Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance

Zhang, Yongzhao; Li, Yingxia; Niepel, Michele W.; Kawano, Yuki; Han, Shuxin; Liu, Sihao; Marsili, Alessandro; Larsen, P. Reed; Lee, Chih‐Hao; Cohen, David E.

doi:10.1073/pnas.1116011109

Cited by 92 publications

(119 citation statements)

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“…The level of free fatty acids is significantly altered in brown adipose tissue and liver in ACOT11 and ACOT13 knockout mice, respectively (30,31). However, in the present study, ACOT11 and ACOT13 knockdown did not affect the level of total amount of free fatty acid in CL1-0 cells.…”

Section: Discussioncontrasting

confidence: 53%

“…Although a previous study suggested that the START domain may be an important regulatory element for ACOT11 (29), the exact mechanisms underlying the regulation and function of ACOT11 remain unknown in lung adenocarcinoma and other tissues. ACOT11 knockout mice revealed increased energy consumption and resistance to high fat diet-induced obesity compared with control mice (30). In addition, loss of ACOT11 leads to resistance to obesity-induced inflammation and endoplasmic reticulum stress (30).…”

Section: Discussionmentioning

confidence: 99%

“…ACOT11 knockout mice revealed increased energy consumption and resistance to high fat diet-induced obesity compared with control mice (30). In addition, loss of ACOT11 leads to resistance to obesity-induced inflammation and endoplasmic reticulum stress (30). A high fat diet significantly induced ACOT11 expression in mouse liver (3).…”

Section: Discussionmentioning

confidence: 99%

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Overexpression and proliferation dependence of acyl-CoA thioesterase 11 and 13 in lung adenocarcinoma

et al. 2017

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Abstract. The metabolites of fatty acyl-Coenzyme A (CoA) and metabolic enzymes contribute to lipid biosynthesis, signal transduction, and gene transcription. Previous studies have indicated that elevated concentrations of specific free fatty acids in the plasma and overexpression of specific fatty acyl-CoA metabolic enzymes are observed in patients with lung adenocarcinoma. However, there are >30 enzymes in this metabolic network and have been fully investigated. In the present study, the expression levels of enzymes in the acyl-CoA synthetase (ACS) and acyl-CoA thioesterase (ACOT) families were analyzed from six microarray expression datasets that were collected from Gene Expression Omnibus. Compared with adjacent non-tumor lung tissue, lung adenocarcinoma tissue exhibited significantly higher ACOT11 and ACOT13 expression. Kaplan-Meier plotter database analysis demonstrated that high levels of ACOT11 and ACOT13 were associated with a worse overall survival rate. The proliferation of the lung adenocarcinoma cell lines CL1-0 and CL1-5 was inhibited when ACOT11 and ACOT13 were downregulated by short hairpin RNA. Although ACOT11 and ACOT13 knockdown did not significantly affect the total amount of intracellular and medium-free fatty acids, ACOT11 and ACOT13 knockdown-mediated growth inhibition was rescued by the addition of fatty acids. In conclusion, ACOT11 and ACOT13 were upregulated in clinical specimens of lung adenocarcinoma, which may contribute to increased cell proliferation through the increased availability of fatty acids. The metabolites of the two enzymes may be critical for development of lung adenocarcinoma. IntroductionMetabolites are currently considered targets for cancer treatments, particularly amino acids and glucose (1). Fatty acyl-Coenzyme A (CoA) esters are essential components in lipid metabolism and are regulators of multiple cellular functions (2). Enzymes of the acyl-CoA synthetase (ACS) family, including the ACS long-chain, ACS medium-chain, ACS short-chain and ACS bubblegum families, ligate different lengths of fatty acid with CoA. Fatty acyl-CoA esters are hydrolyzed into free fatty acids and CoA by enzymes of the acyl-CoA thioesterase (ACOT) family (3,4). There are >15 ACOT enzymes and 20 ACS enzymes in humans, and these enzymes exhibit different tissue distribution, subcellular location and substrate specificity (3,4).Lung cancer is a leading cause of cancer-associated mortality and is the second most commonly diagnosed cancer (5). The majority (~85-90%) of diagnosed cases of lung cancer are diagnosed as non-small cell lung cancer (NSCLC) and adenocarcinoma is the most common subtype of NSCLC (6). Compared with healthy individuals, patients with lung adenocarcinoma possess a significantly higher level of fatty acids (including arachidonic, palmitic, linoleic and oleic acid) in their plasma (7,8). In addition, overexpression of ACOT8 is associated with metastasis in lung adenocarcinoma (9). However, the cellular functions and the regulatory mechanisms of the majority of ACOT and ACS e...

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Section: Discussioncontrasting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

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Overexpression and proliferation dependence of acyl-CoA thioesterase 11 and 13 in lung adenocarcinoma

et al. 2017

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“…Finally, Adams et al (1) demonstrated that Bfit/Acot11 is induced by cold, and higher gene expression is observed in obesity-resistant strains. However, Acot11 knockout protects against obesity and promotes energy expenditure (42). This study suggested that Acot11 decreases energy expenditure and conserves energy.…”

Section: Discussionmentioning

confidence: 93%

Rorα deficiency and decreased adiposity are associated with induction of thermogenic gene expression in subcutaneous white adipose and brown adipose tissue

Lau

Tuong

Wang

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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deficiency and decreased adiposity are associated with induction of thermogenic gene expression in subcutaneous white adipose and brown adipose tissue. Am J Physiol Endocrinol Metab 308: E159-E171, 2015. First published November 25, 2014; doi:10.1152/ajpendo.00056.2014.-The Rarrelated orphan receptor-␣ (Ror␣) is a nuclear receptor that regulates adiposity and is a potential regulator of energy homeostasis. We have demonstrated that the Ror␣-deficient staggerer (sg/sg) mice display a lean and obesity-resistant phenotype. Adaptive Ucp1-dependent thermogenesis in beige/brite and brown adipose tissue serves as a mechanism to increase energy expenditure and resist obesity. DEXA and MRI analysis demonstrated significantly decreased total fat mass and fat/lean mass tissue ratio in male chow-fed sg/sg mice relative to wt mice. In addition, we observed increased Ucp1 expression in brown adipose and subcutaneous white adipose tissue but not in visceral adipose tissue from Ror␣-deficient mice. Moreover, this was associated with significant increases in the expression of the mRNAs encoding the thermogenic genes (i.e., markers of brown and beige adipose) Ppar␣, Err␣, Dio2, Acot11/Bfit, Cpt1␤, and Cidea in the subcutaneous adipose in the sg/sg relative to WT mice. These changes in thermogenic gene expression involved the significantly increased expression of the (cell-fate controlling) histone-lysine N-methyltransferase 1 (Ehmt1), which stabilizes the Prdm16 transcriptional complex. Moreover, primary brown adipocytes from sg/sg mice displayed a higher metabolic rate, and further analysis was consistent with increased uncoupling. Finally, core body temperature analysis and infrared thermography demonstrated that the sg/sg mice maintained greater thermal control and cold tolerance relative to the WT littermates. We suggest that enhanced Ucp1 and thermogenic gene expression/activity may be an important contributor to the lean, obesityresistant phenotype in Ror␣-deficient mice.retinoic acid receptor-related orphan receptor-␣; obesity; adiposity; adipose tissue; uncoupling protein-1 OBESITY IS A METABOLIC DISEASE that affects more than 10% of the global population. Energy imbalance as a result of excess dietary energy intake or genetic susceptibility results in increased energy storage and adiposity. Current strategies to ameliorate this disease include increasing energy expenditure through physical exercise and reducing energy consumption. However, the success rate is limited by compliance and the genetic disposition to maintain energy balance.Adaptive thermogenesis is an adrenergic/sympathetic-dependent mechanism utilized by mammals to increase energy expenditure in response to excessive dietary intake and/or cold stimulus. Thermogenesis occurs in both brown adipose tissue and beige fat [white adipose tissue cells that acquire a brown adipose phenotype (37, 41)]. This process involves increased (fatty acid-dependent) expression and activity of the thermogenic mitochondrial uncoupling protein (Ucp1). The function of Ucp1 is to me...

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“…However, recent gene-knockout studies on a subgroup of ACOTs revealed that they profoundly affect lipid homeostasis in association with fatty liver development, obesity, and insulin resistance. [5][6][7] Of the ACOT family members, ACOT1 (cytosolic), ACOT2 (mitochondrial), and ACOT7 (cytosolic) have been well characterized for their enzymatic properties (see refs. 1 and 3 for a review).…”

mentioning

confidence: 99%

Identification of Acyl-CoA Thioesterase in Mouse Mesenteric Lymph Nodes

Ohtomo

Nakao

Sumiya

et al. 2013

Biological & Pharmaceutical Bulletin

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Acyl-CoA thioesterases (ACOTs) are a group of enzymes that catalyze the hydrolysis of fatty acyl-CoAs to free fatty acids and CoA, with the potential to regulate the intracellular levels of these molecules. In this study, we show that a cytosolic isoform, ACOT7, is expressed at a significant level in the mesenteric lymph nodes (MLNs) of mice. While crude preparations of the mesenteric visceral fat contained significant levels of palmitoyl-CoA thioesterase activity, enzyme activity was concentrated 6.9-fold in MLNs compared with the residual adipose portion after excision of MLNs. When MLN homogenates were centrifuged, 82% of the enzyme activity was recovered in the cytosolic fraction, concomitant with almost exclusive recovery of ACOT7. Immunoprecipitation using anti-ACOT7 antibody estimated that 87% of enzyme activity in the homogenates was accounted for by ACOT7. On MLN sections, the germinal centers of secondary lymphoid follicles were immunostained with the antibody. In MLNs of mice fasted for 16 h, ACOT7 levels were induced 1.8-fold, which reflected a 1.5-fold increase in enzyme activity. These findings suggest that ACOT7 may be involved in dietary intake-associated responses in fatty acid metabolism in MLNs.Key words acyl-CoA thioesterase; acyl-CoA thioesterase 7; mesenteric lymph node; visceral fat Acyl-CoA thioesterases (ACOTs) comprise a group of enzymes that catalyze the hydrolysis of fatty acyl-CoA thioesters to corresponding free fatty acids and CoA. To date, 15 mammalian genes have been identified as ACOT family members.1-4) While ACOTs have the potential to regulate the intracellular levels of acyl-CoAs, free fatty acids, and CoA, their physiological functions are not fully understood. However, recent gene-knockout studies on a subgroup of ACOTs revealed that they profoundly affect lipid homeostasis in association with fatty liver development, obesity, and insulin resistance.5-7) Of the ACOT family members, ACOT1 (cytosolic), ACOT2 (mitochondrial), and ACOT7 (cytosolic) have been well characterized for their enzymatic properties (see refs. 1 and 3 for a review). These ACOTs share a common feature in that their expression is markedly induced by ligands for peroxisome proliferator-activated receptor α (PPARα), a nuclear receptor that regulates lipid metabolism-related genes, including the fibrate-class of hypolipidemic drugs. Moreover, ACOT1 and ACOT2 have been implicated in fatty acid catabolism, as emphasized by their upregulation in the liver and heart of fasted or high-fat diet-fed animals. [8][9][10][11] However, ACOT7 has enzyme activity two orders of magnitude higher than ACOT1 and ACOT2, and its expression is prominent in neurons of the central and peripheral nervous systems. [12][13][14] Thus, ACOT7 may have a role in cellular events other than energy metabolism, as the overexpression of ACOT7 in a macrophage cell line modified the production of prostaglandins.15) Recently, we examined the expression of ACOTs in fat tissues of rats 16,17) and unexpectedly found a significant level of acyl-Co...

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Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance

Cited by 92 publications

References 34 publications

Overexpression and proliferation dependence of acyl-CoA thioesterase 11 and 13 in lung adenocarcinoma

Overexpression and proliferation dependence of acyl-CoA thioesterase 11 and 13 in lung adenocarcinoma

Rorα deficiency and decreased adiposity are associated with induction of thermogenic gene expression in subcutaneous white adipose and brown adipose tissue

Identification of Acyl-CoA Thioesterase in Mouse Mesenteric Lymph Nodes

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