessed by hyperinsulinemic-euglycemic clamps and isotopic tracers for glucose and FA.Transcript 1C, one of two major transcripts in adipose tissue, that is restricted to adipocytes predicted systemic and tissue (adipose, liver, and muscle) insulin sensitivity, suggesting adipocyte CD36 protects against insulin resistance. Transcripts 1B and 1A, the major transcripts in skeletal muscle, correlated with FA disposal rate and triglyceride clearance, supporting importance of muscle CD36 in clearance of circulating FA. Additionally, the common CD36 single nucleotide polymorphism rs1761667 selectively influenced CD36 transcripts and exacerbated insulin resistance of glucose disposal by muscle.Alternative CD36 transcripts differentially influence tissue CD36 and consequently FA homeostasis and insulin sensitivity. Adipocyte CD36 appears to be metabolically protective, and its selective upregulation might have therapeutic potential in insulin resistance.

| S-EPMC4067395 | biostudies-literature

Downregulation of adipose tissue fatty acid trafficking in obesity: a driver for ectopic fat deposition?

Project description:ObjectiveLipotoxicity and ectopic fat deposition reduce insulin signaling. It is not clear whether excess fat deposition in nonadipose tissue arises from excessive fatty acid delivery from adipose tissue or from impaired adipose tissue storage of ingested fat.Research design and methodsTo investigate this we used a whole-body integrative physiological approach with multiple and simultaneous stable-isotope fatty acid tracers to assess delivery and transport of endogenous and exogenous fatty acid in adipose tissue over a diurnal cycle in lean (n = 9) and abdominally obese men (n = 10).ResultsAbdominally obese men had substantially (2.5-fold) greater adipose tissue mass than lean control subjects, but the rates of delivery of nonesterified fatty acids (NEFA) were downregulated, resulting in normal systemic NEFA concentrations over a 24-h period. However, adipose tissue fat storage after meals was substantially depressed in the obese men. This was especially so for chylomicron-derived fatty acids, representing the direct storage pathway for dietary fat. Adipose tissue from the obese men showed a transcriptional signature consistent with this impaired fat storage function.ConclusionsEnlargement of adipose tissue mass leads to an appropriate downregulation of systemic NEFA delivery with maintained plasma NEFA concentrations. However the implicit reduction in adipose tissue fatty acid uptake goes beyond this and shows a maladaptive response with a severely impaired pathway for direct dietary fat storage. This adipose tissue response to obesity may provide the pathophysiological basis for ectopic fat deposition and lipotoxicity.

| S-EPMC3012196 | biostudies-literature

Effect of glucocorticoid hormones on fatty acid mobilization and re-esterification in rat adipose tissue.

Project description:1. The effect of dexamethasone and cortisol on fatty acid mobilization and re-esterification has been studied in intact adipose tissue and isolated fat cells of the rat. 2. Dexamethasone added in vitro inhibited both the re-esterification of mobilized free fatty acids and the esterification of palmitate in the medium. 3. Under several conditions (low concentrations of dexamethasone, cortisol at a high concentration, with tissue from starved animals), steroid-induced release of free fatty acids could be accounted for by decreased re-esterification only, overall lipolytic activity remaining unmodified. At higher concentrations of dexamethasone, however, stimulation of lipolytic activity also occurred. 4. Decreased re-esterification produced by dexamethasone was observed in the total absence of glucose from the incubation medium. Further, dexamethasone stimulated the disappearance of prelabelled [(14)C]glycogen from the tissue. 5. The evidence presented suggests that mobilization of free fatty acids induced by glucocorticoid hormones under physiological conditions is primarily due to a decrease of the re-esterification rate rather than to lipase activation.

| S-EPMC1270460 | biostudies-other

Factors regulating subcutaneous adipose tissue storage, fibrosis, and inflammation may underlie low fatty acid mobilization in insulin-sensitive obese adults.

Project description:Although the rate of fatty acid release from adipose tissue into the systemic circulation is very high in most obese adults, some obese adults maintain relatively low rates of fatty acid release, which helps protect them against the development of systemic insulin resistance. The primary aim of this study was to identify factors in adipose tissue that may underlie low vs. high rates of fatty acid mobilization in a relatively homogeneous cohort of obese adults. We measured systemic fatty acid rate of appearance (FA Ra) via 13C-palmitate isotope dilution, and we obtained subcutaneous abdominal adipose tissue samples from 30 obese adults (BMI: 38?±?1 kg/m2, age: 30?±?2 yr) after an overnight fast. We then measured insulin sensitivity using a hyperinsulinemic-euglycemic clamp. Confirming our previous work, insulin sensitivity was inversely proportional to FA Ra (R2?=?0.50; P < 0.001). Immunoblot analysis of subcutaneous adipose tissue samples revealed that, compared with obese adults with high FA Ra, those with low FA Ra had lower markers of lipase activation and higher abundance of glycerol-3-phosphate acyltransferase, which is a primary enzyme for fatty acid esterification. Microarray and pathway analysis provided evidence of lower fibrosis and lower SAPK/JNK pathway activation in obese adults with low FA Ra compared with those with high FA Ra. Our findings suggest that alterations in factors regulating triglyceride storage in adipose tissue, along with lower fibrosis and inflammatory pathway activation, may underlie maintenance of a relatively low FA Ra in obesity, which may help protect against the development of insulin resistance.

| S-EPMC5668599 | biostudies-literature

Endothelial Cell CD36 Optimizes Tissue Fatty Acid Uptake

Project description:Endothelial Cell CD36 Optimizes Tissue Fatty Acid Uptake

| PRJNA478230 | ENA

Nitro-fatty acid pharmacokinetics in the adipose tissue compartment.

Project description:Electrophilic nitro-FAs (NO2-FAs) promote adaptive and anti-inflammatory cell signaling responses as a result of an electrophilic character that supports posttranslational protein modifications. A unique pharmacokinetic profile is expected for NO2-FAs because of an ability to undergo reversible reactions including Michael addition with cysteine-containing proteins and esterification into complex lipids. Herein, we report via quantitative whole-body autoradiography analysis of rats gavaged with radiolabeled 10-nitro-[14C]oleic acid, preferential accumulation in adipose tissue over 2 weeks. To better define the metabolism and incorporation of NO2-FAs and their metabolites in adipose tissue lipids, adipocyte cultures were supplemented with 10-nitro-oleic acid (10-NO2-OA), nitro-stearic acid, nitro-conjugated linoleic acid, and nitro-linolenic acid. Then, quantitative HPLC-MS/MS analysis was performed on adipocyte neutral and polar lipid fractions, both before and after acid hydrolysis of esterified FAs. NO2-FAs preferentially incorporated in monoacyl- and diacylglycerides, while reduced metabolites were highly enriched in triacylglycerides. This differential distribution profile was confirmed in vivo in the adipose tissue of NO2-OA-treated mice. This pattern of NO2-FA deposition lends new insight into the unique pharmacokinetics and pharmacologic actions that could be expected for this chemically-reactive class of endogenous signaling mediators and synthetic drug candidates.

| S-EPMC5282953 | biostudies-literature

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