Whole-body lipolysis and triglyceride-fatty acid cycling in cachectic patients with esophageal cancer.

Klein, Samuel; Wolfe, Robert R.

doi:10.1172/jci114854

Cited by 78 publications

(51 citation statements)

References 32 publications

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“…6,[11][12][13][14]37,38 Mechanistic studies suggest PKA-induced lipolysis is not enhanced in late stage cachexia; 38 instead, increased expression of lipases may be responsible for lipid catabolism in adipose tissue in these more advanced stages of cachexia. 13,38 Studies have also reported enhanced lipid accumulation in muscle in cachectic patients with increased weight loss 29,39 and hepatic steatosis in fully-established cachexia in experimental tumor-bearing animals.…”

Section: Discussionmentioning

confidence: 99%

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Adipose tissue lipolysis and energy metabolism in early cancer cachexia in mice

Kliewer

Tian

et al. 2014

Cancer Biology & Therapy

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Keywords: colon-26 adenocarcinoma, early cachexia, energy expenditure, lipid metabolism, lipolysis, thermogenesis Abbreviations: eWAT, epididymal white adipose tissue; iWAT, inguinal white adipose tissue; iBAT, interscapular brown adipose tissue; PKA, protein kinase A; ATGL, adipose triglyceride lipase; HSL, hormone sensitive lipase; UCP, uncoupling protein; PPAR, peroxisome proliferator activated receptor; PGC, peroxisome proliferator activated receptor gamma coactivator; CPT, carnitine palmitoyltransferase; DIO, iodothyronine deiodinase; MuRF, muscle ring finger protein; COX, cytochrome c oxidase subunits; GYK, glycerokinase; PRDM, PR domain zinc finger protein; ACOX, acyl CoA oxidase; CRP, C-reactive protein; LPL, lipoprotein lipase; H&E, hematoxylin and eosin; TEE, total energy expenditure; RER, respiratory exchange ratio.Cancer cachexia is a progressive metabolic disorder that results in depletion of adipose tissue and skeletal muscle. A growing body of literature suggests that maintaining adipose tissue mass in cachexia may improve quality-of-life and survival outcomes. Studies of lipid metabolism in cachexia, however, have generally focused on later stages of the disorder when severe loss of adipose tissue has already occurred. Here, we investigated lipid metabolism in adipose, liver and muscle tissues during early stage cachexia -before severe fat loss -in the colon-26 murine model of cachexia. White adipose tissue mass in cachectic mice was moderately reduced (34-42%) and weight loss was less than 10% of initial body weight in this study of early cachexia. In white adipose depots of cachectic mice, we found evidence of enhanced protein kinase A -activated lipolysis which coincided with elevated total energy expenditure and increased expression of markers of brown (but not white) adipose tissue thermogenesis and the acute phase response. Total lipids in liver and muscle were unchanged in early cachexia while markers of fatty oxidation were increased. Many of these initial metabolic responses contrast with reports of lipid metabolism in later stages of cachexia. Our observations suggest intervention studies to preserve fat mass in cachexia should be tailored to the stage of cachexia. Our observations also highlight a need for studies that delineate the contribution of cachexia stage and animal model to altered lipid metabolism in cancer cachexia and identify those that most closely mimic the human condition.

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Section: Discussionmentioning

confidence: 99%

“…[10][11][12][13][14][15][16] Elevated rates of lipolysis in cachexia would contribute to loss of total body fat only if lipid utilization were also increased. Indeed, clinical studies have reported elevated rates of whole body fatty acid oxidation in weight losing (10% of initial body weight) cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Adipose tissue lipolysis and energy metabolism in early cancer cachexia in mice

Kliewer

Tian

et al. 2014

Cancer Biology & Therapy

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“…This triglyceride-fatty acid (TG-FA) cycle, is composed of an intra-adipose tissue cycle and an extra-adipose tissue cycle. FA released into plasma are taken up by the liver, reesterified, and secreted as very large density lipoprotein (VLDL)-TG, which are then transported to the periphery to be reincorporated into adipose tissue TG (Newsholme and Crabtree, 1976;Klein and Wolfe, 1990;Frayn et al, 1994). As proposed by Newsholme et al (Newsholme and Crabtree, 1976), the existence of TG-FA cycle provides for increased sensitivity and flexibility in controlling lipid mobilization.…”

Section: Introductionmentioning

confidence: 99%

A computational model of adipose tissue metabolism: Evidence for intracellular compartmentation and differential activation of lipases

Kim

Saidel

Kalhan

2008

Journal of Theoretical Biology

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Regulation of lipolysis in adipose tissue is critical to whole body fuel homeostasis and to the development of insulin resistance. Due to the challenging nature of laboratory investigations of regulatory mechanisms in adipose tissue, mathematical models could provide a valuable adjunct to such experimental work. We have developed a computational model to analyze key components of adipose tissue metabolism in vivo in human in the fasting state. The various key components included triglyceride-fatty acid cycling, regulation of lipolytic reactions, and glyceroneogenesis. The model, consisting of spatially lumped blood and cellular compartments, included essential transport processes and biochemical reactions. Concentration dynamics for major substrates were described by mass balance equations. Model equations were solved numerically to simulate dynamic responses to intravenous epinephrine infusion. Model simulations were compared with the corresponding experimental measurements of the arteriovenous difference across the abdominal subcutaneous fat bed in humans. The model can simulate physiological responses arising from the different expression levels of lipases. Key findings of this study are as follows: (1) Distinguishing the active metabolic subdomain (~3% of total tissue volume) is critical for simulating data. (2) During epinephrine infusion, lipases are differentially activated such that diglyceride breakdown is ~4 times faster than triglyceride breakdown. (3) Glyceroneogenesis contributes more to glycerol-3-phosphate synthesis during epinephrine infusion when pyruvate oxidation is inhibited by a high acetyl-CoA/free-CoA ratio.

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“…Almost 30 years ago, Newsholme and Crabtree (3) discussed the importance of this cycle in metabolic regulation and heat production. Quantitative estimates of the triglyceride/fatty acid cycle in human adults and newborn infants and studies in animals show that only a small fraction of the FFA released as a result of lipolysis in the WAT are oxidized, and the majority are re-esterified to triglycerides in various tissues (2)(3)(4)(5)(6)(7)(8)(9). The quantitative estimates of triglyceride/fatty acid cycling vary in different studies in humans, depending upon the methodology employed.…”

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confidence: 99%

“…Quantitative changes in the triglyceride/fatty acid cycle have been related to the increased thermogenesis after burns in humans (4), the increased metabolic rate of cachectic patients with esophageal cancer (5), and increased oxygen consumption following leptin administration (6),and to the amplification of substrate flux during acute exercise (7). In addition, triglyceride/fatty acid cycle flux is markedly increased following an 87-h fast in humans (8).…”

mentioning

confidence: 99%