The effects of recombinant tumour necrosis factor (cachectin) on metabolism in isolated rat adipocyte, hepatocyte and muscle preparations

Rofe, Allan M.; Conyers, R. A. J.; Bais, Renze; Gamble, Jennifer R.; Vadas, Mathew A.

doi:10.1042/bj2470789

Cited by 53 publications

(26 citation statements)

References 21 publications

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“…The present study showed that TNF-␣ did not alter gluconeogenesis in hepatocytes isolated from adult rats, confirming the findings of other investigators (17). Hill and McCallum (6) concluded from their in vivo studies that TNF-␣ was a transcriptional regulator of PEPCK and suppressed PEPCK function.…”

Section: Tnf␣ Effects On Hepatocyte Gluconeogenesissupporting

confidence: 92%

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TNFα Decreases Gluconeogenesis in Hepatocytes Isolated from 10-Day-Old Rats

et al. 2001

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Gluconeogenesis decreases during septic shock, but its mechanism is not well known. Tumor necrosis factor alpha (TNF-␣), which is a key cytokine in septic shock, can increase GLUT1 gene expression and glucose uptake in muscles and fatty tissues. TNF-␣ does not alter the metabolism of hepatocytes in which GLUT2 is the predominant glucose transporter. However, GLUT1 is the predominant glucose transporter in hepatocytes of 10-d-old rats. Thus, we hypothesized that TNF-␣ might increase glucose uptake and glycolysis in those cells, and decrease gluconeogenesis. In the present study, hepatocytes isolated from 10-d-old rats were incubated with TNF-␣ at the concentrations of 0, 0.98, 9.8, 98, and 980 ng/mL to evaluate TNF-␣ effects on gluconeogenesis and glucose uptake. TNF-␣ increased glucose uptake (41.1 Ϯ 8 to 114 Ϯ 21.4 mol/10 6 cells at the concentration of 980 ng/mL of TNF-␣) in a dose-dependent manner, and decreased gluconeogenesis (98.2 Ϯ 8.2 to 1.1 Ϯ 3.2 mol/10 6 cells at the concentration of 980 ng/mL of TNF-␣) in a dosedependent manner. The decrease of glucokinase mRNA and GLUT1 mRNA abundance correlated with glucose uptake (r ϭ 0.988 and 0.997, respectively), and the decrease of phosphoenolpyruvate carboxykinase mRNA abundance correlated with the decrease of gluconeogenesis (r ϭ 0.972). The decrease of gluconeogenesis by TNF-␣ correlated with the increase of glucose uptake (r ϭ Ϫ0.988). We concluded that TNF-␣ reciprocally suppressed gluconeogenesis in hepatocytes isolated from 10-dold rats. Gram-negative septic shock in the newborn remains a major medical problem because of its high incidence and mortality. Endotoxin (lipopolysaccharide: LPS), a component of outer cell membrane of Gram-negative bacteria, plays an important role in Gram-negative septic shock. Whereas the LD 90 of Salmonella enteritidis LPS is 0.1 mg/kg in 10-d-old rats, it is 35 mg/kg in adult rats (1), indicating that the newborn is more sensitive to LPS than the adult. The high sensitivity to LPS in the newborn is ascribed to immature pituitary-adrenal function (2), but this alone cannot fully explain the mechanism of the high sensitivity.Glucose dyshomeostasis such as hyperglycemia and hypoglycemia is a common sign in Gram-negative septic shock (1, 3-5). Because severe hypoglycemia may result in severe neurologic sequelae in the newborn, hypoglycemia during shock is a critical problem. During septic shock, glycolysis is increased and gluconeogenesis is decreased in the liver (4, 5). The activity and mRNA abundance of PEPCK, a key gluconeogenic enzyme, are decreased during septic shock (5-7). Because gluconeogenesis is necessary to maintain plasma glucose concentration in the newborn, even at the postprandial state (8), decrease of gluconeogenesis may easily lead to hypoglycemia. Because plasma concentration of insulin, which is a major glucoregulatory hormone and can inhibit gluconeogenesis, increases during septic shock in the adult (1, 3, 9), hyperinsulinemia is postulated to be responsible for the hypoglycemia in adults. In contrast to...

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Section: Tnf␣ Effects On Hepatocyte Gluconeogenesissupporting

confidence: 92%

“…These results suggest that TNF-␣ decreases gluconeogenesis in both newborn and adult animals. In hepatocytes isolated from adult rats, however, gluconeogenesis is not altered after a short incubation with TNF-␣ (17). TNF-␣ effects on glucose metabolism in hepatocytes isolated from newborns are not well known.…”

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confidence: 96%

TNFα Decreases Gluconeogenesis in Hepatocytes Isolated from 10-Day-Old Rats

et al. 2001

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“…It has also been shown that prostaglandin E2 production was increased by these macrophage secretory products and an inhibitor of the cycloocygenase pathway, indomethacin, partially attenuated the stimulation in skeletal muscle protein degradation (Baracos et al, 1983 (Moldawer et al, 1987;Goldberg et al, 1988). Likewise, the involvement of TNF-a on catabolism of proteins has been demonstrated by some studies in vivo (Warren et al, 1987;Flores et al, 1989;Fong et al, 1989) and in vitro Charters & Grimble, 1989) and refuted in others (Kettelhutt & Goldberg, 1988;Moldawer et al, 1987;Rofe et al, 1987;Michie et al, 1988). Nevertheless, the capacity of IL-1 and TNF to cause either weight loss or anorexia in animals has often been noted (Stovroff et al, 1988;Hellestein et al, 1989;Fong et al, 1989;Michie et al, 1988; (Dinarello et al, 1986a), and polyclonal rabbit anti-sera to rhIL-1-a and rhIL-1-P (Dinarello et al, 1986b) were generously provided by Dr Charles A. Dinarello, Tufts University/New England Medical Center (Boston, MA).…”

Section: Discussionmentioning

confidence: 92%

Bioactivity of skeletal muscle proteolysis-inducing factors in the plasma proteins from cancer patients with weight loss

Belizário

Katz²,

Chenker³

et al. 1991

Br J Cancer

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“…The observed differences may reflect the release of other unidentified cytokines in response to endotoxin which promote net protein catabolism (33,34) and/or differences in the mode of administration (i.e., single bolus 10-9 M (48). In vitro, TNF or IL-I did not affect lactate or alanine release, by rat diaphragms within 2 h, although glucose oxidation was mildly stimulated (49). Marked acceleration of glucose transport, glucose transporter synthesis, lactate production and glycogenolysis was observed in a muscle derived cell line (L-6 myotubes) upon exposure to TNF, but not IL-1 (50).…”

Section: Resultsmentioning

confidence: 99%

Administration of endotoxin, tumor necrosis factor, or interleukin 1 to rats activates skeletal muscle branched-chain alpha-keto acid dehydrogenase.

Nawabi¹,

Block²,

Chakrabarti³

et al. 1990

J. Clin. Invest.

111

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Protein catabolic states (i.e., sepsis and trauma) are thought to be associated with accelerated oxidation of branched-chain amino acids (BCAA). Branched-chain a-keto acid dehydrogenase (BCKAD), the rate-limiting enzyme for BCAA oxidation by muscle, is regulated by phosphorylation/dephosphorylation. Skeletal muscle BCKAD was only 2-4% active in control rats. Intravenous injection of Salmonella enteritidis endotoxin (0.25-10 mg/kg) did not change total BCKAI) activity, but increased the percent active enzyme in muscle three-to fourfold in 4-6 h. Identical results were observed in adrenalectomized rats pretreated with one dose of a-methylprednisolone (2.5 mg/kg i.p.) 30-60 min before saline or endotoxin injection, indicating that endotoxin's effect was not mediated by hypersecretion of adrenal hormones. Cortisone pretreatment of normal rats (100 mg/kg per d) for 2 d prevented endotoxin-induced activation of muscle BCKAD, suggesting that endogenous secretion products mediated BCKAD activation by endotoxin. Human recombinant tumor necrosis factor-a and/or IL-1ft or a (50 jig/kg) increased muscle BCKAD activation two-to fourfold in normal rats 4-6 h after intravenous injection. We conclude that cytokine-mediated activation of muscle BCKAD may contribute to accelerated BCAA oxidation in

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The effects of recombinant tumour necrosis factor (cachectin) on metabolism in isolated rat adipocyte, hepatocyte and muscle preparations

Cited by 53 publications

References 21 publications

TNFα Decreases Gluconeogenesis in Hepatocytes Isolated from 10-Day-Old Rats

TNFα Decreases Gluconeogenesis in Hepatocytes Isolated from 10-Day-Old Rats

Bioactivity of skeletal muscle proteolysis-inducing factors in the plasma proteins from cancer patients with weight loss

Administration of endotoxin, tumor necrosis factor, or interleukin 1 to rats activates skeletal muscle branched-chain alpha-keto acid dehydrogenase.

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