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Cytokine control of nutrition and metabolism in critical illness.

During the last two decades, major advances in technology and in our fundamental understanding of the biologic aspects of sepsis and cancer cachexia have dramatically affected the therapeutic strategies available to the surgeon to care for critically ill patients. It is clear, however, that cytokines affect whole body nutrition and metabolism and are responsible for many of the clinically observed nutritional effects of injury, infection, and cancer, including fever, hypermetabolism, anorexia, protein catabolism, cachexia, and altered fat, glucose, and trace mineral metabolism. These metabolic and nutritional effects of cytokines are influenced by the nutritional status of the host, which is generally altered during the course of the critical illness. In the future, the use of specialized diets and the use of selective cytokine blockade are likely to be important components of the overall care of the catabolic patient.

Amino Acids↗

Elevated energy expenditure in hepatocytes from tumor-bearing rats.

Mechanisms for the development of cancer cachexia are not well defined. Oxygen consumption and the capacity of the host liver to metabolize lactate were studied in isolated hepatocytes from sarcoma-bearing rats (TIH) and pair-fed controls (CH). Basal oxygen consumption (without exogenous substrate) is significantly increased by 65% in the TIH as compared to the CH. The addition of a physiologic concentration of lactate stimulated oxygen consumption over the already stimulated basal state by 13% in the TIH compared to 5% in the CH. When the hepatocytes are incubated with 1.5 mM of [U-14C]lactate, glucose production, lactate oxidation, and entry of lactate carbons into nonsecretory protein are significantly increased in the TIH. Associated with this stimulation is a significant decrease in lactate incorporation into glycogen and lipid in the TIH. This study suggests that the tumor-influenced liver utilizes lactate at an increased rate and its intermediary metabolism is directed toward energy utilization rather than energy storage. The enhanced metabolic processes in the tumor-influenced liver are associated with an increased oxygen consumption which may be a contributory factor to the negative energy balance, a characteristic of cancer cachexia.

Animals↗

Impact of exogenous growth hormone on host preservation and tumor cell-cycle distribution in a rat sarcoma model.

Growth hormone (hGH) has been reported to improve nitrogen balances and accrue lean mass tissue in stable subjects. However, the ability of hGH to positively influence host preservation in stressed catabolic states such as cancer-induced cachexia remains unproven. Thirty-seven sham or tumor implanted Fischer 344 rats were randomized to receive either 0.5 mg/kg/day hGH or saline (SAL) subcutaneously from Days 14 to 23 postimplantation. Plasma levels of hGh and somatomedin C/insulin-like growth factor I (IGF I) as well as IGF I bioactivity were determined at sacrifice. Gastrocnemius muscle protein content was used as a index of host lean tissue mass and the tumor response was evaluated via flow cytometry for analysis of cell-cycle distribution. Host cachexia was not attenuated by hGH as muscle protein content was similar in hGH and saline-treated groups. Despite elevated hGH levels (range, 77-222 ng/ml (GH) vs less than 2 ng/ml (SAL], IGF I levels and bioactivity were not elevated in GH-treated groups. In contrast, cancer-induced anorexia markedly decreased IGF I levels (4 U/ml vs 9 U/ml, NTB; P less than 0.01) and this response remained refractory to hGH administration. While final tumor weights were similar between GH- and SAL-treated groups, hGH treatment caused a twofold increase in the proportion of aneuploid cells (P less than 0.05). In conclusion, hGH failed to attenuate lean mass dissolution in the tumor bearing host and this response may be related to the failure of IGF I induction. Conversely, the altered proportion of tumor aneuploid cells suggests a direct influence on tumor cell-cycling populations.

Animals↗

A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF.

Tumor necrosis factor (TNF) is a monocyte-derived cytotoxin that has been implicated in tumor regression, septic shock, and cachexia. The mechanism by which TNF induces these different disease states is unclear. We have identified and characterized a novel, rapidly inducible cell surface cytotoxic integral transmembrane form of TNF. The existence and behavior of this novel form of TNF may explain the complex physiology of this molecule. We suggest that activated monocytes synthesize transmembrane TNF at the site of inflammation and kill their targets by either cell-to-cell contact or local release of the TNF secretory component. In contrast, septic shock and cachexia may result from either acute or chronic systemic activation of monocytes, resulting in the widespread release of TNF secretory component into the circulation of the affected individual. We further suggest that cell borne cytokines and cytotoxins may be the primary mediators of directed inflammatory responses.

Cells, Cultured↗

Effects of natural human interleukin-6 on thrombopoiesis and tumor progression in tumor-bearing mice.

The growth of inoculated colon 26 adenocarcinoma (colon 26) in mice gradually increased the platelet count owing to murine IL-6 secreted from the tumor, while Lewis lung carcinoma (LLC) decreased the platelet count in the hosts, depending on the tumor growth. Natural human IL-6 injections (hIL-6), 280 micrograms/kg/day, stimulated the platelet production in both types of carcinoma-bearing mice. When the administration of mitomycin C or cisplatin decreased the platelet number as a side reaction with a concomitant of suppressing the growth of colon 26 and LLC, respectively, hIL-6 could also increase the platelet count without the augmentation of tumor growth. However, loss of carcass weight was observed in colon 26-bearing mice treated with hIL-6, suggesting the development of cachexia is associated with hIL-6 administration. Despite the possibility of inducing cachexia in some types of tumors, our results suggest that IL-6 could be a useful means of restoring the decreased platelet number in cancer patients after intensive chemotherapy.

Adenocarcinoma↗

Hyaluronidase, from wound healing to cancer.

An explanation is proposed as to how the total amount of cells normally are in a cellular equilibrium which results from an energetic equilibrium. When a group of cells is damaged the body can restore this disturbance by the fight and flight reaction-a mechanism in which the circulating body energy is redistributed and in which all body cells are involved cooperatively. An unfavourable side-effect of this mechanism is a diminished uptake of nutrients from the gastro-intestinal tract. Therefore in chronic irritation, cachexia and a decreased resistance to all forms of insult occurs. The energetic equilibrium becomes severely disturbed. Differentiation from a morula cell to a ripe cell is proposed to be an expression of a decreased nutrient supply to the morula. The predominant mechanism for cellular survival is a change from a demand on nutrient supply to a demand on the specialisation of the cell function. The role of the nutrient supply - regulated by hyaluronidase synthesis - then becomes subsidiary to this specific function. It is proposed that cancer originates because of chronic irritation. As a result of the secondary chronic redistribution of body energy in the direction of the irritated area, these cells are chronically hypernourished and then dedifferentiate again in the direction of the morula cell. As a consequence of the reactive mechanism, the cachexia which is so typical of cancer, then occurs. From theoretical considerations, it is predictable that cancer may be effectively treated by two basic manipulations of the energetic equilibrium: firstly by chronically decreasing the nutrient supply to the cancer cells, thereby stimulating differentiation again, and secondly by restoring the energetic equilibrium. In practice this involves supplementation of hyaluronidase together with hyperalimentation.

Cell Differentiation↗

Effect of structured lipid-enriched total parenteral nutrition in rats bearing yoshida sarcoma.

The efficacy of structured lipid, a triacylglycerol of medium and long chain fatty acids, as an element of nutritional support therapies in cancer cachexia was investigated. Using the Yoshida sarcoma to induce cachexia, male Sprague Dawley rats (90 g) were injected subcutaneously with tumor cells (n = 17) or sterile saline (n = 16). Seven days later, rats were randomized to two intravenous diets for 3 days at 220 kcal/kg body weight/d, including 2 g nitrogen/kg body weight/d and 39% of total calories as either structured lipid or long chain triglyceride. Nitrogen balance, tumor growth rate, energy metabolism, and plasma albumin and free fatty acid levels were measured, and whole-body protein kinetics and liver, muscle, and tumor fractional protein synthetic rates were evaluated by adding (14)C-leucine to the diet during the last 4 hours of feeding. Nitrogen balance improved (P < .05) in both tumor and control rats receiving structured lipid-enriched total parenteral nutrition, and was also greater in tumor rats compared with controls. There were no differences in tumor growth or protein kinetics between diet groups. Albumin was lower (P < .05) in tumor rats, but significantly higher in both tumor and control rats given structured lipid-enriched total parenteral nutrition. Free fatty acid was significantly higher in tumor rats versus controls. Whole-body protein kinetics were similar among the four groups. Liver weight, liver weight to body weight ratio, and liver protein synthetic rate were higher in tumor rats. Also, liver weight to body weight ratio was lower in tumor and control animals given structured lipid-enriched total parenteral nutrition. Muscle protein synthetic rate was significantly lower in tumor rats, but higher in tumor and control rats given long chain triglyceride-enriched total parenteral nutrition. The nutritional benefits of structured lipid-enriched total parenteral nutrition favor support of host tissue without promoting tumor growth.

Journal Article↗

Metabotropic glutamate receptors mediate lipopolysaccharide-induced fever and sickness behavior.

Several mechanisms have been proposed for neuroimmune communication supporting the sickness syndrome (fever, anorexia, inactivity, and cachexia) following infection. We examined the role of glutamate as a neurochemical intermediary of sickness behavior induced by intraperitoneal lipopolysaccharide (LPS). Mice implanted with biotelemetry devices capable of detecting body temperature (Tb) were administered LPS (50 or 500 microg/kg i.p., serotype 0111:B4) with or without i.p. pretreatment with vehicle or broad-spectrum antagonists selective for N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic (AMPA)/kainite, or metabotropic glutamate (mGlu) receptors. While NMDA and AMPA/kainate receptor antagonism failed to attenuate LPS-induced sickness behavior, antagonism of metabotropic receptors with l(+)-AP3 reduced the febrile (0-11h: control: 37.32+/-0.16 degrees C, l(+)-AP3: 36.66+/-0.27), anorexic (control: -87+/-5%, l(+)-AP3: 48+/-12% scotophase food intake), and cachexic (control: -8.9+/-0.4%, l(+)-AP3: -6.1+/-1.3% body weight) effects of 500 microg/kg LPS, and produced a biphasic Tb effect in response to 50 microg/kg LPS (1h: -0.90+/-0.26; 6h: 1.78+/-0.35 degrees C relative to baseline). At this dose the Tb of l(+)-AP3-treated mice was 1.18 degrees C lower than controls 2h post-injection, and 0.68 degrees C greater that controls 8h post-injection. These results suggest a role for mGlu receptors in mediating fever, anorexia, and cachexia possibly via activation of extra-vagal pathways, since the attenuating effect of l(+)-AP3 increased with increasing dosages of LPS. Given the critical role ascribed to mGlu receptors in neurotransmitter release and astrocytic processes, it is possible that these observations reflect an l(+)-AP3-induced attenuation of these systems.

Animals↗

Targets for TNF-alpha-induced lipolysis in human adipocytes.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha)-induced lipolysis may be important for insulin resistance in both obesity and cachexia. In rodent cells TNF-alpha enhances lipolysis through down-regulation of the expression of the membrane proteins Galpha(i) and the lipid droplet-associated protein perilipin (PLIN). In human (but not murine) adipocytes TNF-alpha stimulates lipolysis through the mitogen activated protein kinases (MAPKs) p44/42 and JNK although it is unclear whether this is mediated via PLIN and/or Galpha(i). METHODS: Galpha(i) and PLIN as down-stream effectors of MAPKs were assessed in human adipocytes stimulated with TNF-alpha in the absence or presence of specific MAPK inhibitors. RESULTS: A 48-h incubation with TNF-alpha resulted in a pronounced increase in lipolysis, which was paralleled by a decrease in the mRNA and protein expression of PLIN. Both these effects were inhibited in a concentration-dependent manner in the presence of MAPK inhibitors specific for p44/42 (PD98059) and JNK (SP600125). However, TNF-alpha did not affect Galpha(i) mRNA or protein expression. Furthermore, experiments with pertussis toxin demonstrated that inhibition of Galpha(i) signaling did not affect TNF-alpha-mediated lipolysis. CONCLUSIONS: Our results suggest that TNF-alpha-mediated lipolysis is dependent on down-regulation of PLIN expression via p44/42 and JNK. This could be an important mechanism for the development of insulin resistance in both obesity and cachexia. However, in contrast to findings in rodent cells, Galpha(i) does not appear to be essential for TNF-alpha-induced lipolysis in human adipocytes.

Adipocytes↗

Downregulation of ubiquitin-dependent protein degradation in murine myotubes during hyperthermia by eicosapentaenoic acid.

Muscle atrophy in a number of acute wasting conditions is associated with an increased activity and expression of the ubiquitin-proteasome proteolytic pathway. Although different initiators are involved, it is possible that the intracellular signalling events leading to upregulation of this pathway are the same in all catabolic conditions. This study investigates hyperthermia in murine myotubes as a model for increased protein degradation through the ubiquitin-proteasome pathway. The effect of eicosapentaenoic acid (EPA) on this process should identify common elements, since EPA has been shown to attenuate induction of the ubiquitin-proteasome pathway in cancer cachexia. Increasing the temperature of myotubes caused a progressive increase in protein degradation. This was associated with an increased proteasome 'chymotrypsin-like' enzyme activity, as well as increased expression of both mRNA and protein for 20S proteasome subunits and the ubiquitin-conjugating enzyme (E2(14k)). This upregulation was not seen in cultures treated with EPA (50 microM), suggesting that it acts to prevent transcriptional activation of the ubiquitin-proteasome pathway in hyperthermia. These results suggest that protein catabolism in hyperthermia and cancer cachexia is mediated through a common pathway.

Animals↗

IFN-gamma prevents TNF-alpha-induced apoptosis in C2C12 myotubes through down-regulation of TNF-R2 and increased NF-kappaB activity.

Wasting of skeletal muscle (cachexia) is associated with a variety of chronic or inflammatory disorders and has long been recognized as a poor prognostic sign. It is currently accepted that the cytokine tumor necrosis factor alpha (TNF-alpha; cachectin) plays a key role in the development of this condition. TNF-alpha-induced apoptotic cell death represents a potential mechanism by which muscle wasting can occur. Evidence has accumulated that the cytokine interferon gamma (IFN-gamma) may act as a modulator of TNF-alpha signalling. Thus, the present study was designed to elucidate if TNF-alpha can directly induce apoptosis in differentiated myotubes, to assess the potential anti-apoptotic properties of IFN-gamma and to get insight into the signalling pathways implicated in the modulatory effects of IFN-gamma. Myoblasts of the murine cell line C2C12 were allowed to differentiate in a low serum containing media and myogenesis assessed by muscle specific protein expression. Non-proliferating, polynucleated, fully differentiated myotubes were obtained after seven days in differentiation media. Exposure of C2C12 myotubes to TNF-alpha for 48 h induced apoptosis characterized by enhanced caspase-3 activity, which resulted in poly(ADP-ribose) polymerase (PARP) cleavage and increased histone-associated-DNA fragmentation. These effects were fully reverted in the presence of IFN-gamma. This cytokine induced down-regulation of the subtype 2 of TNF-alpha receptors (TNF-R2), enhanced TNF-alpha-induced NF-kappaB translocation to the nucleus and binding to DNA and increased the immunoreactivity of the protein c-IAP1, a member of the inhibitor of apoptosis (IAP) gene family whose synthesis is stimulated by NF-kappaB at the transcriptional level. Together, these results demonstrate that TNF-alpha directly induces apoptosis in differentiated myotubes and suggest that the cytokine IFN-gamma, might represent a new immunoadjuvant therapeutic tool for managing cachexia.

Active Transport, Cell Nucleus↗

Interferon-gamma polymorphisms correlate with duration of survival in pancreatic cancer.

Despite progress in diagnosis and staging, pancreatic cancer still has a poor prognosis and it remains difficult to predict duration of survival in advanced pancreatic cancer. Nutritional decline, or cachexia, is a contributory factor to decreased survival in advanced pancreatic carcinoma, and it has been demonstrated that proinflammatory cytokines give rise to cachexia. Interferon (IFN)-gamma is a proinflammatory cytokine whose administration increases survival outcomes in a variety of cancers. The human IFN-gamma gene has a variable length CA-repeat sequence, the length that has been shown to influence IFN-gamma production. The current study was performed to ascertain whether polymorphisms of the IFN-gamma gene would influence survival of individuals with advanced pancreatic cancer. The study demonstrated that the presence of allele 2 (12 CA repeats) was consistently associated with increased duration of survival after confirmation of nonresectable pancreatic carcinoma. We therefore propose that the presence of allele 2 may be a useful marker for patient outcome.

Adult↗

Beneficial effects of high doses of growth hormone in the introduction and optimization of medical treatment in decompensated congestive heart failure.

BACKGROUND: Optimizing oral therapy in patients with unstable decompensated and/or dobutamine-dependent congestive heart failure (CHF) is a challenge. METHODS AND RESULTS: We investigated the effects of high doses of recombinant human growth hormone (GH) in 6 patients with cardiac cachexia and unstable decompensated CHF (5 dobutamine-dependent), including its influence in the optimization of oral CHF treatment. Patients received 8 IU of subcutaneous GH per day for median 26 (range 61) days. GH improved the systolic systemic blood pressure (SSBP, in mm Hg) from median 85 (range 34) to 100 (20) (p<.01), and the left ventricular (LV) ejection fraction (in %) from median 23 (range 22) (pretreatment) to 28 (18) (posttreatment) and 38 (28) (later) (p<.007). The NYHA functional class improved from IV to I in 2 patients, from IV to II in 3, and from IV to II-III in one. All patients were discharged from the hospital. It was possible in the hospital to initiate and after discharge to optimize long-term CHF treatment from 37.5 to 50 mg of carvedilol in 5 patients and with higher doses of captopril (from 50 to 150 mg) in all patients. Three patients are alive after 67, 75, and 11 months of follow-up. The remaining 3 patients died from a pulmonary abscess at 9 months, septicemia at 21 months, and progressive heart failure due to unplanned withdrawal of carvedilol at 36 months. CONCLUSION: The use of GH in patients with decompensated CHF and cardiac cachexia provided clinical stability without the need for inotropic drugs permitting introduction of nonpreviously tolerated drugs. This could represent a new option for optimizing long-term CHF therapy and discharging hospitalized patients who are dobutamine-dependent.

Adult↗

Carcass condemnation causes of growth retarded pigs at slaughter.

Condemnation causes of growth retarded pigs were studied in a Spanish abattoir. A total of 513 carcasses out of 6017 (8.5%) were rejected during inspection. The main reasons for condemnation were abscesses, cachexia, catarrhal bronchopneumonia, vertebral osteomyelitis, arthritis, pleuritis, peritonitis and pleuropneumonia. Positive relationships were found between tail lesions and arthritis (OR=5.23) or vertebral osteomyelitis (OR=24.81), while no relationships were found between tail lesions and abscesses. Lower risks were observed among carcasses condemned for cachexia, and were as follows: abscesses (OR=0.18), arthritis (OR=0.32), vertebral osteomyelitis (OR=0.06). Arcanobacterium pyogenes, either alone or in combination with other agents, was the main bacterial species isolated from abscesses, osteomyelitis and arthritis (73.5% of lesions). Direct economical losses associated with condemnation were calculated to be 30,000 Euro.

Animals↗

Priming but not boosting with plasmid DNA encoding mycolyl-transferase Ag85A from Mycobacterium tuberculosis increases the survival time of Mycobacterium bovis BCG vaccinated mice against low dose intravenous challenge with M. tuberculosis H37Rv.

DNA vaccination is a potent means for inducing strong CD4+ (Th1) and particularly CD8+ mediated immune responses and protective immunity against tuberculosis infection in mice. Here we have analyzed the potential of a DNA vaccine encoding the immunodominant mycolyl-transferase Ag85A for increasing the efficacy of the current tuberculosis vaccine Mycobacterium bovis Bacille Calmette-Guérin (BCG) in three long-term survival experiments. BALB/c mice were vaccinated with BCG either following DNA priming or prior to DNA boosting. Ag85A specific CD4+ and CD8+ mediated IFN-gamma responses were increased in mice primed with DNA prior to BCG, and in BCG vaccinated mice subsequently boosted with DNA. In the latter immunization protocol, antigenic stimulation also induced significant levels of IL-17. Mice were monitored for cachexia and survival following a low dose intravenous challenge with M. tuberculosis H37Rv. Priming with Ag85A but not control DNA increased significantly the protective efficacy of the BCG vaccine as indicated by reduced cachexia and prolonged survival time: 32 weeks versus 23 weeks in one experiment and 33 weeks versus 26 weeks in another experiment (MST in control, TB infected mice: 17 weeks in both experiments). On the other hand, boosting of BCG by subsequent Ag85A DNA in saline or vaxfectin--or recombinant 85A protein or MVA-85A for that matter--did not augment the efficacy of BCG (MST 19-21 weeks in all vaccinated groups versus 11 weeks in control, TB infected mice). Our results demonstrate that Ag85A DNA priming can increase efficacy of BCG and that boosting protocols of BCG may possibly be hampered by the induction of Th(IL-17) cells.

Acyltransferases↗

Epidemiology of weight loss in humans with special reference to wasting in the elderly.

Unintentional weight loss in older adults is a problem that occurs frequently in clinical practice. Although slight declines in weight have been observed with aging alone, clinically important weight loss (decrements of 5% or more of usual body weight) is almost always the result of disease, disuse, and/or psychosocial factors. Adverse health outcomes associated with weight loss include decreased functional abilities and increased morbidity and mortality. Case series and prospective studies have helped to identify the most common causes of weight loss in older adults, and are reviewed herein. Knowledge of these frequent underlying etiologies can help guide an appropriate and cost-effective evaluation of patients presenting with weight loss. In many cases the causes are remediable and weight loss may slow or reverse with appropriate intervention. In some cases no clear etiology can be identified but the patient may still respond to nutritional support therapies that include hypercaloric feeding and appetite stimulants. Increasing caloric intake alone, however, is usually not sufficient to mitigate against losses in body mass (especially muscle mass) that are the result of chronic inflammatory or other severe disease states (cachexia). Potential strategies to help reduce losses in lean body mass and the functional decline that often accompanies weight loss include anabolic agents, exercise/physical activity, and cytokine inhibition. This article reviews the epidemiology of weight loss in older adults with special attention to the problem of cachexia. Diagnostic and treatment algorithms are provided to help guide clinical evaluation of, and therapeutic interventions for, older adults presenting with weight loss.

Aged↗

[POEMS syndrome].

POEMS syndrome is an acronym defined by Bardwick (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal component and Skin changes). Other various clinical and biological features are reported: edema, cachexia, microangiopathic glomerulopathy, most rarely pulmonary hypertension, cutaneous necrosis. Thrombocytosis or polycythemia may be a prominent feature. POEMS syndrome is sometimes associated with lymphoproliferative disorder. Castelman-like disease is frequently observed as pathologic findings on lymph nodes. Distinction between POEMS syndrome and osteosclerotic myeloma is delicate. The rate of the monoclonal protein is modest-always less than 30 g/L-and is almost of the lambda light chain class. In contrast to multiple myeloma this syndrome is rarely associated with hypercalcemia, skeletal fracture, renal involvement and increasing of M component during evolution. Bone marrow plasmocytosis is usually less than 15% and the kinetic phenotype and genetic characteristics of the plasma cell remain those found in monoclonal gammopathy of undetermined significance. The pathophysiology of this syndrome remains largely unknown but overproduction of pro-inflammatory cytokines are reported, especially TNF alpha, IL-6 and IL-1 beta. Some clinical manifestations seem to be cytokine related. Polyneuropathy and cachexia are the main cause of death. A part corticosteroid and cure of solitary bone lesion, treatment is disappointing and survival is 60% at five years.

Humans↗

Lipid metabolism in tumour-bearing mice: studies with knockout mice for tumour necrosis factor receptor 1 protein.

The implantation of the Lewis lung carcinoma (a fast-growing mouse tumour that induces cachexia) to both wild-type and gene-deficient mice for the tumour necrosis factor (TNF) receptor type I protein (Tnfr1(0)/Tnfr1(0)), resulted in a considerable loss of carcass (26%) and white (77%) and brown adipose (37%) tissue weights in the wild-type mice, while it induced much less marked effects in the gene-deficient mice. Tumour burden also inflicted an important decrease in total lipoprotein lipase (LPL) activity in epididymal white adipose tissue (50%) in the wild-type mice while no changes were observed in the knockout mice. In addition, all tumour-bearing animals were clearly hypertriglyceridaemic (80% increase in circulating triacylglycerols in wild-type and 36% in knockout mice). It is concluded that although TNF seems to be to some extent responsible for adipose waste, LPL changes and hyperlipaemia (via receptor I), the role of other cytokines (alone or in combination with TNF) in promoting changes in lipid metabolism during cancer cachexia cannot be discarded.

Adipose Tissue↗