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Biomedical subjects

C Grunfeld

Publications and source records attributed to C Grunfeld.

At least 109 records · Page 6Linked to original sources
PubMed1993

Chylomicrons alter the fate of endotoxin, decreasing tumor necrosis factor release and preventing death.

The hypertriglyceridemia of infection was traditionally thought to represent the mobilization of substrate to fuel the body's response to the infectious challenge. However, we have previously shown that triglyceride-rich lipoproteins can protect against endotoxin-induced lethality. The current studies examine the mechanism by which this protection occurs. Rats infused with a lethal dose of endotoxin preincubated with chylomicrons had a reduced mortality compared with rats infused with endotoxin alone (15 vs. 76%, P < 0.001). Preincubation with chylomicrons increased the rate of clearance of endotoxin from plasma and doubled the amount of endotoxin cleared by the liver (30 +/- 1 vs. 14 +/- 2% of the total infused radiolabel, P < 0.001). In addition, autoradiographic studies showed that chylomicrons directed more of the endotoxin to hepatocytes and away from hepatic macrophages. Rats infused with endotoxin plus chylomicrons also showed reduced peak serum levels of tumor necrosis factor as compared with controls (14.2 +/- 3.3 vs. 44.9 +/- 9.5 ng/ml, mean +/- SEM, P = 0.014). In separate experiments, chylomicrons (1,000 mg triglyceride/kg) or saline were infused 10 min before the infusion of endotoxin. Chylomicron pretreatment resulted in a reduced mortality compared with rats infused with endotoxin alone (22 vs. 78%, P < 0.005). Therefore, chylomicrons can protect against endotoxin-induced lethality with and without preincubation with endotoxin. The mechanism by which chylomicrons protect against endotoxin appears to involve the shunting of endotoxin to hepatocytes and away from macrophages, thereby decreasing macrophage activation and the secretion of cytokines.

Animals↗
PubMed1993

Endotoxin increases parathyroid hormone-related protein mRNA levels in mouse spleen. Mediation by tumor necrosis factor.

Parathyroid hormone-related protein (PTHrP) causes hypercalcemia in malignancy. However, the role and regulation of PTHrP in normal physiology is just beginning to be explored. PTHrP is found in the spleen and has several other features common to cytokines. Since endotoxin (LPS) causes many of its effects indirectly by inducing cytokines, studies were undertaken to determine whether LPS might also induce splenic PTHrP expression. LPS (100 ng/mouse) increased splenic PTHrP mRNA levels 3.6-fold in C3H/OuJ mice. This effect was maximal at 2 h and returned to baseline by 4 h. PTHrP peptide levels also increased 3.3-fold in splenic extracts in response to LPS (1 microgram/mouse). Murine TNF-alpha and human IL-1 beta, cytokines that mediate many of the effects of LPS, also increased splenic PTHrP mRNA levels. LPS-resistant C3H/HeJ mice, which produce minimal amounts of TNF and IL-1 in response to LPS, were resistant to LPS induction of splenic PTHrP mRNA, while TNF-alpha and IL-1 beta readily increased PTHrP mRNA levels in C3H/HeJ mice. Anti-TNF antibody blocked LPS induction of splenic PTHrP mRNA in C3H/OuJ mice by 68%, indicating that TNF is a mediator of the LPS induction of PTHrP levels. In contrast, an IL-1 receptor antagonist (IL-1ra) was ineffective. The increase in PTHrP in the spleen during the immune response suggests that PTHrP may play an important role in immune modulation, perhaps by mediating changes in lymphocyte proliferation and/or function.

Animals↗
PubMed1993

Tumor necrosis factor mediates the effects of endotoxin on cholesterol and triglyceride metabolism in mice.

The host response to infection is frequently accompanied by changes in cholesterol and triglyceride (TG) metabolism. To determine the role of cytokines in mediating these changes, we studied the effects of endotoxin (LPS), tumor necrosis factor-alpha (TNF) and interleukin-1 beta (IL-1) on cholesterol and TG metabolism in C57Bl/6 (LPS-sensitive) mice and in C3H/HeJ (LPS-resistant) mice whose macrophages do not produce TNF and IL-1 in response to LPS. Sixteen hours after administration, LPS (1 micrograms/mouse) produced a 41% increase in serum cholesterol and a 62% increase in serum TG levels in C57Bl/6 mice whereas a 100-fold higher dose of LPS did not have a significant effect in C3H/HeJ mice. LPS (1 microgram/mouse) also produced a 8.6-fold increase in hepatic cholesterol synthesis and a 2.7-fold increase in hepatic fatty acid synthesis in C57Bl/6 mice but had no effect in C3H/HeJ mice. This suggests that macrophage produced cytokines such as TNF and IL-1 may be involved in mediating these effects of LPS. Additionally, LPS also increased the activity of hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. As seen with LPS, TNF and IL-1 also increased serum cholesterol and TG levels in C57Bl/6 mice. Moreover, TNF and IL-1 produced a 2.3- and 2.1-fold increase in hepatic HMG-CoA reductase activity, respectively. Finally, pretreatment of mice with anti-TNF antibodies, but not with an IL-1 receptor antagonist, blocked the effect of LPS on serum cholesterol and TG levels, hepatic cholesterol and fatty acid synthesis, and hepatic HMG-CoA reductase activity. These results suggest that whereas both TNF and IL-1 mimic the effects of LPS on cholesterol and TG metabolism, TNF may be the in vivo mediator of these late effects of LPS in mice.

Animals↗
PubMed1993

Increased de novo hepatic lipogenesis in human immunodeficiency virus infection.

We measured de novo lipogenesis in human immunodeficiency virus (HIV) infected men using a newly developed stable isotope method. HIV-infected subjects with a history of weight loss (n = 17, mean weight loss 14.9 +/- 3.2 kg), asymptomatic HIV-seropositive subjects with normal CD4 T-cell counts (n = 7) and healthy HIV seronegative controls (n = 11) were studied. Hepatic lipogenesis was determined by infusion of [2-13C]-acetate, using the recently described xenobiotic probe technique with mass isotopomer analysis. Hepatic acetyl-coenzyme A enrichment was measured by high performance liquid chromatography/mass spectrometry of secreted sulfamethoxazole-acetate, with measurement of incorporation into very low density lipoprotein-fatty acids by gas chromatography-mass spectrometry. Circulating tumor necrosis factor (TNF), interleukin-1 (IL-1), interferon alpha (IFN alpha), insulin, and triglycerides were measured concurrently, and 7-day weighed food records were performed. De novo hepatic lipogenesis was increased 3- to 4-fold in HIV-infected subjects with weight loss compared to normal controls (P < 0.05 for palmitate and stearate in both overnight-fasted and fed states), and was also significantly increased in asymptomatic HIV seropositive subjects. Circulating TNF and IL-1 were not measurable in any subject (detection limit 2 pg/ml for IL-1 and 20 pg/ml for TNF). Serum IFN alpha was measurable in 11 out of 17 subjects with wasting and correlated significantly with de novo lipogenesis in overnight-fasted but not fed states. Serum IFN alpha was unmeasurable in asymptomatic HIV-infected subjects despite elevated lipogenic rates. Serum triglyceride concentrations were elevated in subjects with weight loss (2.09 +/- 0.28 mmol/L) and asymptomatic HIV-positives (1.34 +/- 0.34 mmol/L) in comparison to controls (0.67 +/- 0.08 mmol/L), and correlated with lipogenesis. Food intake correlated inversely with lipogenesis in the overnight-fasted state. We conclude that HIV infection is characterized by abnormal fat anabolism. This applies to subjects with reduced lean body mass and to asymptomatic HIV-positive subjects with normal T-cell counts. The former observation may have implications for the pathophysiology and treatment of the wasting syndrome. The latter observation is consistent with activation of the immune response and a state of viral nonlatency in early HIV disease.

Adult↗
PubMed1993

The hypertriglyceridemia of acquired immunodeficiency syndrome is associated with an increased prevalence of low density lipoprotein subclass pattern B.

Plasma low density lipoproteins (LDL) comprise multiple discrete subclasses, differing in size, density, and chemical composition. Gradient gel electrophoresis of LDL has demonstrated three common subclass patterns based on the predominant LDL subclass: large LDL, designated subclass pattern A; small LDL particles, designated subclass pattern B; and an intermediate pattern. Genetic studies have demonstrated that these patterns are inherited, but several lines of evidence suggest that environmental factors are important in the phenotypic expression of the pattern. The LDL B pattern is associated with increased levels of plasma triglyceride, reduced high density lipoprotein (HDL), and obesity. To better define the role of environmental factors on LDL phenotypic expression, we determined LDL patterns in patients with the acquired immunodeficiency syndrome (AIDS), an infection characterized by hypertriglyceridemia and weight loss. Similar to previous studies, plasma triglyceride levels were increased, whereas plasma cholesterol, LDL cholesterol, and HDL cholesterol levels were decreased in the AIDS subjects compared to those in age-matched controls. The percentage of AIDS subjects with the LDL B phenotype was increased 2.5-fold, demonstrating an increased prevalence of the LDL B phenotype in an acquired form of hypertriglyceridemia. For each LDL phenotype in AIDS, serum triglyceride levels were higher than the same phenotypic pattern in controls, with the most marked elevations in triglycerides found in AIDS subjects with the LDL B phenotype. In contrast to what was observed in controls, HDL cholesterol levels were decreased in all AIDS subjects and were unrelated to LDL pattern. Total and LDL cholesterol levels were higher in controls with the LDL B phenotype than in those with the LDL A phenotype, but there was no difference in total and LDL cholesterol in AIDS subjects with LDL B compared to A. On multiple regression analysis in subjects with AIDS, plasma triglyceride levels, age, and HDL cholesterol all contribute to the occurrence of the LDL B phenotype, but elevations in plasma triglyceride levels are the strongest independent predictor. Body mass index was not a predictor of LDL B phenotype in AIDS. These results suggest that disturbances in triglyceride metabolism that are caused by AIDS lead to the appearance of the LDL subclass B phenotype and provide further evidence that environmental or disease states that perturb lipid metabolism can produce an increased prevalence of the LDL B phenotype.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Anabolic effects of recombinant human growth hormone in patients with wasting associated with human immunodeficiency virus infection.

Body wasting, characterized by disproportionate loss of body cell mass, is a feature of many chronic diseases, including infection with the human immunodeficiency virus (HIV). Therapies that merely increase energy intake do not consistently restore body cell mass in patients with the wasting syndrome. Because treatment with GH has induced nitrogen (N) retention in catabolic patients after surgery, burns, cancer, and hypocaloric feeding, we designed this study to determine whether GH could also produce an anabolic response in persons with HIV-associated weight loss. Six HIV-positive (HIV+) men with an average weight loss of 19% and six healthy weight-stable controls (HIV-) were hospitalized on a metabolic ward, where they consumed a constant metabolic diet during successive 5-day precontrol, 7-day baseline, and 7-day treatment [recombinant human GH (rhGH), 0.1 mg/kg.day] periods. The effects of rhGH on body weight, N and electrolyte excretion, energy expenditure, substrate oxidation, and integrated lipid and carbohydrate metabolism were assessed. Body weight increased promptly and progressively during treatment (2.0 +/- 0.3 and 1.6 +/- 0.2 kg in HIV+ and HIV-, respectively). Urinary N excretion decreased by 288 +/- 17 and 287 +/- 42 mmol/day in HIV+ and HIV-, respectively. Resting energy expenditure increased by 7.5% in both groups. Protein oxidation decreased, whereas lipid oxidation increased significantly. Glucose flux increased, and modest increases in fasting plasma triglyceride, glucose, and insulin levels were observed. Thus, short term rhGH treatment increased both protein anabolism and protein-sparing lipid oxidation, effects that should increase body cell mass if sustained during chronic therapy.

Adult↗
PubMed1993

The protective effect of serum lipoproteins against bacterial lipopolysaccharide.

Lipoproteins bind and inactivate bacterial endotoxin, both in vitro and in vivo. Both cholesterol ester-rich and TG-rich lipoproteins, and TG-rich lipid emulsions can prevent death in mice when pre-incubated with a lethal dose of endotoxin before intraperitoneal administration. Chylomicrons can also prevent death when given intravenously after endotoxin in rats. The metabolic fate of lipoprotein-bound endotoxin appears to be directed by the lipoprotein particle. When administered with chylomicrons, the plasma clearance and hepatic uptake of endotoxin are enhanced. Endotoxin is shunted preferentially to hepatocytes and away from hepatic macrophages, thereby increasing endotoxin excretion [corrected] in bile. The survival benefit and alterations in metabolism afforded by chylomicrons correlate with a reduction in peak serum levels of tumour necrosis factor (TNF), providing a possible mechanism by which lipoproteins protect against endotoxin-induced death. These findings suggest a possible role for lipoproteins or lipid emulsions in the body's defence against endotoxaemia.

Animals↗
PubMed1993

Effect of endotoxin on cholesterol biosynthesis and distribution in serum lipoproteins in Syrian hamsters.

Infection and inflammation increase serum triglyceride and cholesterol levels in rodents and rabbits. Endotoxin (LPS) has been used as a model of infection and its effects on triglyceride metabolism have been previously characterized. In the present study we demonstrate that both low (100 ng/100 g body weight) and high dose (100 micrograms/100 g body weight) LPS increase serum cholesterol levels in hamsters. The increase in serum cholesterol is first observed 16 h after LPS and persists for at least 24 h. This increase is primarily due to an increase in low density lipoprotein (LDL) cholesterol. High density lipoprotein (HDL) cholesterol levels decrease after LPS treatment. Both low and high dose LPS increase hepatic cholesterol synthesis (low dose 85%, high dose 205%) and total HMG-CoA reductase activity (low dose 2.97-fold, high dose 9.96-fold). However, the proportion of HMG-CoA reductase in the active form is reduced by LPS treatment. Additionally, the mass of HMG-CoA reductase protein in the liver, measured by Western blotting, is increased after LPS. Moreover, LPS increases hepatic HMG-CoA reductase mRNA levels (low dose 3.1-fold, high dose 14.2-fold). The increase in hepatic HMG-CoA reductase mRNA levels is first seen 4 h after LPS and persists for at least 24 h. In contrast, LPS had only minimal effects on hepatic LDL receptor protein and mRNA levels. These results suggest that LPS increases serum cholesterol levels by increasing hepatic cholesterol synthesis. LPS administration decreases apoE mRNA levels in the liver while having no effect on apoA-I mRNA levels. These results suggest that HMG-CoA reductase is a member of a group of hepatic proteins that are positively regulated by inflammatory stimuli (acute phase proteins) while apoE can be considered a negative acute phase protein in hamsters. It is possible that increases in hepatic HMG-CoA reductase provide cholesterol that allows for the increased production of lipoproteins and elevations in serum lipid levels that may be beneficial to the body's host defense.

Animals↗
PubMed1992

Resting energy expenditure, caloric intake, and short-term weight change in human immunodeficiency virus infection and the acquired immunodeficiency syndrome.

To assess the causes of short-term weight loss in patients with acquired immunodeficiency syndrome (AIDS), we measured resting energy expenditure (REE), caloric intake, and the 28-d weight trend in control subjects, human immunodeficiency virus (HIV)+ subjects, AIDS patients, and AIDS patients during secondary infection (AIDS-SI). REE was increased in HIV+ (11%), AIDS (25%), and AIDS-SI (29%). Caloric intake was similar in control subjects, HIV+, and AIDS but reduced 36% in AIDS-SI, who consumed 17% fewer calories than their REE. Average short-term weight was stable for HIV+ and AIDS but decreased 5% in AIDS-SI. Weight trend correlated with caloric intake but not with REE. Thus HIV+ and AIDS are able to partially compensate for increased REE because they do not show short-term weight loss. Decreased caloric intake is critical for short-term weight loss and is seen during secondary infection. Inability of decreased caloric intake to decrease REE during infection accelerates short-term weight loss. Rapid weight loss with anorexia may be a harbinger of secondary infection in AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1992

The role of the cytokines, interferon alpha and tumor necrosis factor in the hypertriglyceridemia and wasting of AIDs.

The hypertriglyceridemia of infection is mediated by many of the cytokines that regulate the immune response, including the tumor necrosis factors, the interleukins and the interferons. In the acquired immunodeficiency syndrome (AIDS), hypertriglyceridemia is most likely due to increased circulating levels of interferon alpha. Both in AIDS and in animal models there is no direct association between the presence of hypertriglyceridemia and the syndrome of wasting. Rather, circulating lipoproteins may neutralize infectious organisms and therefore contribute to host defense.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Differential effects of interleukin-1 and tumor necrosis factor on ketogenesis.

To determine the role of cytokines in mediating the decrease in ketones associated with infection, we studied the effect of endotoxin (LPS), interleukin-1 (IL-1), and tumor necrosis factor (TNF) on serum and hepatic ketone body levels (KB), serum free fatty acids (FFA), and hepatic malonyl-CoA levels. LPS decreased serum and hepatic KB in C57Bl/6 (LPS sensitive) mice, whereas it had little effect in C3H/HeJ (LPS resistant) mice, whose macrophages lack the ability to produce IL-1 and TNF in response to LPS, suggesting that IL-1 and TNF may mediate this effect. IL-1 and TNF decreased serum KB in both strains of mice. As seen with LPS, IL-1 decreased hepatic KB, whereas TNF had no such effect. LPS, IL-1, and TNF increased hepatic malonyl-CoA levels. TNF acutely raised serum FFA, whereas LPS and IL-1 did not. Postulating that the TNF-induced increase in FFA overrides the inhibitory effect of malonyl-CoA on fatty acid oxidation and ketogenesis, we used R-2-phenylisopropyladenosine to block TNF-induced lipolysis and demonstrated that in the absence of increased fatty acid flux, TNF inhibits KB formation. As seen with LPS, IL-1, but not TNF, decreased KB in the fasting state. These data suggest that IL-1 and TNF may mediate the antiketogenic effect of infection and that IL-1 has properties closest to that of LPS.

Animals↗
PubMed1992

LDL subclass phenotypes and triglyceride metabolism in non-insulin-dependent diabetes.

Plasma low density lipoprotein (LDL) comprises multiple discrete subclasses differing in size, density, and chemical composition. A common, heritable phenotype characterized by the predominance of small, dense LDL particles (LDL subclass phenotype B) is associated with relatively increased concentrations of plasma triglycerides, reduced levels of high density lipoprotein, and increased risk of coronary artery disease in comparison with subjects with larger LDL (LDL subclass phenotype A). Population studies have indicated that approximately 20-30% of adult men have phenotype B, and another 15-20% have LDL of intermediate size. The lipid changes in phenotype B are similar to those that have been observed in patients with non-insulin-dependent diabetes mellitus (NIDDM). In the present study, we have assessed LDL subclass phenotypes in normolipidemic men with NIDDM and in age-matched control subjects who had similar lipid levels. There was a greater than twofold increase in the percentage of individuals with the LDL B phenotype in the NIDDM subjects. The LDL B phenotype was associated with higher plasma triglyceride levels and a trend toward lower high density lipoprotein cholesterol levels compared with the LDL A phenotype in the NIDDM subjects, as has been previously observed in control groups. Indices of diabetic control, such as fasting and hemoglobin A1 levels, were similar regardless of LDL phenotype pattern, suggesting that glycemic control was not likely to account for the increase in the LDL B phenotype. In both control and NIDDM subjects, the clearance of triglyceride-rich lipoproteins was slowed in the subjects with the LDL phenotype B compared with those with the A phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Role for monokines in the metabolic effects of endotoxin. Interferon-gamma restores responsiveness of C3H/HeJ mice in vivo.

To examine the role of cytokines in mediating the lipogenic effects of endotoxin (LPS), we studied the effects of LPS and cytokines on hepatic fatty acid synthesis in LPS-sensitive C3H/OuJ mice and in LPS-resistant C3H/HeJ mice, whose macrophages are defective in the ability to produce tumor necrosis factor (TNF) and IL-1 in response to LPS. HeJ mice were 16-fold less sensitive than OuJ mice to the lipogenic effect of LPS. In OuJ mice, 10 micrograms of LPS caused a maximal increase in hepatic lipogenesis (3.86 +/- 0.41-fold), whereas in HeJ mice the maximal increase was only 1.79 +/- 0.32-fold after 100 micrograms of LPS. This lipogenic response paralleled the decreased ability of LPS to increase hepatic and splenic levels of mRNAs for TNF and IL-1 and serum levels of TNF in HeJ mice. In contrast, the maximal effect of TNF on lipogenesis was greater and the sensitivity to TNF was increased 2.4-fold in HeJ mice compared to OuJ mice. Administration of IFN-gamma before LPS in HeJ mice had no effect on IL-1 mRNA, but partially restored the LPS-induced increase in hepatic and splenic mRNA for TNF and serum TNF levels, which may account for the partial restoration of sensitivity to the lipogenic effect of LPS after IFN-gamma treatment. These results indicate that cytokines produced by mononuclear leukocytes mediate the lipogenic effects of LPS.

Animals↗
PubMed1992

Cutaneous barrier perturbation stimulates cytokine production in the epidermis of mice.

The disruption of the cutaneous permeability barrier results in metabolic events that ultimately restore barrier function. These include increased epidermal sterol, fatty acid, and sphingolipid synthesis, as well as increased epidermal DNA synthesis. Because tumor necrosis factor (TNF) and other cytokines are known products of keratinocytes and have been shown to modulate lipid and DNA synthesis in other systems, their levels were examined in two acute models and one chronic model of barrier perturbation in hairless mice. Acute barrier disruption with acetone results in a 72% increase in epidermal TNF 2.5 h after treatment, as determined by Western blotting. Furthermore, epidermal TNF mRNA was elevated ninefold over controls 2.5 h after acetone treatment. This elevation in TNF mRNA was maximal at 1 h after acetone, and decreased to control levels by 8 h. After tape stripping, a second acute model of barrier disruption that avoids application of potentially toxic chemicals, TNF mRNA was elevated fivefold over controls at 2.5 h. Moreover, the mRNA levels for epidermal IL-1 alpha, IL-1 beta, and granulocyte macrophage-colony-stimulating factor (GM-CSF) also were elevated several-fold over controls, after either acetone treatment or tape stripping, but their kinetics differed. GM-CSF mRNA reached a maximal level at 1 h after acetone, while IL-1 alpha and IL-1 beta were maximal at 4 h after treatment. In contrast, mRNAs encoding IL-6 and IFN gamma were not detected either in control murine epidermis or in samples obtained at various times after tape stripping or acetone treatment. The relationship of the cytokine response to barrier function is further strengthened by results obtained in essential fatty acid deficient mice. In this chronic model of barrier perturbation mRNA levels for epidermal TNF, IL-1 alpha, IL-1 beta, and GM-CSF were each elevated several-fold over controls. These results suggest that epidermal cytokine production is increased after barrier disruption and may play a role in restoring the cutaneous permeability barrier.

Animals↗
PubMed1992

Stimulation of lipolysis in cultured fat cells by tumor necrosis factor, interleukin-1, and the interferons is blocked by inhibition of prostaglandin synthesis.

Multiple cytokines induce a number of alterations in lipid metabolism which can produce hyperlipidemia. Recent studies have demonstrated that tumor necrosis factor (TNF) increases lipolysis, resulting in an increase in circulating FFA levels, which stimulates hepatic triglyceride production, thereby contributing to the hyperlipidemia induced by TNF. In the present investigation we have determined the effects of a variety of cytokines on lipolysis in cultured 3T3-F442A adipocytes. TNF increased lipolysis approximately 3-fold with a maximal effect at 100 ng/ml and a half-maximal increase at 5-10 ng/ml. This increase was first observed 8 h after incubation with TNF. Interleukin-1 (IL-1) and interferon-alpha (IFN), -beta, and -gamma also stimulated lipolysis in cultured adipocytes. The half-maximal increase in lipolysis occurred at approximately 10 ng/ml IL-1, 5 ng/ml IFN alpha, 10 ng/ml IFN beta, and 8 ng/ml of IFN gamma. Maximal lipolysis was observed at approximately 100 ng/ml for each of these cytokines, with the exception of IFN beta, for which maximal stimulation was observed at 1000 ng/ml. Neither platelet-activating factor nor IL-6 stimulated lipolysis; therefore, it is unlikely that these compounds mediate the increase in lipolysis induced by cytokines. However, indomethacin, a well known inhibitor of prostaglandin synthesis, prevented the increase in lipolysis induced by TNF, IL-1, IFN alpha, IFN beta, or IFN gamma. Indomethacin did not affect basal lipolysis or the acute stimulation of lipolysis induced by epinephrine. These results demonstrate that multiple cytokines can increase lipolysis and that this increase is mediated by cytokine-induced stimulation of prostaglandin synthesis.

3T3 Cells↗
PubMed1992

In vivo effects of interferon-alpha and interferon-gamma on lipolysis and ketogenesis.

The host response to infection and cancer produces disturbances in fatty acid (FA) oxidation and ketogenesis. Interferons (IFNs) stimulate lipolysis in cultured adipocytes. Since FA mobilization is a major stimulus for ketogenesis, we studied the effect of IFN alpha and IFN gamma on lipolysis and ketogenesis in intact mice. Both IFNs acutely stimulated lipolysis; however, their effects on ketogenesis differed. INF gamma increased serum and hepatic ketone body levels in parallel to its effect on serum FFA, whereas IFN alpha exerted a biphasic effect on ketogenesis. At low doses, IFN alpha increased serum and hepatic ketone body levels, whereas at higher doses, this ketogenic effect was abolished. To determine the mechanism of the biphasic response, we studied the effect of IFN alpha on hepatic malonyl-coenzyme-A (malonyl-CoA), the first committed intermediate in FA synthesis and an inhibitor of FA oxidation and ketogenesis. At low doses, IFN alpha had no effect on malonyl-CoA; however, higher doses of IFN alpha significantly increased malonyl-CoA levels, which could counterbalance its mobilization of FFA. In contrast, INF gamma had little effect on malonyl-CoA, and hence, the FA oxidation was not opposed. By using phenylisopropyladenosine to block IFN-induced lipolysis, we found that in the absence of increased FA flux, INF gamma did not exert a ketogenic effect. However, when IFN alpha-induced lipolysis was blocked, the higher doses of IFN alpha that raise malonyl-CoA levels were antiketogenic. These data suggest that both IFNs exert a ketogenic effect by stimulating lipolysis, but at higher doses the ketogenic effect of IFN alpha is counteracted by its effect on hepatic FA synthesis.

3-Hydroxybutyric Acid↗