Desnutrin/ATGL Activates PPARδ to Promote Mitochondrial Function for Insulin Secretion in Islet β Cells

Tang, Tsung-Ta; Abbott, Marcia J.; Ahmadian, Maryam; Lopes, Andressa Bolsoni; Wang, Yuhui; Sul, Hei Sook

doi:10.1016/j.cmet.2013.10.012

Cited by 96 publications

(116 citation statements)

References 46 publications

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“…In striking contrast to this highly dynamic regulation of lipolysis, recent stable isotope studies in human skeletal muscle have suggested that basal lipolytic rates in muscle are relatively high and that free fatty acids entering the myocytes necessarily traffic via the intramyocellular TAG stored within LDs before being oxidized (7). Concordant observations were also recently reported in cardiomyocytes, hepatocytes, and islets (8)(9)(10). How, then, are these important functional differences mediated?…”

Section: Discussionsupporting

confidence: 54%

“…The situation in the liver is more complex, because here neutral lipids can be repackaged into lipoproteins for subsequent export (6). Intriguing work by several groups has recently suggested that fatty acids traffic via the LDs in myocytes (7), cardiomyocytes (8), hepatocytes (9), and pancreatic islets (10). These studies also imply and, in some cases (7) actually demonstrate, that this is a somewhat more constitutive process than in adipocytes, raising the question of exactly how lipolysis is coordinated in these cells, which under normal circumstances do not express perilipin 1.…”

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confidence: 99%

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Perilipins 2 and 3 lack a carboxy-terminal domain present in perilipin 1 involved in sequestering ABHD5 and suppressing basal lipolysis

Patel

Yang

Kozusko

et al. 2014

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

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Lipid droplets (LDs) are a conserved feature of most organisms. Vertebrate adipocytes have evolved to efficiently store and release lipids for the whole organism from a single droplet. Perilipin 1, the most abundant lipid-coat protein in adipocytes, plays a key role in regulating lipolysis. In other tissues such as liver and muscle, LDs serve very different biological functions, buffering surplus lipids for subsequent oxidation or export. These tissues express perilipins 2 or 3, rather than perilipin 1. We sought to understand the role of perilipins 2 and 3 in regulating basal lipolysis. Bimolecular fluorescence complementation studies suggested that whereas perilipin 1 prevents the activation of adipose tissue triacylglycerol lipase by its coactivator, AB-hydrolase domain containing-5 (ABHD5), perilipins 2 and 3 do so less effectively. These differences are mediated by a conserved region within the carboxy terminus of perilipin 1 that binds and stabilizes ABHD5 by retarding its degradation by the proteosome. Chimeric proteins generated by fusing the carboxy terminus of perilipin 1 to the amino terminus of perilipins 2 or 3 stabilize ABHD5 and suppress basal lipolysis more effectively than WT perilipins 2 or 3. Furthermore, knockdown of perilipin 1 in adipocytes leads to replacement of perilipin 2 on LDs. In these cells we observed reduced ABHD5 expression and LD localization and a corresponding increase in basal lipolysis. Collectively these data suggest that whereas perilipin 1 potently suppresses basal lipolysis in adipocytes, perilipins 2 and 3 facilitate higher rates of basal lipolysis in other tissues where constitutive traffic of fatty acids via LDs is a necessary step in their metabolism.

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Section: Discussionsupporting

confidence: 54%

mentioning

confidence: 99%

Perilipins 2 and 3 lack a carboxy-terminal domain present in perilipin 1 involved in sequestering ABHD5 and suppressing basal lipolysis

Patel

Yang

Kozusko

et al. 2014

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

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“…PEPCK and GYK are both PPAR and cAMP response element targets, which may explain their differential regulation among the adipose tissue depots (see below). Recent work from various labs indicates that lipolysis also contributes to cellular signaling events ( 10,11,14,41 ) by providing ligands for PPAR ␣ and ␦ , which in turn serve to match lipid oxidation with supply ( 9 ). We therefore reasoned that lipolysis was also driving the increase in lipogenesis and oxidation, and we tested this by deleting ATGL in adipose tissue of adult mice using an inducible model.…”

Section: Discussionmentioning

confidence: 99%

Coupling of lipolysis and de novo lipogenesis in brown, beige, and white adipose tissues during chronic β3-adrenergic receptor activation

Mottillo

Balasubramanian

Lee

et al. 2014

Journal of Lipid Research

237

204

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This article is available online at http://www.jlr.org Classic interscapular brown adipose tissue (BAT) is a thermogenic organ that has a high capacity for uncoupled oxidative metabolism ( 1 ). In contrast, white adipose tissue (WAT) has low oxidative capacity because its main function under normal conditions is to store excess energy as TGs. However, chronic stimulation by ␤ 3-adrenergic receptors ( ␤ 3-ARs) expands the oxidative capacity of WAT and converts it into a tissue resembling BAT. This phenomenon has been termed "browning" of white fat ( 2-4 ) and is marked by increased expression of oxidative genes, induction of uncoupling protein 1 (UCP1), and activation of oxidative metabolism ( 5 ). Importantly, lipolysis plays a central role in the catabolic activity of BAT and WAT. Acutely, mobilized FAs uncouple oxidative phosphorylation and provide fuel that supports both coupled and uncoupled respiration ( 6 ). Lipolysis also provides ligands for PPAR ␣ , which plays a central role in catabolic remodeling of WAT by upregulating oxidative metabolism and limiting FA-induced infl ammation ( 7,8 ). Indeed, several recent studies have demonstrated the importance of lipolysis in providing ligands for activation of PPAR target genes in BAT ( 9, 10 ), heart ( 11 ), liver ( 12, 13 ), and pancreatic ␤ cells ( 14 ).Abstract Chronic activation of ␤ 3-adrenergic receptors ( ␤ 3-ARs) expands the catabolic activity of both brown and white adipose tissue by engaging uncoupling protein 1 (UCP1)-dependent and UCP1-independent processes. The present work examined de novo lipogenesis (DNL) and TG/glycerol dynamics in classic brown, subcutaneous "beige," and classic white adipose tissues during sustained ␤ 3-AR activation by CL 316,243 (CL) and also addressed the contribution of TG hydrolysis to these dynamics. CL treatment for 7 days dramatically increased DNL and TG turnover similarly in all adipose depots, despite great differences in UCP1 abundance. Increased lipid turnover was accompanied by the simultaneous upregulation of genes involved in FAS, glycerol metabolism, and FA oxidation. Inducible, adipocyte-specifi c deletion of adipose TG lipase (ATGL), the rate-limiting enzyme for lipolysis, demonstrates that TG hydrolysis is required for CL-induced increases in DNL, TG turnover, and mitochondrial electron transport in all depots. Interestingly, the effect of ATGL deletion on induction of specifi c genes involved in FA oxidation and synthesis varied among fat depots. Overall, these studies indicate that FAS and FA oxidation are tightly coupled in adipose tissues during chronic adrenergic activation, and this effect critically depends on the activity of adipocyte ATGL. -

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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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Desnutrin/ATGL Activates PPARδ to Promote Mitochondrial Function for Insulin Secretion in Islet β Cells

Cited by 96 publications

References 46 publications

Perilipins 2 and 3 lack a carboxy-terminal domain present in perilipin 1 involved in sequestering ABHD5 and suppressing basal lipolysis

Perilipins 2 and 3 lack a carboxy-terminal domain present in perilipin 1 involved in sequestering ABHD5 and suppressing basal lipolysis

Coupling of lipolysis and de novo lipogenesis in brown, beige, and white adipose tissues during chronic β3-adrenergic receptor activation

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

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