Hepatic ATGL knockdown uncouples glucose intolerance from liver TAG accumulation

Ong, Kuok Teong; Mashek, Mara T.; Bu, So Young; Mashek, Douglas G.

doi:10.1096/fj.12-213454

Cited by 47 publications

(52 citation statements)

References 48 publications

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“…As mentioned before, in 2006 our group found that ATGL-KO led to fatty liver but not to systemic insulin resistance ( 13 ). This fi nding was supported by a very recent study, where HFD feeding to liver-specifi c ATGL-KO mice enhanced liver TG contents and primary hepatocytes derived from these livers exhibited improved glucose tolerance despite unaltered insulin signaling ( 16 ). Importantly, diseases are known to be caused by inactive ATGL protein due to a genetic defect (neutral lipid storage disease with myopathy) ( 23 ), or to be caused by functional ATGL yet inactive by lack of functional coactivator CGI-58 (neutral lipid storage disease with ichtyosis, Chanarin-Dorfman syndrome) ( 24 ).…”

Section: Discussionsupporting

confidence: 66%

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The impact of genetic stress by ATGL deficiency on the lipidome of lipid droplets from murine hepatocytes

Chitraju

Trötzmüller

Hartler

et al. 2013

Journal of Lipid Research

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In a preceding study, we carried out intervention trials with wild-type (WT) mice fed normal chow, exposed to short-time starvation, or treated with high-fat diet (HFD). The aim was to assess the effect of these forms of nutritional stress on the lipidome of lipid droplets (LDs) isolated from hepatocytes. Lipidomic analysis by LC-MS enabled profi ling of all species from glycerolipid and glycerophospholipid classes and revealed particularly the triacylglycerol (TG) lipidome to be best suited for phenotyping nutritional stresses applied to the animals. In addition, structural analysis by MS/MS at lipid molecular species level provided metabolic relationships characteristic for hepatocyte lipid metabolism ( 1 ). To further probe the phenotypic information potential inherent in the lipidome of hepatocyte LDs, we have now extended the question to genetic stress; we have characterized a mouse model lacking adipocyte triglyceride lipase (ATGL), which shows a marked defect in lipid metabolism in many tissues including the liver . Community's Seventh Framework Programme (FP7/2007 Abbreviations: ATGL, adipocyte triglyceride lipase; CGI-58, comparative gene identifi cation 58; DG, diacylglycerol; FAS, fasted before sacrifi ce; FED, received control chow; HFD, high-fat diet; KO, knockout; LD, lipid droplet; LDA, Lipid Data Analyzer; PC, phosphatidylcholine; PCA, principal component analysis; PC1, principal component 1; PC2, principal component 2; PE, phosphatidylethanolamine; PI, phosphatidylinositol; PS, phosphatidylserine; TG, triacylglycerol; VLC, very long-chain; WT, wild-type; WT-FED, WT-FAS, KO-FED, KO-FAS, hepatocyte LD sample groups from wild-type or knockout mice fed chow or kept in fasted condition, respectively . The research leading to these results received funding from the European

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Section: Discussionsupporting

confidence: 66%

“…The latter fi nding, however, was not supported by a subsequent study ( 15 ). Also, hepatic ATGL-KO uncoupled glucose intolerance from liver TG accumulation ( 16,17 ).…”

Section: Determination Of Ld Lipid Profi Les and Molecular Species Bymentioning

confidence: 83%

The impact of genetic stress by ATGL deficiency on the lipidome of lipid droplets from murine hepatocytes

Chitraju

Trötzmüller

Hartler

et al. 2013

Journal of Lipid Research

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“…Of interest, both deletion (current study) and overexpression (36) of ATGL in adipocytes improves hepatic steatosis and insulin resistance, suggesting that adipocyte lipolysis may be a therapeutic target for these disorders. In contrast, modulating ATGL action within skeletal muscle (22) and liver (37)(38)(39) do not significantly influence glucose homeostasis and insulin signaling. Interestingly, despite a comparable reduction in adipocyte lipolysis, GAKO mice have increased rather than decreased susceptibility to hepatic inflammation, presumably because hepatic ATGL action is required not only for hepatic lipid homeostasis but for activation of PPAR␣'s anti-inflammatory effects (40).…”

Section: Discussionmentioning

confidence: 85%

Impact of Reduced ATGL-Mediated Adipocyte Lipolysis on Obesity-Associated Insulin Resistance and Inflammation in Male Mice

et al. 2015

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Emerging evidence suggests that impaired regulation of adipocyte lipolysis contributes to the proinflammatory immune cell infiltration of metabolic tissues in obesity, a process that is proposed to contribute to the development and exacerbation of insulin resistance. To test this hypothesis in vivo, we generated mice with adipocyte-specific deletion of adipose triglyceride lipase (ATGL), the rate-limiting enzyme catalyzing triacylglycerol hydrolysis. In contrast to previous models, adiponectin-driven Cre expression was used for targeted ATGL deletion. The resulting adipocyte-specific ATGL knockout (AAKO) mice were then characterized for metabolic and immune phenotypes. Lean and diet-induced obese AAKO mice had reduced adipocyte lipolysis, serum lipids, systemic lipid oxidation, and expression of peroxisome proliferator-activated receptor alpha target genes in adipose tissue (AT) and liver. These changes did not increase overall body weight or fat mass in AAKO mice by 24 weeks of age, in part due to reduced expression of genes involved in lipid uptake, synthesis, and adipogenesis. Systemic glucose and insulin tolerance were improved in AAKO mice, primarily due to enhanced hepatic insulin signaling, which was accompanied by marked reduction in diet-induced hepatic steatosis as well as hepatic immune cell infiltration and activation. In contrast, although adipocyte ATGL deletion reduced AT immune cell infiltration in response to an acute lipolytic stimulus, it was not sufficient to ameliorate, and may even exacerbate, chronic inflammatory changes that occur in AT in response to diet-induced obesity.

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“…Mice lacking ATGL show improved glucose tolerance and are resistant to high-fat diet-induced insulin resistance (21)(22)(23). ATGL deficiency also improves insulin signaling in white adipose tissue (21).…”

Section: Catecholamine-induced Inhibition Of Glucose Uptake and Insulinmentioning

confidence: 99%

Catecholamine-induced lipolysis causes mTOR complex dissociation and inhibits glucose uptake in adipocytes

Mullins¹,

Wang

Raje³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Anabolic and catabolic signaling oppose one another in adipose tissue to maintain cellular and organismal homeostasis, but these pathways are often dysregulated in metabolic disorders. Although it has long been established that stimulation of the β-adrenergic receptor inhibits insulin-stimulated glucose uptake in adipocytes, the mechanism has remained unclear. Here we report that β-adrenergic-mediated inhibition of glucose uptake requires lipolysis. We also show that lipolysis suppresses glucose uptake by inhibiting the mammalian target of rapamycin (mTOR) complexes 1 and 2 through complex dissociation. In addition, we show that products of lipolysis inhibit mTOR through complex dissociation in vitro. These findings reveal a previously unrecognized intracellular signaling mechanism whereby lipolysis blocks the phosphoinositide 3-kinase-Akt-mTOR pathway, resulting in decreased glucose uptake. This previously unidentified mechanism of mTOR regulation likely contributes to the development of insulin resistance.A dipose tissue plays an essential role in maintaining wholebody energy homeostasis by storing or releasing nutrients. This balance is controlled by opposing signaling pathways where anabolic processes are activated by insulin (INS) and catabolic actions are activated by catecholamines. An important unanswered question in adipose biology is how catecholamine-induced β-adrenergic signaling opposes insulin-stimulated glucose uptake (1-6). Surprisingly, the underlying mechanism for this wellestablished physiological response in adipocytes is still unknown.When nutrients are plentiful, insulin is released by the pancreas and stimulates the absorption of glucose and fatty acids in adipose tissue, where they are packaged and stored as triacylglycerol (TAG) in cellular lipid droplets. Insulin signaling in adipocytes is mediated by the phosphoinositide 3-kinase (PI3K)-Akt-mTOR pathway. mTOR is a highly conserved serine/threonine protein kinase that functions in either of two distinct multiprotein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 is defined primarily by the association of mTOR with raptor, whereas mTORC2 includes mTOR with rictor (7). Importantly, mTORC2 phosphorylation of Akt at S473 is required for Akt activity on AS160, which is necessary for glucose uptake in response to insulin (8-11). Of note, for both mTORC1 and mTORC2, the integrity of these protein complexes is essential for kinase substrate specificity and proper signaling (12, 13).During periods of fasting or stress, catecholamines are released by the sympathetic nervous system to activate lipolysis. Stimulation of the β-adrenergic receptor on adipocytes activates adenylyl cyclase (AC), leading to elevated cAMP and protein kinase A (PKA) activity. PKA initiates lipolysis by direct phosphorylation of hormone-sensitive lipase (HSL) and perilipin (14-16) and indirect activation of adipose triglyceride lipase (ATGL) (17-19). Lipolysis involves hydrolysis of TAG stored in the lipid droplet to produce diacylglycerol (DAG), mo...

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Hepatic ATGL knockdown uncouples glucose intolerance from liver TAG accumulation

Cited by 47 publications

References 48 publications

The impact of genetic stress by ATGL deficiency on the lipidome of lipid droplets from murine hepatocytes

The impact of genetic stress by ATGL deficiency on the lipidome of lipid droplets from murine hepatocytes

Impact of Reduced ATGL-Mediated Adipocyte Lipolysis on Obesity-Associated Insulin Resistance and Inflammation in Male Mice

Catecholamine-induced lipolysis causes mTOR complex dissociation and inhibits glucose uptake in adipocytes

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