Lipolytic Products Activate Peroxisome Proliferator-activated Receptor (PPAR) α and δ in Brown Adipocytes to Match Fatty Acid Oxidation with Supply

Background: NAT8L (N-acetyltransferase 8-like) synthesizes N-acetylaspartate and is required for myelination in the brain. Its function in other tissues was undefined. Results: Nat8l is highly expressed in adipose tissues and impacts adipogenic marker gene expression, lipid turnover, and energy metabolism in brown adipocytes. Conclusion: Nat8l expression influences cellular bioenergetics in adipocytes. Significance: These findings establish a novel pathway in brown adipocyte metabolism.

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“…Furthermore, the activation potential of PPAR␣ is enhanced by lipolytic products (30). We observed both increased lipolysis (Fig.…”

Section: Nat8l Is Expressed In Adipocytes and Located In Mitochondriamentioning

confidence: 48%

NAT8L (N-Acetyltransferase 8-Like) Accelerates Lipid Turnover and Increases Energy Expenditure in Brown Adipocytes

Pessentheiner

Pelzmann

Walenta

et al. 2013

Journal of Biological Chemistry

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“…Because cAMP signaling has been shown to activate PPARd, 45,46 it is possible that PPARd plays a role in the effect of iloprost on APP processing. Indeed, iloprost treatment increased PPARd protein expression (Figure 3(a)).…”

Section: Resultsmentioning

confidence: 99%

“…We demonstrated that PPARd-siRNA abolished iloprostinduced expression of ADAM10, indicating that PPARd was a major mediator of the iloprost-induced expression of ADAM10. Since cAMP signaling has been shown to activate PPARd, 8,45,46 it is likely that activation of IP-cAMP signaling augments ADAM10 expression via activation of PPARd (Figure 7). It has also been reported that in vitro both PGI 2 and iloprost could directly bind to PPARd, 8,58,59 therefore, we cannot rule out the possibility that direct activation of PPARd by iloprost might contribute to increase in expression of ADAM10.…”

mentioning

confidence: 99%

Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-α in cerebral microvessels

Santhanam

Lü

et al. 2016

J Cereb Blood Flow Metab

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We tested hypothesis that activation of the prostacyclin (PGI 2 ) receptor (IP receptor) signaling pathway in cerebral microvessels plays an important role in the metabolism of amyloid precursor protein (APP). In human brain microvascular endothelial cells activation of IP receptor with the stable analogue of PGI 2 , iloprost, stimulated expression of amyloid precursor protein and a disintegrin and metalloprotease 10 (ADAM10), resulting in an increased production of the neuroprotective and anticoagulant molecule, soluble APPa (sAPPa). Selective agonist of IP receptor, cicaprost, and adenylyl cyclase activator, forskolin, also enhanced expression of amyloid precursor protein and ADAM10. Notably, in cerebral microvessels of IP receptor knockout mice, protein levels of APP and ADAM10 were reduced. In addition, iloprost increased protein levels of peroxisome proliferator-activated receptor d (PPARd) in human brain microvascular endothelial cells. PPARd-siRNA abolished iloprost-augmented protein expression of ADAM10. In contrast, GW501516 (a selective agonist of PPARd) upregulated ADAM10 and increased production of sAPPa. Genetic deletion of endothelial PPARd (ePPARd À/À ) in mice significantly reduced cerebral microvascular expression of ADAM10 and production of sAPPa. In vivo treatment with GW501516 increased sAPPa content in hippocampus of wild type mice but not in hippocampus of ePPARd À/À mice. Our findings identified previously unrecognized role of IP-PPARd signal transduction pathway in the production of sAPPa in cerebral microvasculature.

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“…ATGL-mediated lipolysis is also required for functional PPAR-α and PPAR-δ signaling in oxidative tissues and the pancreatic β-cell, respectively (16,(33)(34)(35). For example, absence of ATGL in cardiac muscle leads to reduced PPARα-mediated mitochondrial biogenesis, substrate oxidation, and respiration, resulting in the lethal cardiomyopathy (16).…”

Section: Discussionmentioning

confidence: 99%

Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity

Schreiber

Hofer

Taschler

et al. 2015

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

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Adipose triglyceride lipase (ATGL) initiates intracellular triglyceride (TG) catabolism. In humans, ATGL deficiency causes neutral lipid storage disease with myopathy (NLSDM) characterized by a systemic TG accumulation. Mice with a genetic deletion of ATGL (AKO) also accumulate TG in many tissues. However, neither NLSDM patients nor AKO mice are exceedingly obese. This phenotype is unexpected considering the importance of the enzyme for TG catabolism in white adipose tissue (WAT). In this study, we identified the counteracting mechanisms that prevent excessive obesity in the absence of ATGL. We used "healthy" AKO mice expressing ATGL exclusively in cardiomyocytes (AKO/cTg) to circumvent the cardiomyopathy and premature lethality observed in AKO mice. AKO/cTg mice were protected from high-fat diet (HFD)-induced obesity despite complete ATGL deficiency in WAT and normal adipocyte differentiation. AKO/cTg mice were highly insulin sensitive under hyperinsulinemic-euglycemic clamp conditions, eliminating insulin insensitivity as a possible protective mechanism. Instead, reduced food intake and altered signaling by peroxisome proliferator-activated receptor-gamma (PPAR-γ) and sterol regulatory element binding protein-1c in WAT accounted for the phenotype. These adaptations led to reduced lipid synthesis and storage in WAT of HFD-fed AKO/cTg mice. Treatment with the PPAR-γ agonist rosiglitazone reversed the phenotype. These results argue for the existence of an adaptive interdependence between lipolysis and lipid synthesis. Pharmacological inhibition of ATGL may prove useful to prevent HFDinduced obesity and insulin resistance.E ssentially all organisms face the problem of continuous energy demand in an environment of irregular food supply. To overcome this dilemma, metazoan organisms developed special storage depots for substrates that are used for energy production. In vertebrates, by far the most efficient energy reservoir is adipose tissue (1). This highly expandable organ is able to store all major nutritional components (fat, carbohydrates, and proteins) as triglycerides (TGs). Adipose tissue mass and TG content depend on the balance of anabolic and catabolic pathways. Lipid storage in response to nutrient supply involves the generation of adipocytes (adipogenesis), the induction of fatty acid (FA) synthesis from glucose and amino acids (de novo lipogenesis), and the synthesis of TGs (lipid synthesis). These processes are activated by a complex transcriptional network involving CCAAT/ enhancer-binding proteins (C/EBPs), sterol regulatory enhancer binding proteins (SREBPs), and the heterodimer of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and retinoid-X receptor (RXR) (2, 3).The opposing metabolic pathway of TG catabolism (lipolysis) requires activation of enzymes called lipases. Adipose TG lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase (MGL) hydrolyze all three ester bonds of TGs in a stepwise manner to yield FAs and glycerol (4). Lipolysis is an exquisitely regulated proce...

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Lipolytic Products Activate Peroxisome Proliferator-activated Receptor (PPAR) α and δ in Brown Adipocytes to Match Fatty Acid Oxidation with Supply

Cited by 169 publications

References 54 publications

NAT8L (N-Acetyltransferase 8-Like) Accelerates Lipid Turnover and Increases Energy Expenditure in Brown Adipocytes

NAT8L (N-Acetyltransferase 8-Like) Accelerates Lipid Turnover and Increases Energy Expenditure in Brown Adipocytes

Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-α in cerebral microvessels

Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity

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