Lipid Metabolism In White Adipose Tissue Research Articles

Garlic Scape (Allium sativum L.) Extract Decreases Adipogenesis by Activating AMK-Activated Protein Kinase During the Differentiation in 3T3-L1 Adipocytes.

Regulating adipogenesis and lipogenesis in white adipose tissue (WAT) is an efficient strategy to reduce obesity. This study investigates whether garlic scape extract (GSE) has anti-adipogenic and anti-lipogenic effects and which stage of adipogenesis is critical for its effect using 3T3-L1 cells. 3T3-L1 cells that were treated with GSE during adipogenesis and differentiation exhibited reduced peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein a (Cebpa) and Cebpb, acetyl-CoA carboxylase, fatty acid synthase, sterol regulatory element binding protein 1c, diacylglycerol acyltransferase 1, and perilipin 1 genes. When the cells were treated with GSE during postdifferentiation or during preadipocytes, they showed less reduction and no change, respectively. Consistent with this, lipid accumulation was strongly reduced in the cells that were treated during adipogenesis and differentiation and to a lesser extent in the cells that were treated during preadipocytes and postdifferentiation. Phosphorylation on AMP-activated protein kinase (AMPK) and its downstream proteins was increased together with increased carnitine palmitoyl transferase 1α and phosphorylation on hormone-sensitive lipase in the cells that were treated with GSE during differentiation. In summary, GSE reduced intracellular lipid accumulation by suppressing adipogenic and lipogenic genes and proteins by possibly the activation of AMPK signaling pathway during adipocyte differentiation. This result indicates that garlic scape may have the potential to prevent obesity by regulating lipid metabolism in WAT.

Deletion of Trim28 in committed adipocytes promotes obesity but preserves glucose tolerance

The effective storage of lipids in white adipose tissue (WAT) critically impacts whole body energy homeostasis. Many genes have been implicated in WAT lipid metabolism, including tripartite motif containing 28 (Trim28), a gene proposed to primarily influence adiposity via epigenetic mechanisms in embryonic development. However, in the current study we demonstrate that mice with deletion of Trim28 specifically in committed adipocytes, also develop obesity similar to global Trim28 deletion models, highlighting a post-developmental role for Trim28. These effects were exacerbated in female mice, contributing to the growing notion that Trim28 is a sex-specific regulator of obesity. Mechanistically, this phenotype involves alterations in lipolysis and triglyceride metabolism, explained in part by loss of Klf14 expression, a gene previously demonstrated to modulate adipocyte size and body composition in a sex-specific manner. Thus, these findings provide evidence that Trim28 is a bona fide, sex specific regulator of post-developmental adiposity and WAT function.

A maple syrup extract alters lipid metabolism in obese type 2 diabetic model mice

BackgroundSome polyphenols are known to improve the symptoms of diabetes. In the present study, we investigated the effects of a polyphenol-rich extract of maple syrup (MSx) on a diabetic mouse model.MethodsKK-Ay mice were fed a normal or 0.05% MSx-supplemented diet for 42 days. Body weight, food intake, serum biochemical parameters, and fecal total bile acid were measured. Gene expression of liver and epididymal white adipose tissue (WAT) and cecal microbiota were analyzed. Data were analyzed with an unpaired two-tailed Student’s t test or Welch’s t test according to the results of the F test.ResultsSerum low-density lipoprotein cholesterol levels were significantly reduced in mice that consumed MSx. Hepatic genes related to fatty acid degradation and cholesterol catabolism were upregulated in mice that consumed MSx. In contrast, the expression of genes related to lipid metabolism in WAT was unaffected by the intake of MSx. There were no significant differences between the two groups in terms of total bile acid level in the feces and the relative abundance of bacteria in the cecum.ConclusionOur results primarily indicate that MSx can help alleviate one of the symptoms of dyslipidemia.

A phosphorylation-deficient mutant of retinoid X receptor α at Thr 167 alters fasting response and energy metabolism in mice

Retinoid X receptor α (RXRα) has a conserved phosphorylation motif at threonine 162 (humans) and threonine 167 (mice) within the DNA-binding domain. Here we have generated RXRα knock-in mice (RxrαT167A) bearing a single mutation of Thr 167 to alanine and examined the roles of Thr 167 in the regulation of energy metabolism within adipose, muscle, and liver tissues. RxrαT167A mice exhibited down-regulation of metabolic pathways converting glucose to fatty acids, such as acetyl-CoA carboxylase in the white adipose tissue (WAT) and ATP citrate lyase in the muscle. They also reduced gene expression for genes related to fatty acid catabolism and triglyceride synthesis in WAT and controlled heat factors such as adrenergic receptor β1 in muscles. In contrast, hepatic gluconeogenic pathways and synthetic pathways related to fatty acids remained unaffected by this mutation. Expression of multiple genes that were affected by the Thr 167 mutation in adipose tissue exhibited clear response to LG100268, a synthetic RXR agonist. Thus, the altered gene expression in mutant mice adipose appeared to be a direct effect of RXRα Thr 167 mutation and by some secondary effect of the mutation. Blood glucose levels remained normal in RxrαT167A during feeding, as observed with RXRα wild-type mice. However, RxrαT167A mice exhibited an attenuated decrease of blood glucose levels that occurred after fasting. This attenuation correlated with a concomitant down-regulation of lipid metabolism in WAT and was associated with RXRα phosphorylation at Thr 167. Thus, Thr 167 enabled RXRα to coordinate these three organs for regulation of energy metabolism and maintenance of glucose homeostasis.

PO-201 Aging attenuates the effect of aerobic capacity in muscle and serum metabolic profile but not in white adipose tissue

Objective Aerobic capacity is a quantitative predictor of the morbidity and mortality in many diverse patient populations. While aging is the main factor affecting aerobic capacity. The present study aimed to assess the effect of aerobic capacity and aging on metabolic profile in rats and to investigate the metabolic interactions between white adipose tissue (WAT), muscle and serum.
 Methods In this study, we used rat models that were selectively bred to differ in maximal running capacity (High capacity runners (HCR) and Low capacity runners (LCR)). Part of the rats were sacrificed after 9 months and the rest at 21 months. The effect of aerobic capacity on metabolic profile was assessed from 9 months old young rats (HCR-Y and LCR-Y), while the effect of aging on the metabolic profile in different capacity rats was determined comparing 9 months to 21 months old rats (HCR-O and LCR-O). Nuclear magnetic resonance (NMR) spectroscopy was performed to detect the metabolomics of WAT, muscle and serum. Partial least-squares-discriminant analysis (PLS-DA) was used for pattern recognition between HCR-Y and LCR-Y and between HCR-O and LCR-O. Metabolites with variable influence on projection (VIP) >1.0 and p<0.05 were classified as significantly different metabolites between groups. Spearman correlation was used to assess the metabolic interactions between white adipose tissue (WAT), muscle and serum.
 Results HCR-Y rats had significantly higher skeletal muscle mass-to-body mass ratio (p<0.001), while lower body mass (p<0.001), fat mass (p<0.001), skeletal muscle mass (p=0.035) and fat mass to body mass ratio (p=0.004) than LCR-Y rats. The running capacity of HCR-Y rats was 132.7% (best running speed) better than LCR-Y rats (p<0.001). However, with age, the difference between body compositions between the two capacity groups became insignificant. HCR-O only had significantly lower body mass than the LCR-O (p=0.02). Running capacity (p=0.06) was 86.4% (best running speed) higher in the HCR-O rats than that of the LCR-O rats. PLS-DA revealed marked effects of aerobic capacity on metabolic profile in all three tissue types between HCR-Y and LCR-Y. The metabolic profile classification and prediction was best (i.e. sharper) in muscle than in WAT and serum. In addition, muscle and serum contained more significantly different metabolites than WAT in HCR-Y than in LCR-Y. Pathway analysis of the significantly different metabolites between HCR-Y and LCR-Y revealed that all the pathways belong to the lipid metabolism and amino acid metabolism in muscle while in serum it is only amino acid metabolism. However, in the case of the old groups, the PLS-DA gave reversed results. It revealed that WAT performed best in terms of classification and prediction of metabolites between HCR-O and LCR-O and had the most significantly different metabolites out of the three tissue types. The significantly different metabolites’ pathways belong to lipid metabolism in WAT. When assessing the metabolic interaction between different tissue types, all significantly different metabolites between HCR and LCR rats in young and old groups were moderately or strongly correlated (Spearman correlation between 0.45-0.9) with one or more metabolites in any of the three tissues.
 Conclusions In this study, we assessed the metabolic profile and body composition of WAT, muscle and serum in young and old rats with different aerobic capacities. We found that aerobic capacity greatly impacts body composition and the metabolic profile in muscle and serum in young rats, however the impact is attenuated with age. In addition, it is aging and not aerobic capacity that had the most influence on WAT metabolites. This suggest that WAT has more important role in aging process than previously assumed.

Consumption of an EPA and DHA Rich Diet Rescues Changes in White Adipose Tissue Lipid Metabolism and Oxylipin Production Induced in Fads2‐null Mice

Omega‐3 polyunsaturated fatty acids (PUFA) influence lipid metabolism and inflammatory signaling pathways in white adipose tissue (WAT). Alpha‐linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the three primary dietary omega‐3 PUFAs that have wide‐ranging functions in humans. There is currently a limited understanding of the independent effects of individual omega‐3 PUFAs because ALA is continuously converted endogenously into EPA and DHA via the fatty acid desaturase (FADS) pathway. The fatty acid desaturase 2 gene (Fads2) encodes the rate‐limiting delta‐6 desaturase enzyme in this pathway. This study examined the role of Fads2 on WAT omega‐3 PUFA metabolism and whether the consumption of a diet supplemented with menhaden oil (MD), which is rich in EPA and DHA, could rescue changes in WAT associated with a Fads2 deficiency. Weaned Fads2 knockout (Fads2−/−) and wild type (WT) mice were fed one of two low fat (7% w/w) AIN93G diets for 9 weeks containing either flaxseed oil + ARASCO (FD, 55% ALA) or menhaden oil (MD, 30% EPA/DHA). RT‐qPCR was used to analyze expression of genes related to PUFA metabolism. Thin‐layer and gas chromatography were used to measure fatty acid content in the phospholipid and triacylglycerol fractions in WAT. Analysis of oxylipins was undertaken using liquid chromatography–tandem mass spectrometry. Western blotting was performed for delta‐5‐desaturase (D5D) protein quantification. Fads2−/− mice fed FD had increased expression of Fads1 and Elovl2, and decreased expression of Elovl5 genes (p<0.05). These changes were abrogated with MD feeding. Estimated D5D activity (arachidonic acid: dihomo‐γ‐linolenic acid ratio) was increased in Fads2−/− mice fed FD in WAT (p<0.05), but this change was not mirrored in FADS1 protein content. EPA and DHA levels were depleted in WAT of Fads2−/− mice fed FD, as were their derived oxylipins; however, feeding Fads2−/− mice MD restored both omega‐3 PUFA and oxylipin profiles. In conclusion, these results demonstrate that Fads2 has an important role regulating omega‐3 PUFA and oxylipin content in WAT. Moreover, changes in WAT associated with a Fads2 deficiency can be rescued with a nutritional intervention containing EPA and DHA.Support or Funding InformationThis work was supported by the Canadian Institutes of Health Research.

Undaria pinnatifida and Fucoxanthin Ameliorate Lipogenesis and Markers of Both Inflammation and Cardiovascular Dysfunction in an Animal Model of Diet-Induced Obesity.

Brown algae and its carotenoids have been shown to have a positive influence on obesity and its comorbidities. This study evaluated the effect of Undaria pinnatifida and fucoxanthin on biochemical, physiological and inflammation markers related to obesity and on the expression of genes engaged on white adipose tissue lipid metabolism in a murine model of diet-induced obesity. The treatments improved energy expenditure, β-oxidation and adipogenesis by upregulating PPARα, PGC1α, PPARγ and UCP-1. Adipogenesis was also confirmed by image analysis of the retroperitoneal adipose tissue, by measuring cell area, perimeter and cellular density. Additionally, the treatments, ameliorated adipose tissue accumulation, insulin resistance, blood pressure, cholesterol and triglycerides concentration in serum, and reduced lipogenesis and inflammation by downregulating acetyl-CoA carboxylase (ACC) gene expression, increasing serum concentration and expression of adiponectin as well as downregulating IL-6 expression. Both fucoxanthin and Undaria pinnatifida may be considered for treating obesity and other diseases related.

Molecular correlates of fat mass expansion in C57BL/6J mice after short‐term exposure to dietary fat

Heterogeneity of obesity within a population of inbred mice fed an obesogenic high-fat diet (HFD) is associated with changes of gene expression in white adipose tissue (WAT). One gene in particular with large variations among mice, mesoderm-specific transcript (Mest), has been shown to be highly inducible after being fed a short-term HFD, and its expression in WAT before HFD feeding is predictive for susceptibility to the development of obesity. To gain further insight into the association of Mest with rapid changes in body composition, 96 individually housed C57BL/6J mice were fed an HFD for only 2 weeks, resulting in a 12-fold and 90-fold variation in Mest mRNA in visceral epididymal and subcutaneous inguinal WAT, respectively. WAT Mest mRNA was positively associated with interindividual variation of fat mass. Surprisingly, there was only a slight association of WAT Mest with food intake when normalized by body weight or lean mass. In addition, WAT Mest expression coincided highly with the expression of the transcription factor Kruppel-like factor 14 (Klf14), an imprinted gene that regulates lipid metabolism in WAT. Our data suggest that KLF14 transcriptional activity may partially mediate, or act in concert with, MEST as part of an epigenetic mechanism that promotes fat mass accumulation in mice fed an obesogenic diet.

Altered Lipid Metabolism in Residual White Adipose Tissues of Bscl2 Deficient Mice

Mutations in BSCL2 underlie human congenital generalized lipodystrophy type 2 disease. We previously reported that Bscl2 −/− mice develop lipodystrophy of white adipose tissue (WAT) due to unbridled lipolysis. The residual epididymal WAT (EWAT) displays a browning phenotype with much smaller lipid droplets (LD) and higher expression of brown adipose tissue marker proteins. Here we used targeted lipidomics and gene expression profiling to analyze lipid profiles as well as genes involved in lipid metabolism in WAT of wild-type and Bscl2−/− mice. Analysis of total saponified fatty acids revealed that the residual EWAT of Bscl2−/− mice contained a much higher proportion of oleic18:1n9 acid concomitant with a lower proportion of palmitic16:0 acid, as well as increased n3- polyunsaturated fatty acids (PUFA) remodeling. The acyl chains in major species of triacylglyceride (TG) and diacylglyceride (DG) in the residual EWAT of Bscl2−/− mice were also enriched with dietary fatty acids. These changes could be reflected by upregulation of several fatty acid elongases and desaturases. Meanwhile, Bscl2−/− adipocytes from EWAT had increased gene expression in lipid uptake and TG synthesis but not de novo lipogenesis. Both mitochondria and peroxisomal β-oxidation genes were also markedly increased in Bscl2−/− adipocytes, highlighting that these machineries were accelerated to shunt the lipolysis liberated fatty acids through uncoupling to dissipate energy. The residual subcutaneous white adipose tissue (ScWAT) was not browning but displays similar changes in lipid metabolism. Overall, our data emphasize that, other than being essential for adipocyte differentiation, Bscl2 is also important in fatty acid remodeling and energy homeostasis.

Combination of fucoxanthin and conjugated linoleic acid attenuates body weight gain and improves lipid metabolism in high-fat diet-induced obese rats

The present study investigated the effects of combined fucoxanthin (Fc) and conjugated linoleic acid (CLA) on high-fat diet-induced obese rats. Thirty five rats were divided into four groups, fed a high-fat diet (Control, 15% fat, wt/wt), supplemented with low Fc (FCL, 0.083mg/kg/bw), high Fc (FCH, 0.167mg/kg/bw) and FCL (0.083mg/kg/bw) plus CLA (0.15g/kg/bw) (FCL+CLA) for 52d. Body weight and white adipose tissue (WAT) weight were significantly suppressed in FCL+CLA group than those in control group. WAT weight was also markedly attenuated in FCL and FCH groups. Accumulation of hepatic lipid droplets and the perirenal adipocyte size of FCL, FCH and FCL+CLA groups were diminished compared to control group. Serum total cholesterol level in FCH group, triacylglycerol and leptin levels in FCL, FCH and FCL+CLA groups, and glucose concentration in FCH and FCL+CLA groups were significantly decreased than those in control group. The mRNA expression of adiponectin, adipose triacylglycerol lipase, carnitine palmitoyltransferase 1A was remarkably up-regulated in FCL, FCH and FCL+CLA groups. These results suggest that Fc and FCL+CLA could reduce serum levels of triacylglycerol, glucose and leptin, and FCL+CLA could exert anti-obesity effects by regulating mRNA expression of enzymes related to lipid metabolism in WAT of diet-induced obesity rats.

Type 2 Corticotropin-Releasing Factor Receptor in the Ventromedial Nucleus of Hypothalamus Is Critical in Regulating Feeding and Lipid Metabolism in White Adipose Tissue

Ventromedial nucleus of hypothalamus (VMH) plays a critical role in regulating feeding and energy metabolism. The nucleus expresses high levels of the type 2 corticotropin-releasing factor receptor (CRFR2) and receives prominent innervation of nerve fibers containing Urocortin 3 (Ucn 3), an endogenous ligand of the receptor. In the present study, we showed that mice deficient in Ucn 3 had elevated basal feeding and increased nocturnal food intake after overnight fasting compared with the wild-type (WT) littermates. The Ucn 3 null mice also had lower circulating insulin levels compared with those of the WT mice. Interestingly, the mutant mice maintained a comparable body weight with the WT littermates. Mice with reduced CRFR2 expression in the VMH by small hairpin RNA knockdown (KD) recapitulated feeding phenotypes observed in the Ucn 3 null mice. However, VMH CRFR2 KD mice gained significantly more weight than control mice. The weight gain was due to an accumulation of white adipose tissue (WAT) accompanied by reduced plasma free fatty acids and glycerol levels, increased respiratory quotients, and improved glucose tolerance. On the other hand, plasma insulin levels were comparable with the receptor KD and control mice. Furthermore, the expression of several genes, including hormone-sensitive lipase, was significantly reduced in the WAT of VMH CRFR2 KD mice compared with controls. These results indicate that Ucn 3 signaling through CRFR2 is a critical molecular mediator in the VMH in regulating feeding and lipid metabolism in WAT.

The Cannabinoid Receptor Agonist THC Attenuates Weight Loss in a Rodent Model of Activity-Based Anorexia

Anorexia nervosa (AN) is characterized by anhedonia whereby patients experience little pleasure or reward in many aspects of their lives. Reward pathways and the endocannabionid system have been implicated in the mediation of food intake. The potential to exploit these systems to reverse weight loss is investigated in a rodent model of activity-based anorexia (ABA). The effect of subchronic (6 days) Δ(9)-tetrahydrocannabinol (THC) treatment (0.1, 0.5, or 2.0 mg/kg/day) was assessed on chow and high-fat diet (HFD) intake, body weight, running wheel activity (RWA) as well as thermogenesis in brown adipose tissue (BAT) and lipid metabolism in white adipose tissue (WAT). Limited time availability of food and continuous access to running wheels led to anorexia and significantly reduced body weight. THC treatment (0.5 and 2.0 mg/kg/day) transiently stimulated chow intake with a moderate effect on RWA. THC (2.0 mg/kg/day) significantly reduced body weight loss and shifted markers of thermogenesis in BAT and lipid metabolism in WAT in directions consistent with reduced energy expenditure and lipolysis. THC (2.0 mg/kg/day) combined with HFD, produced a transient increase in food intake, reduction in RWA, attenuation of body weight loss, and changes in markers of thermogensis in BAT and lipolysis in the WAT. These changes were significantly greater than those seen in vehicle (HFD), vehicle (chow), and THC (chow)-treated animals. These data show for the first time the effectiveness of the endocannabinoid system in attenuating the weight loss associated with the development of ABA via a mechanism involving reduced energy expenditure.

CHRONIC APOCYNIN TREATMENT IMPROVES NORADRENERGIC PRESYNAPTIC REUPTAKE, INHIBITS SYMPATHETIC-MEDIATED LIPOLYSIS AND FAT LOSS IN A AGING RAT MODEL OF HEART FAILURE: 1A.04

Cardiac cachexia including fat loss is detrimental for advanced aged heart failure patients. Advanced heart failure is characterized by neurohormonal and oxidative stress imbalance. This study evaluated in old male spontaneously hypertensive rats (SHR), developing heart failure, the effects of long-term inhibition of NAD(P)H oxidase with Apocynin on subcutaneous white adipose tissue lipid metabolism and sympathetic turnover, expressed by interstitial norepinephrine release (NE) and presynaptic NE reuptake evaluation (through desipramine microdialysis probe perfusion). Blood pressure, heart rate and body weight were measured on 51 SHR from 72 weeks old until the development of overt heart failure. Thirteen age-matched Wistar-Kyoto rats (WKY) were normotensive controls. At 72 weeks, SHR underwent a basal microdialysis procedure which showed a higher interstitial subcutaneous glycerol level, expressing an increased local triglyceride breakdown and lipolysis, and higher NE level associated with a reduced presynaptic reuptake as compared to WKY. SHRs were then separated: 1) untreated SHR (n = 27) and 2) SHR (n = 24) treated with Apocynin (2.5 mg/kg/d in drinking water) until death or 88 weeks of age, when the rats repeated the microdialysis procedure.Thirty-three % of untreated SHR showed a body weight reduction of more than 15% (at 88 weeks of age) whereas in Apocynin-treated SHR only 4 (16%) developed cachexia. Glycerol interstitial levels were higher in cachectic than non-cachectic untreated SHR. Cachectic SHR showed higher NE level and a blunted response to desipramine, indicating a marked reduction of presynaptic reuptake. Non-cachectic apocynin-treated SHR showed a reduced interstitial level of glycerol and NE and improved presynaptic NE reuptake. These results suggest that chronic Apocynin treatment could improve subcutaneous NE reuptake and reduce interstitial NE concentrations and NE-induced lipolysis, as expressed by lower interstitial glycerol level. This drug seems to be able to attenuate cachexia development in this animal model of heart failure.

Site-specific modulation of white adipose tissue lipid metabolism by oleoyl-estrone and/or rosiglitazone in overweight rats

In spite of their shared decrease of insulin resistance, oleoyl-estrone [OE], and rosiglitazone show diverging effects on body fat mass and distribution. In this study, we studied whether their effects on white adipose tissue [WAT] were due to a shared or synergistic mechanism of action. Combined effects of OE and rosiglitazone 10-day treatment on WAT lipid, cell mass/number, and the expression of key lipid metabolism and regulatory agents were studied using an adult male overweight rat model. OE decreased WAT cell mass and lipids, parameters not changed by rosiglitazone. The effects of OE and--specially--rosiglitazone were more marked in small-cell WAT (i.e., mesenteric and subcutaneous sites) than in larger cell WAT (retroperitoneal and perigonadal). OE decreased the expressions in WAT of lipogenic enzymes, lipoprotein lipase, PPARs, and SREBP1c, effects symmetrically reversed by rosiglitazone. OE showed no effects on hormone-sensitive lipase expression, which was increased by rosiglitazone. OE strongly inhibited WAT lipogenesis, leaving lipolysis unchanged, thus unbalancing (and helping mobilize) WAT lipid stores. Rosiglitazone acted practically only on small-cell WAT sites, where it favored lipogenesis, but also stimulated lipolysis, which resulted in limited changes in lipid stores. Combination of OE and rosiglitazone induced less fat loss than OE alone.

Prolonged AICAR-induced AMP-kinase activation promotes energy dissipation in white adipocytes: novel mechanisms integrating HSL and ATGL

This study was designed to investigate the effects of prolonged activation of AMP-activated protein kinase (AMPK) on lipid partitioning and the potential molecular mechanisms involved in these processes in white adipose tissue (WAT). Rat epididymal adipocytes were incubated with 5'-aminoimidasole-4-carboxamide-1-beta-d-ribofuranoside (AICAR;0.5 mM) for 15 h. Also, epididymal adipocytes were isolated 15 h after AICAR was injected (i.p. 0.7 g/kg body weight) in rats. Adipocytes were utilized for various metabolic assays and for determination of gene expression and protein content. Time-dependent in vivo plasma NEFA concentrations were determined. AICAR treatment significantly increased AMPK activation, inhibited lipogenesis, and increased FA oxidation. This was accompanied by upregulation of peroxisome proliferator-activated receptor (PPAR)alpha, PPARdelta, and PPARgamma-coactivator-1alpha (PGC-1alpha) mRNA levels. Lipolysis was first suppressed, but then increased, both in vitro and in vivo, with prolonged AICAR treatment. Exposure to AICAR increased adipose triglyceride lipase (ATGL) content and FA release, despite inhibition of basal and epinephrine-stimulated hormone-sensitive lipase (HSL) activity. Here, we provide evidence that prolonged AICAR-induced AMPK activation can remodel adipocyte metabolism by upregulating pathways that favor energy dissipation versus lipid storage in WAT. Additionally, we show novel time-dependent effects of AICAR-induced AMPK activation on lipolysis, which involves antagonistic modulation of HSL and ATGL.