Inhibiting Adipose Tissue Lipogenesis Reprograms Thermogenesis and PPARγ Activation to Decrease Diet-Induced Obesity

Lodhi, Irfan J.; Li, Yin; Jensen-Urstad, Anne P.L.; Funai, Katsuhiko; Coleman, Trey; Baird, John H.; Ramahi, Meral K. El; Razani, Babak; Song, Houyan; Hsu, Fong‐Fu; Turk, John; Semenkovich, Clay F.

doi:10.1016/j.cmet.2012.06.013

Cited by 219 publications

(239 citation statements)

References 65 publications

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“…However, lipolysis is also closely linked to thermogenesis and energy expenditure by supplying fatty acids for β-oxidation (Haemmerle et al 2006, Chondronikola et al 2016. On the other hand, inhibiting adipose lipogenesis by fatty acid synthase deficiency promotes energy expenditure and protects from diet-induced obesity and insulin resistance (Lodhi et al 2012). These findings suggest that the balance between lipogenesis and lipolysis is critical for maintaining systemic energy homeostasis and insulin sensitivity.…”

Section: :3mentioning

confidence: 72%

Adipose tissue in control of metabolism

Luo

Liu

2016

Journal of Endocrinology

505

331

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Adipose tissue plays a central role in regulating whole-body energy and glucose homeostasis through its subtle functions at both organ and systemic levels. On one hand, adipose tissue stores energy in the form of lipid and controls the lipid mobilization and distribution in the body. On the other hand, adipose tissue acts as an endocrine organ and produces numerous bioactive factors such as adipokines that communicate with other organs and modulate a range of metabolic pathways. Moreover, brown and beige adipose tissue burn lipid by dissipating energy in the form of heat to maintain euthermia, and have been considered as a new way to counteract obesity. Therefore, adipose tissue dysfunction plays a prominent role in the development of obesity and its related disorders such as insulin resistance, cardiovascular disease, diabetes, depression and cancer. In this review, we will summarize the recent findings of adipose tissue in the control of metabolism, focusing on its endocrine and thermogenic function.

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Section: :3mentioning

confidence: 72%

Adipose tissue in control of metabolism

Luo

Liu

2016

Journal of Endocrinology

505

331

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“…DNL produces lipid species that are biologically active and are functionally distinct from dietary lipids ( 47,48 ), as is the case with the production of a FASN-dependent PPAR ␥ ligand in adipose tissue ( 49 ). In this regard, PPAR ␦ activation in liver generates ligands that activate skeletal muscle PPAR ␣ , thereby matching hepatic lipogenesis with muscle lipid oxidation ( 50 ).…”

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

243

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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“…In the fed state, cytoplasmic FAS is phosphorylated to limit lipid production resulting in PPAR ␣ activation, while membrane FAS, less susceptible to phosphorylation, likely produces lipids for energy storage or export. Given the rapid demands of lipid synthesis prompted by transition from the fasting to the fed state, the induction of membrane FAS may be predominantly substrate-driven through allosteric Physiological, mass spectrometric, and crystal structure data indicate that phospholipids interact with nuclear receptors ( 6,(25)(26)(27)(28)(29). FAS appears to be linked to PPAR ␣ through phosphatidylcholine synthesis mediated by the Kennedy pathway ( 6 ).…”

Section: Discussionmentioning

confidence: 99%

Nutrient-dependent phosphorylation channels lipid synthesis to regulate PPARα

Jensen-Urstad

Song

Lodhi

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org targeted to treat lipid disorders, diabetes, and obesity, is highly expressed in the liver. Its induction by fasting promotes lipid uptake, fatty acid ␤ -oxidation, ketogenesis, and gluconeogenesis ( 1, 2 ). Ligand binding to PPAR ␣ causes it to heterodimerize with retinoid X receptor (RXR) ␣ , allowing activation of gene transcription at peroxisome proliferator response elements (PPRE) ( 3, 4 ). Synthetic PPAR ␣ ligands, such as fi brates, used for human lipid disorders ( 5 ) have been known for decades, but potential endogenous ligands were identifi ed only recently ( 6, 7 ). Mice with liver-specifi c deletion of the lipogenic enzyme fatty acid synthase (FAS) have impaired PPAR ␣ activity ( 8 ), and FAS activates PPAR ␣ by producing an endogenous phospholipid ligand ( 6 ). FAS also activates PPAR ␣ in brain and macrophages ( 9, 10 ).Mammalian FAS synthesizes long-chain fatty acids, primarily palmitate, through the activities of seven functional domains: acyl carrier, acyl transferase, ␤ -ketoacyl synthase, ␤ -ketoacyl reductase, ␤ -hydroxyacyl dehydratase, enoyl reductase, and thioesterase ( 11 ). Like PPAR ␣ , FAS is highly expressed in liver ( 12 ). In times of nutrient excess, hepatic FAS converts carbohydrate to lipid that is stored in lipid droplets or secreted in the form of VLDL ( 13 ). Nutrient excess is associated with elevated levels of insulin, known to induce FAS expression.These accepted physiological roles for PPAR ␣ and FAS appear to confl ict with the observation that inactivation of FAS impairs PPAR ␣ activation. How might FAS activate a process stimulated by feeding such as insulin-responsive lipogenesis and also activate a process stimulated by fasting such as the induction of PPAR ␣ -dependent gene expression?We hypothesized that distinct subcellular pools of FAS mediate these disparate effects. Compartmentalization would permit regulation of an FAS pool generating lipids for signaling that would be distinct from an FAS pool generating lipids for energy storage. In support of this hypothesis, Abstract Peroxisome proliferator-activated receptor (PPAR) ␣ is a nuclear receptor that coordinates liver metabolism during fasting. Fatty acid synthase (FAS) is an enzyme that stores excess calories as fat during feeding, but it also activates hepatic PPAR ␣ by promoting synthesis of an endogenous ligand. Here we show that the mechanism underlying this paradoxical relationship involves the differential regulation of FAS in at least two distinct subcellular pools: cytoplasmic and membrane-associated. In mouse liver and cultured hepatoma cells, the ratio of cytoplasmic to membrane FAS-specifi c activity was increased with fasting, indicating higher cytoplasmic FAS activity under conditions associated with PPAR ␣ activation. This effect was due to a nutrient-dependent and compartment-selective covalent modifi cation of FAS. Cytoplasmic FAS was preferentially phosphorylated during feeding or insulin treatment at Thr-1029 and Thr-1033, which fl ank a d...

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Inhibiting Adipose Tissue Lipogenesis Reprograms Thermogenesis and PPARγ Activation to Decrease Diet-Induced Obesity

Cited by 219 publications

References 65 publications

Adipose tissue in control of metabolism

Adipose tissue in control of metabolism

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

Nutrient-dependent phosphorylation channels lipid synthesis to regulate PPARα

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