Adipose tissue administration

The first hormonal signal found to comply with the characteristics of both a satiety and an adiposity signal was insulin [1]. Insulin levels reflect substrate (carbohydrate) intake and stores, as they rise with blood glucose levels and fall with starvation. In addition, they may reflect the size of adipose stores, because a fatter person secretes more insulin than a lean individual in response to a given increase of blood glucose. This increased insulin secretion in obesity can be explained by the reduced insulin sensitivity of liver, muscle, and adipose tissue. Insulin is known to enter the brain, and direct administration of insulin to the brain reduces food intake. The adipostatic role of insulin is supported by the observation that mutant mice lacking the neuronal insulin receptor (NDRKO mice) develop obesity. 

Leptin is a cytokine produced and secreted by adipose tissue in proportion to the body fat content [3]. Mice and humans lacking leptin or its receptor develop a severe hyperphagia and a dramatic degree of obesity which is considerably more pronounced than that of the NDRKO mouse. Thus, leptin is the key adiposity signal in rodents and humans. Leptin secretion appears to reflect the metabolic status of the adipocyte rather than the sheer size of triglyceride deposits, and leptin levels may transiently be dissociated from total body fat. Nonetheless, over the course of a day with unrestricted food supply, plasma leptin levels reliably reflect the amount of total body fat. Local administration of leptin into the brain results in reduced food intake. The vast majority of patients with obesity have elevated serum levels of leptin. Thus, it is believed that the polygenic obesity is due to leptin resistance rather than to inadequate leptin secretion, or to a reduced blood/brain transport of the cytokine. 

Free fatty acids and glycerol rise in the plasma following caffeine and methylxanthine administration, showing a major effect on adipose tissues. 

No studies were located regarding distribution in humans after oral exposure to hexachlorobutadiene. In animals, 5-14% of ( C) radiolabeled hexachlorobutadiene was retained in the tissues and carcass 72 hours after compound administration (Dekant et al. 1988a Reichert et al. 1985). The kidney (outer medulla), liver, and adipose tissue appeared to concentrate hexachlorobutadiene label when single doses of up to 200 mg/kg ( C) hexachlorobutadiene in corn oil were administered by gavage (Dekant et al. 1988a Nash et al. 1984 Reichert et al. 1985). In one report, the brain was also determined to contain a relatively high concentration of label 72 hours after exposure (Reichert et al. 1985). Label in the kidney 72 hours after exposure was more extensively covalently bound to proteins than that in the liver (Reichert et al. 1985). 

In a study using doses of 0.1 and 300 mg/kg intraperitoneally-administered hexachlorobutadiene, the label was found in the liver, kidney, and adipose tissue. Very little of the label was found in the brain, lung, heart, and muscle tissue at 48 hours after dosing (Davis et al. 1980). The reported levels in the brain in this study differ from those reported at 72 hours following oral administration (Reichert et al. 1985). This may indicate that there is a gradual deposition of labeled hexachlorobutadiene and/or its metabolites in the brain lipids over time. 

Poorly perfused tissues (adipose tissue, connective tissue, and bone) require hours to come into equilibrium with plasma drug concentrations (Fig. 25.1). Since the accumulation of anesthetic in body fat is relatively small soon after its IV administration, it is common clinical practice to calculate drug dosage on the basis of lean body mass rather than on total body weight. Thus, an obese patient may receive the same dose of IV anesthetic as a patient of normal body weight. 

Mitotane is incompletely absorbed from the gastrointestinal tract after oral administration. However, once absorbed, it tends to accumulate in adipose tissue. Mitotane is slowly excreted and will appear in the urine for several years. The major toxicities associated with its use are anorexia, nausea, diarrhea, lethargy, somnolence, dizziness, and dermatitis. 

Chloro-ort/70-toluidine or its hydrochloride was tested for carcinogenicity by oral administration in two experiments in mice and in two experiments in rats. The compounds increased the incidence of haemangiosarcomas in the spleen and adipose tissue in both male and female mice, but no increase in the incidence of tumours was observed in rats. 

Chloro-ort/2o-toluidine was tested for carcinogenicity by oral administration in one experiment in mice and in one experiment in rats. In mice, it increased the incidence of haemangiosarcomas (mostly of adipose tissue) and of hepatocellular carcinomas in both males and females. In rats, no carcinogenic effect was observed. 

Administration of a single gavage dose of C-2,2, 4,4 -5-pentaBDE to rats resulted in preferential deposition of label in the carcass (38%), adipose tissue (38.%), and blood (1.4%) 72 hours after dosing (Hakk et al. 1999). No other tissue had more than 1% of the radioactivity at 72 hours. Fractionation of the carcass showed that the majority of the label was in the skin. When deposition was expressed as concentration, the lipid-rich tissues such as adipose tissue, skin, and adrenals contained the highest concentration of radioactivity. 

Sanders et al. (1988) administered u-butyl [2,3- 4C]acrylate to rats orally at doses of 4, 40 and 400 mg/kg bw and intravenously at 40 mg/kg bw. After oral administration, n-but l aciy late was very rapidly absorbed and hydrolysed to acrylic acid, with more than 75% of the dose eliminated as its metabolic end product 4CO2 Some 10% of the dose was excreted in the urine, two metabolites being identified as the mercapturic acid N-acct>l-.S -(2-carboxycthyl)cystcinc and its sulfoxide. The elimination pattern of was essentially identical at all doses, but additional unidentified C peaks were present in the urine at 400 mg/kg. Comparison of the data from the two routes of administration suggested that u-butyl acrylate exhibited a first-pass efiect after oral dosing, but this was not investigated further. -Butyl acrylate was rapidly and extensively excreted, the tissues being cleared of -C by 24-72 h. After an initial rapid reduction, a small amount of O was retained in whole blood and adipose tissue, possibly by incorporation of C via the one-carbon pool. 

Effects on lipid metabolism Adipose tissue responds within minutes to administration of insulin, which causes a significant reduc tion in the release of fatty acids ... 

---