Adipose Overexpression of Desnutrin Promotes Fatty Acid Use and Attenuates Diet-Induced Obesity

Ahmadian, Maryam; Duncan, Robin E.; Varady, Krista A; Frasson, Danúbia; Hellerstein, Marc K.; Birkenfeld, Andreas L.; Samuel, Varman T.; Shulman, Gerald I.; Wang, Yuhui; Kang, Chulho; Sul, Hei Sook

doi:10.2337/db08-1644

Cited by 167 publications

(179 citation statements)

References 33 publications

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“…The decrease in plasma unesterified EPA also may be due to reduced adipose triglyceride lipolysis, which was reported to decrease with age (Caimari et al 2008). Adipose lipolysis is regulated by hormone sensitive lipase and triglyceride lipase, which may be PUFA-selective (Gavino and Gavino 1992;Ahmadian et al 2009;Jaworski et al 2009). In one rat study, aging impaired fasting-induced increase in triglyceride lipase expression (Caimari et al 2008).…”

Section: Ementioning

confidence: 99%

RETRACTED ARTICLE: Aging decreases rate of docosahexaenoic acid synthesis-secretion from circulating unesterified α-linolenic acid by rat liver

Gao

Taha

et al. 2012

AGE

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Docosahexaenoic acid (DHA,, an n-3 polyunsaturated fatty acid (PUFA) found at high concentrations in brain and retina and critical to their function, can be obtained from fish products or be synthesized from circulating α-linolenic acid (α-LNA, 18:3n-3) mainly in the liver. With aging, liver synthetic enzymes are reported reduced or unchanged in the rat. To test whether liver synthesis-secretion of DHA from α-LNA changes with age, we measured whole-body DHA conversion coefficients and rates in unanesthetized adult male Fischer-344 rats aged 10, 20, or 30 months, fed an eicosapentaenoic acid (EPA, 20:5n-3)-and DHAcontaining diet. Unesterified [U-13 C]α-LNA bound to albumin was infused intravenously for 2 h, while [ 13 C]-esterified n-3 PUFAs were measured in arterial plasma, as were unlabeled unesterified and esterified PUFA concentrations. Plasma unesterified n-3 PUFA concentrations declined with age, but esterified n-3 PUFA concentrations did not change significantly. Calculated conversion coefficients were not changed significantly with age, whereas synthesis-secretion rates (product of conversion coefficient and unesterified plasma α-LNA concentration) of esterified DHA and n-3 DPA were reduced. Turnovers of esterified n-3 PUFAs in plasma decreased with age, whereas half-lives increased. The results suggest that hepatic capacity to synthesize DHA and other n-3 PUFAs from circulating α-LNA is maintained with age in the rat, but that reduced plasma α-LNA availability reduces net synthesis-secretion. As unesterified plasma DHA is the form that is incorporated preferentially into brain phospholipid, its reduced synthesis may be deleterious to brain function in aged rats.

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Section: Ementioning

confidence: 99%

RETRACTED ARTICLE: Aging decreases rate of docosahexaenoic acid synthesis-secretion from circulating unesterified α-linolenic acid by rat liver

Gao

Taha

et al. 2012

AGE

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“…It is now unequivocal that ATGL mediates basal and ␤-adrenergic TG lipolysis in adipocytes (1,5,42,49,84) and other cell types, including skeletal muscle (80), hepatocytes (61), embryonic kidney (48), and cancer cells (69). These cell-based studies are supported by interventions in several lower-order species (e.g., S. cerevisiae, Drosophila) (30,47) and mice (1,31), showing that ATGL deletion induces obesity and that ATGL overexpression confers a lean phenotype. Similarly, in vivo ATGL overexpression in skeletal muscle (80) or liver (61) reduced TG mass.…”

Section: Regulation Of Tg Lipasesmentioning

confidence: 95%

“…ATGL exhibits high substrate specificity for TG, very weak activity against DG, and no activity against cholesterol or retinyl ester bonds (84). It is now unequivocal that ATGL mediates basal and ␤-adrenergic TG lipolysis in adipocytes (1,5,42,49,84) and other cell types, including skeletal muscle (80), hepatocytes (61), embryonic kidney (48), and cancer cells (69). These cell-based studies are supported by interventions in several lower-order species (e.g., S. cerevisiae, Drosophila) (30,47) and mice (1,31), showing that ATGL deletion induces obesity and that ATGL overexpression confers a lean phenotype.…”

Section: Regulation Of Tg Lipasesmentioning

confidence: 99%

Triacylglycerol lipases and metabolic control: implications for health and disease

Watt

Spriet

2010

American Journal of Physiology-Endocrinology and Metabolism

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Watt MJ, Spriet LL. Triacylglycerol lipases and metabolic control: implications for health and disease. Am J Physiol Endocrinol Metab 299: E162-E168, 2010. First published January 12, 2010; doi:10.1152/ajpendo.00698.2009.-Fatty acids derived from the hydrolysis of adipose tissue and skeletal muscle triacylglycerol (TG) are an important energy substrate at rest and during physical activity. This review outlines the identification of the new TG lipase, adipose triglyceride lipase, the current understanding of how cellular TG lipases are regulated, and the implications for understanding the integrated control of TG lipolysis. Furthermore, this review outlines recent advances that propose a "revised" role for TG lipases in cellular function, metabolic homeostasis, and disease prevention. fatty acid; metabolism; adipose; skeletal muscle TRIACYLGLYCEROLS (TG) are stored within discrete cytosolic lipid droplets within most tissues. Contrary to the common misconception in the literature that the TG pool is "inert," these droplets are highly dynamic, and the TG within is highly labile. The overall TG content within these droplets is ultimately dependent on the balance between the rates of TG hydrolysis and fatty acid uptake, oxidation, and storage. The fatty acids derived from TG breakdown participate in a variety of cellular processes, including membrane biosynthesis, signal transduction, and, most critically for this review, ATP production after ␤-oxidation. From a systemic viewpoint, fatty acids can be derived from both intracellular and extracellular sources, and with the exception of adipose tissue, the latter is most prevalent due to limited intracellular stores. Under postprandial conditions, ϳ30% of total energy expenditure is reliant on fatty acids derived from adipose TG hydrolysis, and this becomes quantitatively more important with extended fasting or exercise. In cases of caloric surplus leading to obesity, elevated circulating fatty acids may contribute to the accumulation of intramyocellular and hepatic lipids, which are associated with secondary metabolic complications such as insulin resistance (77). Therefore, the liberation of fatty acids from adipocyte TG and release into the systemic circulation is under most conditions the first point of control in the regulation of fatty acid metabolism, and accordingly, tight control of adipocyte lipolysis is a critical mediator of whole body metabolic homeostasis. Similarly, an emerging body of evidence indicates that altering TG metabolism within ectopic tissues, such as liver and skeletal muscle, can influence local fatty acid metabolism with implications for obesity-related metabolic disorders.This review will first focus on the regulation of TG lipolysis and how the understanding of TG regulation has evolved since the discovery and partial characterization of adipose triglyceride lipase (ATGL) only 5 years ago. The review will then outline how changes in TG metabolism can influence adipocyte and skeletal muscle metabolism and summarize the recent evidence sug...

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“…Most notably, ATGL-null mice showed enhanced adiposity along with impaired adipocyte lipolysis under both basal and isoproterenol-stimulated conditions (23). Conversely, mice overexpressing ATGL specifically in adipose tissue were leaner with decreased TAG content in adipocytes and were resistant to diet-induced obesity with improved insulin sensitivity (24).…”

mentioning

confidence: 97%

Relative Contribution of Adipose Triglyceride Lipase and Hormone-sensitive Lipase to Tumor Necrosis Factor-α (TNF-α)-induced Lipolysis in Adipocytes

Yang

Zhang

Heckmann

et al. 2011

Journal of Biological Chemistry

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TNF-␣ potently stimulates basal lipolysis in adipocytes, which may contribute to hyperlipidemia and peripheral insulin resistance in obesity. Recent studies show that adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) act sequentially in catalyzing the first two steps of adipose lipolysis in response to ␤-adrenergic stimulation. Here, we sought to determine their functional roles in TNF-␣-induced lipolysis. Silencing of ATGL expression in adipocytes almost completely abolished basal and TNF-␣-induced glycerol release. In comparison, the glycerol release under the same conditions was only partially decreased upon reduction in expression of either HSL or the ATGL coactivator CGI-58. Interestingly, overexpression of ATGL restored the lipolytic rates in cells with silenced HSL or CGI-58, indicating a predominant role for ATGL. While expression of ATGL, HSL and CGI-58 remains mostly unaffected, TNF-␣ treatment caused a rapid abrogation of the ATGL inhibitory protein G0S2. TNF-␣ drastically decreased the level of G0S2 mRNA, and the level of G0S2 protein could be maintained by inhibiting proteasomal protein degradation using MG-132. Furthermore, coexpression of G0S2 was able to significantly decrease TNF-␣-stimulated lipolysis mediated by overexpressed ATGL or CGI-58. We propose that the early reduction in G0S2 content is permissive for TNF-␣-induced lipolysis.During extended starvation and exercise, catecholamines stimulate the hydrolysis of triacylglycerol (TAG) 2 stores within the lipid droplets (LDs) in adipocytes. The so-called lipolysis makes available surplus fuel in the form of free fatty acids (FFAs) and glycerol for use by other organs and tissues. During the instances of nutritional overload such as obesity, elevated basal adipose lipolysis contributes to the increase of systemic FFA levels, thereby exacerbating peripheral lipotoxicity and insulin resistance (1-4). Considering the importance of TAG turnover at both physiological and pathological levels, it is not surprising that enzymes governing lipolysis have attracted immense research interest over the years. Among many intracellular lipases identified thus far that possess in vitro capacity to hydrolyze TAG, hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) are the most characterized functionally (5, 6). A body of evidence has emerged recently, suggesting that ATGL and HSL act sequentially in mediating adipocyte lipolysis in response to ␤-adrenergic stimulation (7-12). In this newly established model, ATGL initiates lipolysis by specifically removing the first FA from TAGs to produce DAG substrates, which are then hydrolyzed by HSL to generate an additional FA and MAG substrates. MAGs are converted into FA and glycerol by MAG lipase in the final step of lipolysis.HSL was discovered nearly half a century ago due to its induction during fasting and by catabolic hormones (13,14). It has broad substrate specificity toward acylglycerols, including TAG, DAG, and MAG, as well as cholesteryl, retinyl, and lipoidal esters....

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Adipose Overexpression of Desnutrin Promotes Fatty Acid Use and Attenuates Diet-Induced Obesity

Cited by 167 publications

References 33 publications

RETRACTED ARTICLE: Aging decreases rate of docosahexaenoic acid synthesis-secretion from circulating unesterified α-linolenic acid by rat liver

RETRACTED ARTICLE: Aging decreases rate of docosahexaenoic acid synthesis-secretion from circulating unesterified α-linolenic acid by rat liver

Triacylglycerol lipases and metabolic control: implications for health and disease

Relative Contribution of Adipose Triglyceride Lipase and Hormone-sensitive Lipase to Tumor Necrosis Factor-α (TNF-α)-induced Lipolysis in Adipocytes

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