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B B Lowell

Publications and source records attributed to B B Lowell.

65 records · Page 4Linked to original sources
PubMed1992

Human adipsin is identical to complement factor D and is expressed at high levels in adipose tissue.

A cDNA for human adipsin was isolated and shown to encode a protein sharing 98% amino acid sequence similarity with the protein sequence previously determined for purified natural human complement factor D. Like mouse adipsin, recombinant human adipsin displays the enzymatic activity of human complement factor D, cleaving complement factor B only when B is complexed with activated complement component C3. We conclude that human adipsin is equivalent to complement factor D and that adipsin is the homologue of factor D in rodents. Adipose tissue is a major site of synthesis of human adipsin/complement factor D mRNA, but unlike the case in rodents, human adipsin mRNA is also expressed in monocytes/macrophages. The data presented here, demonstrating the equivalence of human adipsin to complement factor D and its high level of expression in fat, suggest a previously unsuspected role for adipose tissue in immune system biology.

Adipose Tissue↗
PubMed1991

Alterations in sympathetic nervous system activity do not regulate adipsin gene expression in mice.

Adipsin gene expression is severely diminished in certain forms of genetic and acquired rodent obesity. Common to many of these models of obesity is decreased sympathetic nervous system (SNS) activity. In addition, treatment of MSG obese mice with the sympathomimetic drug mixture ephedrine and caffeine restores adipsin deficiency to normal, while reversing obesity. Based on these observations, we hypothesized that adipsin gene expression might be regulated through changes in SNS activity with deficient adipsin gene expression in obesity being the result of impaired SNS activity. In the present study we used three models to assess the role of the SNS in regulating adipsin gene expression. First we exposed mice to the cold (4 degrees C), a potent activator of SNS activity. Second, we chemically sympathectomized mice with 60H-dopamine. Third, we treated mice with BRL 26830A, an atypical beta adrenoreceptor agonist. In contrast to our initial hypothesis, these studies demonstrate that alterations of SNS activity do not affect adipsin gene expression in normal mice. Neither increased SNS activity secondary to cold exposure nor decreased SNS activity resulting from sympathectomy alter serum adipsin concentration or adipsin mRNA levels in white (WAT) and brown adipose tissue (BAT). Surprisingly, treatment of lean mice with BRL 26830A decreases both adipsin serum concentrations and adipsin mRNA levels, suggesting a potential role for atypical beta adrenoreceptors in pathways that suppress adipsin expression in vivo. The significance of this observation with respect to adipocyte physiology is unclear at present. Future studies will be aimed at defining the molecular mechanisms by which BRL 26830A suppresses adipsin gene expression and the physiological significance of this effect.

Adipose Tissue↗
PubMed1990

Reduced adipsin expression in murine obesity: effect of age and treatment with the sympathomimetic-thermogenic drug mixture ephedrine and caffeine.

Adipsin gene expression is greatly diminished in certain forms of genetic and acquired obesity. In the present study we evaluate the time course for the development of adipsin deficiency in obesity and its regulation by the sympathomimetic-thermogenic drug mixture ephedrine and caffeine. Previously, it was unknown whether adipsin deficiency occurred before or after the development of massive obesity. In the first series of experiments in which mice were treated with monosodium glutamate (MSG) for the first week of life, we demonstrate that adipsin deficiency occurs early in the development of MSG-induced obesity as evidenced by decreased circulating adipsin concentrations by 1 week of age and deficient adipsin mRNA levels in white adipose tissue (WAT) by 2 weeks. In db/db mice, diminished circulating adipsin was noted at 2 weeks of age. In both models, decreased adipsin gene expression precedes the development of marked obesity. Little is known about the factors which regulate adipsin gene expression in obesity. Common to the ob/ob, db/db and MSG models is diminished thermogenesis and sympathetic nervous system activity. In a second series of experiments we sought to determine whether adipsin deficiency in obesity could be corrected by treatment with ephedrine and caffeine (E+C), a sympathomimetic-thermogenic mixture previously shown to increase thermogenesis and reverse obesity in some models. In the present study, E+C treatment of MSG obese mice reversed obesity and markedly increased serum adipsin and adipsin mRNA levels in WAT and brown adipose tissue (BAT). In ob/ob mice, however, E+C treatment produced a negligible increase in adipsin mRNA levels in WAT and BAT as well as serum adipsin concentrations and this correlated with only a very small decrease in obesity. Thus, the ability of E+C to increase adipsin gene expression correlated with its ability to reverse obesity in these two models. Finally, the effect of E+C on adipsin gene expression may not be exerted directly on the fat cell since treatment of cultured 3T3-F442A adipocytes and isolated rat adipocytes in primary culture produced no effect on adipsin mRNA or secreted protein despite a lipolytic effect as measured by increased glycerol release. In summary, decreased adipsin gene expression occurs early in the development of MSG and db/db obesity and is markedly increased in the MSG model by the sympathomimetic-thermogenic drug mixture, E+C, which also reverses obesity. Elucidation of the factors responsible for these effects may enhance our understanding of fat cell gene regulation and obesity.

Adipose Tissue, Brown↗
PubMed1990

Differentiation dependent biphasic regulation of adipsin gene expression by insulin and insulin-like growth factor-1 in 3T3-F442A adipocytes.

Adipsin is a serine protease with complement factor D activity that is synthesized by adipocytes and secreted into the blood stream. Expression of adipsin is deficient in models of genetic (ob/ob, db/db) and acquired (monosodium glutamate-lesioned) obesity, but the cellular mechanisms responsible for this deficiency are unknown. Because hyperinsulinemia is frequently associated with obesity, we evaluated the effects of this hormone and insulin-like growth factor 1 (IGF-1) on adipsin secretion and adipsin messenger RNA (mRNA) levels in 3T3-F442A adipocytes. In the present study, we report that in fully differentiated adipocytes (after 11 days post confluence), insulin exposure progressively decreases adipsin secretion by 40%, 67%, and 78% after 2, 4, and 6 days of treatment. The inhibition of adipsin secretion by insulin is the result of a corresponding decrease in adipsin mRNA and is specific since two other differentiation-dependent fat cell mRNAs encoding aP2 (a fatty acid binding protein) and glycerophosphate dehydrogenase (GPD), are unaffected. Insulin suppresses adipsin gene expression via high affinity insulin receptors, because physiological levels of insulin produce this effect, and dose-response curves for insulin stimulation of 2-deoxyglucose uptake and glucose utilization are similar to insulin's effect on adipsin. In contrast, insulin when present during days 1-8 post confluence (during differentiation) markedly increases adipsin secretion and adipsin mRNA levels. This stimulation is due to the ability of insulin to accelerate differentiation as evidenced by corresponding increases in aP2 and GPD mRNAs as well. Insulin and IGF-1 are equipotent in this effect, suggesting that both insulin and IGF-1 receptors can mediate this response. In summary, during the differentiation of 3T3-F442A adipocytes, insulin stimulates adipsin gene expression by accelerating differentiation. As the cells become mature adipocytes, they acquire some differentiation-dependent factor, which couples insulin receptor stimulation to inhibition of adipsin gene expression. This model should aid our search for the molecular links between insulin receptor stimulation and altered gene expression.

Adipose Tissue↗
PubMed1987

Protein sparing in skeletal muscle during prolonged starvation. Dependence on lipid fuel availability.

Previous studies indicated that protein sparing in skeletal muscle during prolonged starvation depends on the availability of lipid fuels. To test this relationship further, fasted rats conserving protein were treated in vivo for 6-8 h with the antilipolytic agent nicotinic acid (NA) or with tetradecylglycidate (TDGD), an inhibitor of long-chain fatty acid oxidation. After treatment, protein synthesis and degradation in skeletal muscle were evaluated with the perfused rat hindquarter. NA treatment decreased plasma 3-hydroxybutyrate and free fatty acids and increased plasma urea and urine urea excretion, indicating increased breakdown of body protein. TDGD produced similar metabolic effects, except that plasma free fatty acids were markedly increased as a result of inhibition of fatty acid oxidation. NA and TDGD also decreased plasma insulin and increased plasma corticosteroid. Inhibition of lipid metabolism in vivo resulted in accelerated loss of protein from skeletal muscle due to decreased protein synthesis and increased protein breakdown. NA increased both total (i.e., tyrosine release) and myofibrillar (i.e., 3-methylhistidine release) protein breakdown, whereas TDGD increased the breakdown of only nonmyofibrillar proteins (i.e., 3-methylhistidine release by perfused hindquarter was not altered). These data indicate that lipid fuels may directly modulate protein metabolism in muscle during prolonged starvation and may prevent a rise in catabolic hormones. They also indicate that free fatty acids may directly attenuate the breakdown of myofibrillar proteins in muscle during prolonged starvation and that this may be unrelated to their oxidation.

3-Hydroxybutyric Acid↗
PubMed1986

Evidence that lysosomes are not involved in the degradation of myofibrillar proteins in rat skeletal muscle.

To examine the role of lysosomes in the degradation of skeletal-muscle myofibrillar proteins, we measured the release of N tau-methylhistidine from perfused muscle of starved and fed rats in the presence or absence of agents that inhibit lysosomal proteinase activity. After 1 day of starvation, the release of N tau-methylhistidine by perfused muscle of 4-, 8- and 24-week-old rats increased by 322, 159 and 134% respectively. On the other hand, total protein breakdown, assessed by tyrosine release, increased by 62, 20 and 20% respectively. Inhibitors of lysosomal proteinases as well as high concentrations of insulin or amino acids failed to diminish the release of N tau-methylhistidine by perfused muscle of starved and fed rats, despite a 25-35% inhibition of total protein breakdown. The data strongly suggest that the complete breakdown of myofibrillar proteins occurs via a non-lysosomal pathway. They also suggest that total proteolysis, which primarily reflects non-myofibrillar protein breakdown, occurs at least in part within lysosomes.

Animals↗
PubMed1986

Regulation of myofibrillar protein degradation in rat skeletal muscle during brief and prolonged starvation.

Myofibrillar protein breakdown during brief and prolonged starvation was assessed in perfused rat skeletal muscle from 8-week-old fat-fed rats that conserve skeletal muscle protein during starvation and survive for 12 to 15 days and age-matched chow-fed rats that do not conserve protein and survive only five to six days. Following the inhibition of protein synthesis with cycloheximide, myofibrillar proteolysis was assessed by measuring the release of 3-methylhistidine from the perfused rat hindquarter while simultaneous measurement of total protein breakdown was assessed by measuring tyrosine release. Myofibrillar proteolysis progressed through three distinct phases during starvation: an early phase occurring within 24 hours in which proteolysis increased in all rats, a middle phase, which took three to five days to develop and during which proteolysis decreased and was present only in fat-fed rats, and a late phase in which proteolysis again increased. Total protein breakdown (ie, tyrosine release) changed little in phase I, decreased in phase II, and increased in phase III. The release of 3-methylhistidine from the perfused hindquarter reflected changes in muscle and urine of intact rats suggesting that data obtained with the perfused hindquarter reflected the in vivo situation. Insulin, amino acids, high concentrations of glucose, indomethacin, or epinephrine as well as adrenalectomy failed to attenuate the increase in 3-methylhistidine release from the perfused hindquarter during brief and late starvation. Free fatty acids and ketone bodies were also without effect in vitro. Refeeding fasting rats for four hours decreased myofibrillar proteolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗
PubMed1980

Hypothalamic knife cut obesity in hyper or hypothyroid rats.

Recent evidence indicates that the paraventricular nucleus of the hypothalamus (PVN) contains both neurons that produce thyrotropic releasing hormone (TRH) and neurons that are destroyed or disconnected by the knife cuts that produce hypothalamic hyperphagia and obesity. This, and other evidence, suggested linkage between thyroid regulation and appetite control. As predicted, hyperthyroidism potentiated and hypothyroidism tempered the weight gains of knife cut rats. However, these effects were due entirely to increased and decreased, respectively, linear growth, not to differences in the degree of obesity. Enhanced linear growth and elevated growth hormone levels are a minor component of the enhanced weight gain of hypothalamically knife cut rats. Most of the weight gain is due to fat deposition. Only the enhanced linear growth and growth hormone aspect appear to possibly be mediated via the thyroid. In addition, obesifying knife cuts did not reduce goiterogenesis in PTU treated rats, as would be expected if the elaboration of TRH were blocked by obesifying knife cuts. Thus, neither TRH nor thyroxine is involved in the etiology of hypothalamic obesity.

Animals↗
PubMed1979

Non-effect of Massachusetts cement kiln dust upon the food intake, body weight, or activity of female rats.

The addition of Georgia cement kiln dust to the diet of cattle or weanling male rats has been reported to increase body weight and feed efficiency. We attempted to replicate these effects by adding kiln dust to the Purina laboratory chow of adult female rats. Massachusetts cement kiln dust caused no significant change in food intake, weight gain, or activity. The kiln dust effect appears, therefore to depend upon (a) ingredients peculiar to Georgia kiln dust, (b) age (juveniles vs. adults), (c) sex and/or (d) deficiencies of the control diet.

Animals↗
PubMedDate not supplied

Development of obesity in transgenic mice after genetic ablation of brown adipose tissue.

Brown adipose tissue, because of its capacity for uncoupled mitochondrial respiration, has been implicated as an important site of facultative energy expenditure. This has led to speculation that this tissue normally functions to prevent obesity. Attempts to ablate or denervate brown adipose tissue surgically have been uninformative because it exists in diffuse depots and has substantial capacity for regeneration and hypertrophy. Here we have used a transgenic toxigene approach to create two lines of transgenic mice with primary deficiency of brown adipose tissue. At 16 days, both lines have decreased brown fat and obesity. In one line, brown fat subsequently regenerates and obesity resolves. In the other line, the deficiency persists and obesity, with its morbid complications, advances. Obesity develops in the absence of hyperphagia, indicating that brown fat deficient mice have increased metabolic efficiency. As obesity progresses, transgenic animals develop hyperphagia. This study supports a critical role for brown adipose tissue in the nutritional homeostasis of mice.

Adipose Tissue, Brown↗