The immunosuppressive agents rapamycin, cyclosporin A and tacrolimus increase lipolysis, inhibit lipid storage and alter expression of genes involved in lipid metabolism in human adipose tissue

Pereira, Maria J.; Palming, Jenny; Rizell, Magnus; Aureliano, Manuel; Carvalho, Eugénia; Svensson, Maria; Eriksson, Jan W.

doi:10.1016/j.mce.2012.10.030

Cited by 70 publications

(47 citation statements)

References 58 publications

(67 reference statements)

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“…Because mitochondrial respiration (oxidative phosphorylation) was reduced in Trex1 −/− cells, it is possible that Trex1 −/− mice use fat as an alternate source of energy and become hypermetabolic in vivo. Increased lipolysis has been reported in patients treated with an mTORC1 inhibitor, rapamycin, following organ transplantation (14). S6K −/− or Raptor conditional knockout mice also showed altered lipid metabolic profiles (8,9).…”

Section: Significancementioning

confidence: 97%

Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism

Hašan

Gonugunta

Dobbs

et al. 2017

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

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Three-prime repair exonuclease 1 knockout (Trex1 −/− ) mice suffer from systemic inflammation caused largely by chronic activation of the cyclic GMP-AMP synthase-stimulator of interferon genes-TANKbinding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) signaling pathway. We showed previously that Trex1-deficient cells have reduced mammalian target of rapamycin complex 1 (mTORC1) activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1 −/− mice and cells that revealed both cellular and systemic metabolic defects, including reduced mitochondrial respiration and increased glycolysis, energy expenditure, and fat metabolism. We also genetically separated the inflammatory and metabolic phenotypes by showing that Sting deficiency rescued both inflammatory and metabolic phenotypes, whereas Irf3 deficiency only rescued inflammation on the Trex1 −/− background, and many metabolic defects persist in Trex1 −/− Irf3 −/− cells and mice. We also showed that Leptin deficiency (ob/ob) increased lipogenesis and prolonged survival of Trex1 −/− mice without dampening inflammation. Mechanistically, we identified TBK1 as a key regulator of mTORC1 activity in Trex1 −/− cells. Together, our data demonstrate that chronic innate immune activation of TBK1 suppresses mTORC1 activity, leading to dysregulated cellular metabolism.M ammals have evolved complex and integrated systems of immunity and metabolism to maintain and defend internal and environmental threats. Increasing numbers of immune regulators have been found to play critical roles in metabolism. Studies from recent years have established an integrated view on the shared architecture between adaptive immunity and metabolism, including how they correspond to stimulus in disease settings. However, cell-intrinsic innate immune regulation of metabolic pathways remains poorly understood. This is in part due to the fact that overwhelming systemic inflammation in chronic diseases often masks direct underlying molecular causes.We have previously characterized an autoimmune/autoinflammatory disease mouse model, three-prime repair exonuclease 1 knockout (Trex1 −/− ) (1). TREX1, also known as DNase III, is an exonuclease that localizes to the endoplasmic reticulum (ER) to prevent aberrant accumulation of self-DNA or glycans that would trigger immune activation (2, 3). Mutations of the TREX1 gene have been associated with several autoinflammatory and autoimmune diseases, including Aicardi-Goutières syndrome and systemic lupus erythematosus (SLE) (4). Trex1 −/− mice suffer from systemic inflammation caused largely by chronic activation of the cytosolic DNA sensing pathway through the cyclic GMP-AMP synthase-stimulator of interferon genes-TANK-binding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) cascade (5-7). We showed previously that TREX1 also regulates lysosomal biogenesis through the mTORC1-TFEB pathway and that Trex1 −/− mouse embryonic fibroblasts (MEFs) exhibit drastically reduced mTORC1 activity compare...

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Section: Significancementioning

confidence: 97%

Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism

Hašan

Gonugunta

Dobbs

et al. 2017

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

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“…Epididymal adipocyte size and weight, insulin-stimulated D-[[ 14 C(U)]-glucose uptake, and isoproterenol-stimulated lipolysis in isolated adipocytes were performed as previously described [14,15]. Briefly, for the insulin-stimulated glucose uptake, the isolated adipocytes were diluted ten times and were stimulated or not with human insulin (1000 µU/mL), for 10 min, at 37 • C, in a shaking water-bath.…”

Section: Cell Size and Weight Glucose Uptake And Lipolysis In Isolamentioning

confidence: 99%

Glucose and Lipid Dysmetabolism in a Rat Model of Prediabetes Induced by a High-Sucrose Diet

Burgeiro¹,

Cerqueira²,

Varela-Rodríguez³

et al. 2017

Preprint

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Glucotoxicity and lipotoxicity are key features of type 2 diabetes mellitus, but their molecular nature during the early stages of the disease remains to be elucidated. We aimed to characterize glucose and lipid metabolism in insulin-target organs (liver, skeletal muscle, and white adipose tissue) in a rat model treated with a high-sucrose (HSu) diet. Two groups of 16-week-old male Wistar rats underwent a 9-week protocol: HSu diet (n = 10)-received 35% of sucrose in drinking water; Control (n = 12)-received vehicle (water). Body weight, food, and beverage consumption were monitored and glucose, insulin, and lipid profiles were measured. Serum and liver triglyceride concentrations, as well as the expression of genes and proteins involved in lipid biosynthesis were assessed. The insulin-stimulated glucose uptake and isoproterenol-stimulated lipolysis were also measured in freshly isolated adipocytes. Even in the absence of obesity, this rat model already presented the main features of prediabetes, with fasting normoglycemia but reduced glucose tolerance, postprandial hyperglycemia, compensatory hyperinsulinemia, as well as decreased insulin sensitivity (resistance) and hypertriglyceridemia. In addition, impaired hepatic function, including altered gluconeogenic and lipogenic pathways, as well as increased expression of acetyl-coenzyme A carboxylase 1 and fatty acid synthase in the liver, were observed, suggesting that liver glucose and lipid dysmetabolism may play a major role at this stage of the disease.

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“…Lipolysis was also performed as reported previously (60). Briefly, the adipocyte suspension was incubated in the presence or absence of insulin (1,000 U/ml) in KRH buffer containing 6 mM glucose in a gently shaking water bath at 37°C for 120 min.…”

Section: D-[u-mentioning

confidence: 99%

Glucose uptake and lipid metabolism are impaired in epicardial adipose tissue from heart failure patients with or without diabetes

Burgeiro

Fuhrmann

Cherian

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Glucose uptake and lipid metabolism are impaired in epicardial adipose tissue from heart failure patients with or without diabetes. Am J Physiol Endocrinol Metab 310: E550 -E564, 2016. First published January 26, 2016 doi:10.1152/ajpendo.00384.2015.-Type 2 diabetes mellitus is a complex metabolic disease, and cardiovascular disease is a leading complication of diabetes. Epicardial adipose tissue surrounding the heart displays biochemical, thermogenic, and cardioprotective properties. However, the metabolic cross-talk between epicardial fat and the myocardium is largely unknown. This study sought to understand epicardial adipose tissue metabolism from heart failure patients with or without diabetes. We aimed to unravel possible differences in glucose and lipid metabolism between human epicardial and subcutaneous adipocytes and elucidate the potential underlying mechanisms involved in heart failure. Insulin-stimulated [14 C]glucose uptake and isoproterenol-stimulated lipolysis were measured in isolated epicardial and subcutaneous adipocytes. The expression of genes involved in glucose and lipid metabolism was analyzed by reverse transcription-polymerase chain reaction in adipocytes. In addition, epicardial and subcutaneous fatty acid composition was analyzed by high-resolution proton nuclear magnetic resonance spectroscopy. The difference between basal and insulin conditions in glucose uptake was significantly decreased (P ϭ 0.006) in epicardial compared with subcutaneous adipocytes. Moreover, a significant (P Ͻ 0.001) decrease in the isoproterenol-stimulated lipolysis was also observed when the two fat depots were compared, and it was strongly correlated with lipolysis, lipid storage, and inflammation-related gene expression. Moreover, the fatty acid composition of these tissues was significantly altered by diabetes. These results emphasize potential metabolic differences between both fat depots in the presence of heart failure and highlight epicardial fat as a possible therapeutic target in situ in the cardiac microenvironment.

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The immunosuppressive agents rapamycin, cyclosporin A and tacrolimus increase lipolysis, inhibit lipid storage and alter expression of genes involved in lipid metabolism in human adipose tissue

Cited by 70 publications

References 58 publications

Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism

Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism

Glucose and Lipid Dysmetabolism in a Rat Model of Prediabetes Induced by a High-Sucrose Diet

Glucose uptake and lipid metabolism are impaired in epicardial adipose tissue from heart failure patients with or without diabetes

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