ATGL-Catalyzed Lipolysis Regulates SIRT1 to Control PGC-1α/PPAR-α Signaling

Khan, Salmaan; Sathyanarayan, Aishwarya; Mashek, Mara T.; Ong, Kuok Teong; Wollaston‐Hayden, Edith E.; Mashek, Douglas G.

doi:10.2337/db14-0325

Cited by 148 publications

(125 citation statements)

References 48 publications

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“…In contrast, WAT Ucp1 mRNA in chow-fed Fgf21 -/-mice was not different from WT, and neither the HFD nor naringenin affected its expression ( Figure 3C). As both adipose triglyceride lipase (ATGL, Pnpla2) and hormone sensitive lipase (HSL, Lipe) can liberate fatty acids, which may indirectly activate a PPAR␣ transcription program, we assessed their mRNA abundance (45,46). Lipe was lower in HFD-fed Fgf21 -/-mice compared to HFD-fed WT mice, consistent with increased adiposity in HFD-fed Fgf21 -/-mice.…”

Section: Enhanced Weight Gain In Hfd-fed Fgf21 -/-Mice Is Prevented Bmentioning

confidence: 67%

Naringenin Prevents Obesity, Hepatic Steatosis, and Glucose Intolerance in Male Mice Independent of Fibroblast Growth Factor 21

et al. 2015

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The molecular mechanisms and metabolic pathways whereby the citrus flavonoid, naringenin, reduces dyslipidemia and improves glucose tolerance were investigated in C57BL6/J wild-type mice and fibroblast growth factor 21 (FGF21) null (Fgf21(-/-)) mice. FGF21 regulates energy homeostasis and the metabolic adaptation to fasting. One avenue of this regulation is through induction of peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc1a), a regulator of hepatic fatty acid oxidation and ketogenesis. Because naringenin is a potent activator of hepatic FA oxidation, we hypothesized that induction of FGF21 might be an integral part of naringenin's mechanism of action. Furthermore, we predicted that FGF21 deficiency would potentiate high-fat diet (HFD)-induced metabolic dysregulation and compromise metabolic protection by naringenin. The absence of FGF21 exacerbated the response to a HFD. Interestingly, naringenin supplementation to the HFD robustly prevented obesity in both genotypes. Gene expression analysis suggested that naringenin was not primarily targeting fatty acid metabolism in white adipose tissue. Naringenin corrected hepatic triglyceride concentrations and normalized hepatic expression of Pgc1a, Cpt1a, and Srebf1c in both wild-type and Fgf21(-/-) mice. HFD-fed Fgf21(-/-) mice displayed greater muscle triglyceride deposition, hyperinsulinemia, and impaired glucose tolerance as compared with wild-type mice, confirming the role of FGF21 in insulin sensitivity; however, naringenin supplementation improved these metabolic parameters in both genotypes. We conclude that FGF21 deficiency exacerbates HFD-induced obesity, hepatic steatosis, and insulin resistance. Furthermore, FGF21 is not required for naringenin to protect mice from HFD-induced metabolic dysregulation. Collectively these studies support the concept that naringenin has potent lipid-lowering effects and may act as an insulin sensitizer in vivo.

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Section: Enhanced Weight Gain In Hfd-fed Fgf21 -/-Mice Is Prevented Bmentioning

confidence: 67%

Naringenin Prevents Obesity, Hepatic Steatosis, and Glucose Intolerance in Male Mice Independent of Fibroblast Growth Factor 21

et al. 2015

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“…Our result that ATGL/CGI-58 expression induces PPAR-γ2 activity in transcriptional transactivation experiments is consistent with this concept. Other, more indirect mechanisms to regulate PPAR-γ/RXR activity in response to lipolysis may involve the dissociation and nuclear translocation of lipid droplet-associated transcriptional coregulators or changes in epigenetic modifications of transcription factors/coactivators (32).…”

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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“…18,19). It has been identified to stimulate fatty acid oxidation (FAO) through interactions with several transcription factors including sirtuin 1 (SIRT1), PPARs, and hepatocyte nuclear factor 4 (20)(21)(22)(23)(24)(25), and PGC1a also increases autophagy and thermogenesis through transcription factor EB and uncoupling protein-1, respectively, under stress condition (26)(27)(28)(29)(30). In addition, it has been shown to protect cells against oxidative damage through nuclear factor erythroid 2 (Nrf2) and forkhead box O3 (31)(32)(33).…”

Section: Introductionmentioning

confidence: 99%