Reversal of diet-induced obesity increases insulin transport into cerebrospinal fluid and restores sensitivity to the anorexic action of central insulin in male rats.

Diet-induced obesity (DIO) reduces the ability of centrally administered insulin to reduce feeding behavior and also reduces the transport of insulin from the periphery to the central nervous system (CNS). The current study was designed to determine whether reversal of high-fat DIO restores the anorexic efficacy of central insulin and whether this is accompanied by restoration of the compromised insulin transport. Adult male Long-Evans rats were initially maintained on either a low-fat chow diet (LFD) or a high-fat diet (HFD). After 22 weeks, half of the animals on the HFD were changed to the LFD, whereas the other half continued on the HFD for an additional 8 weeks, such that there were 3 groups: 1) a LFD control group (Con; n = 18), 2) a HFD-fed, DIO group (n = 17), and 3) a HFD to LFD, DIO-reversal group (DIO-rev; n = 18). The DIO reversal resulted in a significant reduction of body weight and epididymal fat weight relative to the DIO group. Acute central insulin administration (8 mU) reduced food intake and caused weight loss in Con and DIO-rev but not DIO rats. Fasting cerebrospinal fluid insulin was higher in DIO than Con animals. However, after a peripheral bolus injection of insulin, cerebrospinal fluid insulin increased in Con and DIO-rev rats but not in the DIO group. These data provide support for previous reports that DIO inhibits both the central effects of insulin and insulin's transport to the CNS. Importantly, DIO-rev restored sensitivity to the effects of central insulin on food intake and insulin transport into the CNS.

Free tryptophan/large neutral amino acids ratios in blood plasma do not predict cerebral spinal fluid tryptophan concentrations in interleukin-1-induced anorexia.

Peripheral administration of interleukin-1 (IL-1) reduces food intake and affects brain serotonergic activity, suggesting a causal relationship. Furthermore, IL-1 increases the brain concentrations of the serotonin precursor, tryptophan (TRP), by unclear mechanism(s). We aimed at confirming the link between IL-1 administration, raised brain TRP concentrations and the development of anorexia, and at investigating the mechanisms of TRP entry into the brain. Thirty adult, overnight fasted Sprague-Dawley rats were randomly assigned to i.p. injections of 1 mug/kg BW of IL-1 alpha (n=10) or vehicle (n=10), or to pair-feeding with IL-1 animals (n=10). After 2 h, food intake, blood plasma concentrations of total TRP, free TRP, large neutral amino acids (LNAA; competing with TRP for brain entry) were measured. Cerebral spinal fluid (CSF) TRP concentrations were also measured. TRP brain availability was assessed by calculating the plasma ratio free TRP/LNAA. Following IL-1 injection, food intake significantly declined in IL-1 rats, which was paralleled by decreased plasma free TRP and increased plasma LNAA. Despite a decrease in the free TRP/LNAA ratios in plasma, IL-1 significantly increased concentrations of TRP in CSF. These data show that the acute peripheral administration of IL-1 induces anorexia and raises CSF TRP levels. Considering the possible role of the raised CSF TRP in influencing brain serotonin activity, it is postulated that increased serotonergic neurotransmission could be involved in IL-1 induced anorexia.

Tumor necrosis factor-alpha and total parenteral nutrition-induced anorexia.

BACKGROUND: We hypothesize that total parenteral nutrition (TPN) induces anorexia by an increase in anorexigenic cytokines (factors with central action via the hypothalamus) and tested this hypothesis by measuring changes in food intake and cytokines in response to TPN. METHODS: Fischer rats with an internal jugular catheter and ad libitum food received saline solution for 10 days. On day 11, rats were randomized to TPN (G:F:AA = 50:30:20) for 4 days (days 11 through 14); control rats received on saline solution for 5 days. On day 14, one half of the TPN group was switched back to saline solution for 1 day. Daily food intake was measured. On day 14 in one half of all rats and on day 15 in the remaining, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 alpha were measured in plasma and cerebrospinal fluid (CSF). Spontaneous in vitro TNF-alpha and IL-1 alpha were also measured in peripheral blood mononuclear cells. RESULTS: With TPN, an 80% decrease (p < 0.01) in food intake occurred; plasma TNF-alpha increased (78 +/- 9 pg/ml vs undetectable; p < 0.001), and IL-1 alpha was undetectable. Spontaneous in vitro TNF-alpha and IL-1 alpha production were unchanged. Stoppage of TPN led to return toward normal of food intake and plasma TNF-alpha. TNF-alpha and IL-1 alpha in CSF were undetectable in both groups during and after TPN. CONCLUSION: Increase in plasma TNF-alpha with no increase in CSF-TNF-alpha during TPN, when food intake decreased, suggests an association between TPN and TNF-alpha but not necessarily cause and effect.

Correlation between food intake and cerebrospinal fluid interleukin 1 alpha in anorectic tumor-bearing rats.

Anorexia is observed in 50% of cancer patients; however, the pathogenesis for cancer anorexia is unclear. We postulate that centrally acting cytokines play a role in the pathogenesis of cancer anorexia. To test our hypothesis we determined whether central interleukin 1 alpha (IL-1 alpha) was related to anorexia in tumor-bearing (TB) rats. Fischer 344 rats were inoculated with either 1 ml of 1 x 10(6) trypan blue viable methylcholanthrene-induced sarcoma cells (TB rats) or normal saline (non-tumor-bearing [NTB] rats). Rats were placed into individual metabolic cages equipped with an Automated Computerized Rat Eater Meter that continuously measured food intake. When TB rats became anorectic, TB and NTB rats were anesthetized and cerebrospinal fluid (CSF) was collected. IL-1 alpha was measured. Food intake in TB was 7.1 +/- 1.1 g, whereas that in NTB was 12 +/- 1.1 g (p < 0.05). Eight of the 13 TB rats had detectable concentrations of CSF IL-1 alpha; the mean CSF IL-1 alpha concentration for TB rats was 73.2 +/- 17.3 pg/ml. In contrast, none of the NTB rats (n = 11) had detectable concentrations of CSF IL-1 alpha. CSF IL-1 alpha concentrations correlated inversely with food intake. Data suggest a link between CSF IL-1 alpha and food intake in anorectic TB rats.

Correlation between food intake and CSF IL-1 alpha in anorectic tumor bearing rats.

Postulating that central IL-1 is involved in the pathogenesis of cancer anorexia we measured IL-1 alpha in cerebrospinal fluid (CSF) from anorectic tumor bearing (TB) rats and non-tumor bearing controls, and correlated their CSF IL-1 alpha with food intake and tumor weight. Food intake in controls was significantly higher than that in anorectic TB rats. Eight of the 13 anorectic TB rats had detectable CSF IL-1 alpha; no CSF IL-1 alpha was detected in controls. In anorectic TB rats a negative correlation existed between CSF IL-1 alpha and food intake and a positive correlation between CSF IL-1 alpha and tumor weight. Data suggest a link between CSF IL-1 alpha and the pathogenesis of cancer anorexia.

Altered cerebrospinal fluid amino acid pattern in the anorexia of aging: relationship with biogenic amine metabolism.

To study the possible role of several amino acids on feeding in the anorexia of aging, we have measured plasma and cerebrospinal fluid (CSF) concentrations of 22 amino acids in 14 elderly persons with idiopathic anorexia and 10 healthy subjects with normal weight in a similar age range. Plasma and CSF amino acid concentrations and CSF homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) levels were all measured by HPLC methods. Elderly anorectic subjects had significantly lower levels of glutamic acid but increased concentrations of glutamine in both plasma and CSF compared to controls. Likewise, a significant increase of histidine, threonine, alanine, arginine, valine, methionine, isoleucine, leucine, phenylalanine, tryptophan, ornithine and lysine was found in CSF, but not in plasma, from patients with anorexia. Besides, the CSF histidine/LNAA (large neutral amino acids) and tryptophan/LNAA ratios were elevated in anorectic patients as compared with controls of similar age. In addition, we found higher CSF concentrations of HVA and 5-HIAA, as well as a positive correlation between CSF LNAA and either HVA (r = 0.74, p = 0.002) or 5-HIAA (r = 0.61, p = 0.020) concentrations in elderly anorectics. CSF tryptophan correlated positively with 5-HIAA levels (r = 0.59, p = 0.026) and CSF tyrosine with HVA levels (r = 0.77, p = 0.002). Our results suggest that changes in the CSF concentration of amino acids could contribute to an increased biogenic amine metabolism in the central nervous system of elderly anorectic subjects, possibly increasing the synaptic liberation of biogenic amines involved in the appetite regulation.