The effect of peripheral nerve section on some metabolic responses of brown adipose tissue in mice.
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Adipose Tissue↗
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Human adipose stromal cells expanded in human serum promote engraftment of human peripheral blood hematopoietic stem cells in NOD/SCID mice.
Human mesenchymal stem cells (hMSC), that have been reported to be present in bone marrow, adipose tissues, dermis, muscles, and peripheral blood, have the potential to differentiate along different lineages including those forming bone, cartilage, fat, muscle, and neuron. Therefore, hMSC are attractive candidates for cell and gene therapy. The optimal conditions for hMSC expansion require medium supplemented with fetal bovine serum (FBS). Some forms of cell therapy will involve multiple doses, raising a concern over immunological reactions caused by medium-derived FBS proteins. In this study, we cultured human adipose stromal cells (hADSC) and bone marrow stroma cells (HBMSC) in human serum (HS) during their isolation and expansion, and demonstrated that they maintain their proliferative capacity and ability for multilineage differentiation and promote engraftment of peripheral blood-derived CD34(+) cells mobilized from bone marrow in NOD/SCID mice. Our results indicate that hADSC and hBMSC cultured in HS can be used for clinical trials of cell and gene therapies, including promotion of engraftment after allogeneic HSC transplantation.
Adipose Tissue↗
Prostaglandin E and prostacyclin receptor expression in tumor and host tissues from MCG 101-bearing mice: a model with prostanoid-related cachexia.
Preclinical and clinical studies in our laboratory have suggested that prostaglandin (PG) E2 is involved in anorexia and cachexia development, although the role of COX pathways on the pathogenesis of cancer cachexia remains to be clarified. Expressions of PGE (EP1, EP2, EP3alpha,beta,gamma and EP4) and PGI (IP) receptors in the central nervous system (brain cortex, hypothalamus and brain stem), in peripheral (liver, white adipose tissue and skeletal muscle) and tumor tissue from MCG-101-bearing mice with and without indomethacin treatment were investigated by RT-PCR and immunohistochemistry. Expression of EP1 in the liver and EP4 receptor in white adipose tissue were upregulated and responded to indomethacin treatment, while downregulated expression of EP3 in skeletal muscle from tumor-bearing mice was unresponsive to indomethacin treatment despite improved carcass weight. Expression of EP and IP receptors in brain and tumor tissue from tumor-bearing mice were neither related nor responsive to systemic PGE2 levels including increased IL-1beta, IL-6 and TNF-alpha host activities. The expression IP receptor in CNS, peripheral tissue and tumor tissue was unchanged by cachexia development. Our results suggest that transcription of EP receptors in liver, fat and skeletal muscle tissue may be a control level for host metabolic alterations during tumor progression, while overall EP and IP receptor expression in CNS did not indicate an important control level for appetite regulation in MCG 101-bearing mice despite prostanoid related anorexia.
Animals↗
Concomitant brainstem axonal dystrophy and necrotizing myopathy in vitamin E-deficient rats.
The purpose of this study was to simultaneously evaluate in rats the effects of vitamin E depletion on tissue alpha-tocopherol (alpha-T) concentrations, electrophysiologic measurements and histopathology. Rats (21-day-old male Wistar) were fed either vitamin E-deficient or supplemented (control) diets (n = 6/group) for 10, 16, and 61 weeks. At these times, electrophysiologic tests (electromyography, spinal and somatosensory evoked potentials, and motor nerve conduction velocity) were performed, the rats were killed and alpha-T concentrations of adipose tissue, sciatic nerve, and cervical and lumbar spinal cord were measured along with histopathologic evaluation of skeletal muscles and the nervous system. By 61 weeks, depletion of alpha-T from adipose tissue and peripheral nerve was more severe (< 1% of controls) than from cervical and lumbar spinal cord (15 and 8% of controls, respectively). Electrophysiologic tests were normal at all times. Histopathologic evaluation at 61 weeks revealed normal peripheral nerve structure, but necrosis of type 1 muscle fibers and increased numbers of spheroids in the gracile and cuneate nuclei. Our results confirm that low alpha-T concentrations in tissues precede histologic changes in peripheral nerves and skeletal muscle. Furthermore, pathologic changes associated with vitamin E deficiency occur independently in muscle and nervous tissue of rats.
Adipose Tissue↗
Lower body subcutaneous fat accumulation and diabetes mellitus risk.
BACKGROUND: Type II diabetes mellitus (DM) is associated with obesity. However, body fat distribution plays an important role in this disease's pathogenesis. The prevailing hypothesis is that a more central distribution of adipose tissue relative to peripheral locations is associated with DM. I hypothesized that preferential accumulation of subcutaneous adipose tissue in the lower body is associated with a lesser likelihood of insulin resistance (IR) and DM than when fat accumulates in a central distribution. This is independent of the body mass index (BMI) or waist circumference. METHODS: Upper and lower body circumferences and skinfold thickness were related to IR and DM in 7634 adults in the Third National Health and Nutrition Survey population that underwent oral glucose tolerance testing after an overnight fast. Logistic regression and contour analyses were used to determine the effect circumference and skinfold thickness measurements had on the presence of IR or DM. The various measurements were then stratified into BMI categories to refine the contribution each factor made to these diseases further. RESULTS: Truncal subcutaneous fat correlated positively with IR and DM after correction for age and BMI. The thigh circumference and skinfold thickness correlated negatively. Regression and graphic analysis of the BMI-thigh skinfold thickness-IR relationship demonstrated that the greatest degree of IR occurred in the obese who had relatively small lower body adipose tissue depots. Those with large accumulations of lower body subcutaneous fat were less likely to have IR or DM. CONCLUSION: The results of this study have shown that the accumulation of fat in lower body subcutaneous adipose tissue depots is associated with a lower likelihood of IR and DM than when it deposits in centrally located sites. Lower body peripheral fat may serve to buffer the effect of excess ingested energy, and central body fat may be involved in the pathogenesis of IR and DM. This effect was independent of overall adiposity in men and women and independent of waist circumference in men.
Age Factors↗
Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance.
HIV-1 protease-inhibitor treatments are associated with a syndrome of peripheral lipodystrophy, central adiposity, breast hypertrophy in women, hyperlipidaemia, and insulin resistance. The catalytic region of HIV-1 protease, to which protease inhibitors bind, has approximately 60% homology to regions within two proteins that regulate lipid metabolism: cytoplasmic retinoic-acid binding protein type 1 (CRABP-1) and low density lipoprotein-receptor-related protein (LRP). We hypothesise that protease inhibitors inhibit CRABP-1-modified, and cytochrome P450 3A-mediated synthesis of cis-9-retinoic acid, a key activator of the retinoid X receptor; and peroxisome proliferator activated receptor type gamma (PPAR-gamma) heterodimer, an adipocyte receptor that regulates peripheral adipocyte differentiation and apoptosis. Protease-inhibitor binding to LRP would impair hepatic chylomicron uptake and triglyceride clearance by the endothelial LRP-lipoprotein lipase complex. The resulting hyperlipidaemia contributes to central fat deposition (and in the breasts in the presence of oestrogen), insulin resistance, and, in susceptible individuals, type 2 diabetes. Understanding the syndrome's pathogenesis should lead to treatment strategies and to the design of protease inhibitors that do not cause this syndrome.
Cytochrome P-450 Enzyme System↗
High-fat feeding exerts minimal effects on rhythmic mRNA expression of clock genes in mouse peripheral tissues.
Recent studies have suggested that the impairment of the circadian molecular clock in peripheral tissues, including adipose tissue, is involved in the development of metabolic syndrome. Although the disorder is often caused by dietary obesity, it remains to be elucidated whether dietary obesity or high-caloric intake per se affects the molecular clock system. To address this issue, this study investigated the effect of high-fat feeding on the rhythmic mRNA expression of clock genes (Clock, Bmal1, Per1, Per2, Cry1, Cry2, and Dbp) in mouse visceral adipose tissue and liver. Mice fed a high-fat diet for 8 wks developed a mild but overt metabolic syndrome of obesity, hyperlipidemia, and hyperglycemia. However, the high-fat feeding had only minimal effects on the rhythmic expression of the clock genes examined in both tissues. On the other hand, daily rhythmicity in the transcript level of cholesterol 7alpha-hydroxylase, a hepatic enzyme controlling circadian cholesterol homeostasis, disappeared in the mice on high-fat chow. These results suggest that high-fat feeding and mild metabolic syndrome scarcely alter the molecular clock system in mouse peripheral tissues, and that physiological circadian rhythms could be affected without altering the system. Further studies are needed to better understand the role of the circadian molecular clock in the development of metabolic syndrome. The first two authors contributed equally to this study.
Animal Feed↗
Microdialysis in adipose tissue and skeletal muscle.
Traditionally, investigation of metabolism in peripheral tissues such as the adipose tissue and muscles has been done by indirect measurements on whole body metabolism or in cannulated limbs. The microdialysis technique (1) was first invented and further developed (2) by neurobiologists for regional measurements in the rat brain. During the last ten years the technique has been used in several other organs in laboratory animals and since the first application in man (3) it has become wide spread for clinical investigation of human metabolism as well as for clinical pharmacology research. In this article some methodological aspects will be discussed and a few examples of the application of the technique will be given.
Adipose Tissue↗
Adipose body of the orbit.
The adipose body of the orbit (ABO) fills most of the orbital cavity, surrounding the eyeball, muscles, nerves, and vessels. It was studied in histologic section in the three basic planes in the fetus, neonate, and adult. In the retrobulbar area, that is, posterior to the eyeball, adipose tissue occupies the space around the optic nerve and penetrates between the recti muscles, describing a four-leafed clover pattern in frontal section. The fatty tissue of the retrobulbar area also includes the peripheral ring of fat that lies between the muscles and the walls of the orbit. In the part of the peribulbar area located between the muscular insertions on the eyeball anteriorly and the emergence of the optic nerve from the sclera posteriorly, the pattern of adipose tissue is identical to the peripheral ring of fat and the fat between the muscles in the retrobulbar area. External to the muscular insertions and the anterior part of the eyeball, there is a thin ring of histologically similar fatty tissue that is continuous anteriorly with the fatty bodies of the upper and lower eyelids. Histologic examination shows that the lobules are large in that part of the retrobulbar area within the muscle cone and that they are smaller with more fibrous septa in the remaining restricted regions, such as the area between the eyeball and muscles and in the rings around the muscles and around the eyeball. In no case was a septum found separating the peripheral adipose ring from the fat located within the muscle cone.
Adipose Tissue↗
Effects of hypothermic deep-anaesthesia on energy metabolism at brain and peripheral levels: a multi-probe microdialysis study in free-moving rat.
Reduction of central energy metabolism is a strategy to protect brain against neurotoxic events. The aim of this microdialysis study in rats is to evaluate changes in energy metabolite levels at central level (striatum) comparatively to peripheral level (subcutaneous adipose tissue) during hypothermic barbituric deep-anaesthesia (sodium pentobarbital 60 mg/kg intraperitoneally). At brain level, extracellular glucose increases (+14.9%) while lactate decreases (-16.6%); opposite results were observed at subcutaneous level (-29.2% for glucose and +68.3% for lactate). Lactate/pyruvate ratio remains unchanged at brain level, but increases at subcutaneous level (+73.5%). In light of previous studies on the effects of pentobarbital on regional blood flow and tissue glucose consumption, our data correlates the fact that pentobarbital reduces preferentially brain energetic metabolism. We suggest that those regional effects are explained, at least for a part, by the fact that central isoform glucose transporters (Glut1 and Glut3) are known to be more sensitive to pentobarbital than peripheral isoforms. Such facts can be involved in the protection of brain tissue against ischemic risk due to decreased cerebral blood flow decrease.
Adjuvants, Anesthesia↗
Deficits in E2-dependent control of feeding, weight gain, and cholecystokinin satiation in ER-alpha null mice.
To test the role of gene expression of the classical ER (ER alpha) in the inhibitory effects of E on food intake and body weight, we ovariectomized and administered E2 benzoate (75 pg/d) or vehicle to wild-type (WT) mice and mice with a null mutation of ER alpha (alpha ERKO). Mice were ovariectomized at age 9 wk, at which time there was no significant effect of genotype on food intake or body weight. During an 18-d test after recovery from ovariectomy, vehicle-treated WT mice increased daily food intake and gained more body weight than E2-treated WT mice, whereas food intake and body weight gain were not different in E2- and vehicle-treated alpha ERKO mice. Carcass analysis revealed parallel changes in body lipid content, but not water or protein content. Because an increase in the potency of the peripheral cholecystokinin (CCK) satiation-signaling system mediates part of E2's influence on feeding in rats, the influence of ip injections of 250 microg of the selective CCK(A) receptor antagonist devazepide was then tested. Devazepide increased 3-h food intake in E2-treated WT mice, but was ineffective in both groups of alpha ERKO mice. Furthermore, ip injections of 4 microg/kg CCK-8 increased the number of cells expressing c-Fos immunoreactivity in the nuclei of the solitary tract of E2-treated WT mice more than it did in vehicle-treated WT mice, whereas E2 had no such effect in alpha ERKO mice. Thus, ER alpha is necessary for normal responsivity of food intake, body weight, adiposity, and the peripheral CCK satiation-signaling system to E2 in mice, and ER beta is not sufficient for any of these effects. This is the first demonstration that ER alpha gene expression is involved in the estrogenic control of feeding behavior and weight regulation of female mice.
Animals↗
[Toxicokinetics of a thioquinoxaline component: the oxythioquinox (author's transl)].
The absorption and distribution of Morestan 35S in the organism of the rat were studied after administration by stomach tube. It was shown that Morestan, in vivo and in vitro, forms a complex with plasma proteins and particularly with albumins. Most of the plasma Morestan is distributed like this. After intravenous admininstration, the constant of elimination, K13, and the biological half-life determination show that plasma Morestan 35S is eliminated very slowly. The K12 and K21 constants indicate that there is an equilibrium between the plasma compartment and a peripheral compartment. After intragastric administration, the increase of radioactivity in epididymal adipose tissue, indicate that the peripheral compartment should include the adipose tissue.
Administration, Oral↗
A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome.
BACKGROUND: Lipodystrophy (LD; peripheral lipoatrophy, central adiposity) hyperlipidaemia and insulin resistance often complicate protease inhibitor-containing antiretroviral therapy. Lipoatrophy and abdominal distension were observed in protease inhibitor-naive nucleoside analogue reverse transcriptase inhibitor (NRTI) recipients with lactic acidaemia and hepatic impairment, which are known NRTI-induced mitochondrial toxicities. DESIGN AND SETTING: Case-control study in a university-based outpatient clinic. PATIENTS AND METHODS: The patients studied included 14 NRTI recipients with lipoatrophy, 32 antiretroviral-naive patients without LD, 28 NRTI recipients without LD, 44 combined NRTI-protease inhibitor recipients without LD, and 102 NRTI-protease inhibitor recipients with LD. Data was obtained on body composition (questionnaire, physical examination, dual-energy x-ray absorptiometry and abdominal computerized tomography), with biochemical, lipid and glycaemic parameters. RESULTS: The NRTI-LD syndrome was characterized by recent onset fatigue and nausea, peripheral lipoatrophy (6 kg loss over 4 months), abdominal distension (ascites +/- hepatomegaly) and elevated lactate (4.6, 1.1, 1.2, 1.4 and 1.7 mmol/l, respectively; P< 0.0001) and liver enzymes. Cases without hepatic involvement also had lower body fat and greater lactate than unaffected controls. Metabolic disturbances and weight improved after cessation. The NRTI-LD syndrome differed from protease inhibitor-related LD syndrome by the presence of recent onset symptoms and weight loss, higher lactate and alanine aminotransferase, and lower albumin, cholesterol, triglycerides, glucose and insulin. In treated controls, current stavudine therapy, protease inhibitor duration, and lactic acidaemia were independently associated with both lipoatrophy and abdominal obesity; total NRTI duration was also associated with lipoatrophy, and lamivudine and protease inhibitor duration with buffalo hump. CONCLUSIONS: A syndrome of lipoatrophy, constitutional illness, lactic acidaemia and hepatic dysfunction can complicate NRTI therapy. Both protease inhibitor and NRTI therapies, particularly if associated with lactic acidaemia, contribute to LD syndrome, but have some distinguishable clinical and metabolic effects.
Acidosis, Lactic↗
Effect of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma-2 gene on adiposity, insulin sensitivity and lipid profile in the Spanish population.
OBJECTIVE: To investigate the role of the Pro12Ala peroxisome proliferator-activated receptor (PPAR) gamma-2 polymorphism in the susceptibility to the insulin resistance syndrome and its metabolic complications in a population-based nationwide multicenter study in Spain. DESIGN: 464 unrelated adults (45.3% men and 54.7% women) aged between 35 and 64 years were randomly chosen from a nationwide population-based survey of obesity and related conditions including insulin resistance and cardiovascular risk factors. METHODS: Anthropometric determinations included: body mass index (BMI), waist-to-hip ratio, sagittal abdominal diameter; biochemical determinations included: fasting plasma glucose concentration and concentration 2 h after an oral glucose tolerance test (OGTT), total cholesterol, high and low density lipoprotein-cholesterol, triglycerides, leptin and insulin. Systolic and diastolic blood pressure were also measured. Genotyping of the PPARgamma-2 Pro12Ala polymorphism was determined by polymerase chain reaction and single strand conformation polymorphism analysis. RESULTS: The Ala12 allele frequency was higher in obese men than in lean men (0.15 vs 0.08, P=0.03). Men carriers of the Ala12 allele had a higher BMI than non-carriers (38.9% vs 21.3%; adjusted odds ratio 2.36, 95% confidence interval 1.10-5.05, P=0.03). However, despite higher BMI obese men carriers of the Ala12 allele had lower sagittal abdominal diameter than Pro12 homozygotes (24.1+/-3.2 vs 26.3+/-2.5 cm, P=0.01). The Ala12 allele was associated with lower total triglycerides levels in the overall population and it was also associated with lower fasting insulin levels and a higher insulin sensitivity by homeostasis model assessment (HOMA) in women. CONCLUSIONS: Our results suggest that the Pro12Ala polymorphism of the PPARgamma-2 gene promotes peripheral deposition of adipose tissue and increased insulin sensitivity for a given BMI. The results in women might be due to their different adipose tissue distribution.
Adipose Tissue↗
An additional dose of cefazolin for intraoperative prophylaxis.
We examined the pancreatic tissue concentrations of cefazolin in ten patients undergoing pancreatectomy, and determined the optimal intraoperative time to deliver a repeat dose of cefazolin. An intravenous bolus dose of 1 g cefazolin was administered at the time of skin incision. Peripheral blood, subcutaneous adipose tissue, and peritoneal samples were obtained intraoperatively every hour for 4 h after the antibiotic was first administered, and pancreatic tissue samples were obtained at the time of pancreatectomy. To determine adequate tissue levels of cefazolin, minimum inhibitory concentrations (MIC) were measured for four bacterial species, namely 360 isolates of methicillin-sensitive Staphylococcus aureus (MSSA), 204 isolates of Klebsiella pneumoniae, 314 isolates of Escherichia coli, and 30 isolates of Streptococcus spp. The antibiotic concentrations in adipose tissue and peritoneum 3 h after the administration of cefazolin were lower than the MIC80 for K. pneumoniae, E. coli, and Streptococcus spp. Most pancreatic tissue samples showed antibiotic concentrations greater than the MIC80 for these bacterial species; however, those from four patients complicated by severe chronic pancreatitis, massive intraoperative bleeding, or obesity showed concentrations lower than the MIC80. Thus, we recommend that a second dose of cefazolin be given 3 h after the first administration to maintain adequate levels of antibiotic activity.
Aged↗
Gastric inhibitory polypeptide: the neglected incretin revisited.
After the ingestion of fat- and glucose-rich meals, gut hormones are secreted into the circulation in order to stimulate insulin secretion. This so-called "incretin effect" is primarily conferred by Glucagon-like peptide 1 (GLP-1) and Gastric Inhibitory Polypeptide (GIP). In contrast to GLP-1, GIP has lost most of its insulinotropic effect in type 2 diabetic patients. In addition to its main physiological role in the regulation of endocrine pancreatic secretion, GIP exerts various peripheral effects on adipose tissue and lipid metabolism, thereby leading to increased lipid deposition in the postprandial state. In some animal models, an influence on gastrointestinal functions has been described. However, such effects do not seem to play an important role in humans. During the last years, the major line of research has focussed on GLP-1, due to its promising potential for the treatment of type 2 diabetes mellitus. However, the physiological importance of GIP in the regulation of insulin secretion has been shown to even exceed that of GLP-1. Furthermore, work from various groups has provided evidence that GIP contributes to the pathogenesis of type 2 diabetes to a considerable degree. Recent data with modified GIP analogues further suggested a possibility of therapeutic use in the treatment of type 2 diabetes. Thus, it seems worthwhile to refocus on this important and-sometimes-neglected incretin hormone. The present work aims to review the physiological functions of GIP, to characterize its role in the pathogenesis of type 2 diabetes, and to discuss possible clinical applications and future perspectives in the light of new findings.
Adipose Tissue↗
Aging and the neuroendocrine regulation of reproduction and body weight.
Aging in men is associated with a decline in trophic factors such as testosterone (T), alterations in body composition and impaired energy and body weight regulation. We performed studies to investigate the mechanisms underlying age-related changes in the neuroendocrine control of testis function, body composition, food intake and body weight in the Brown Norway (BN) rat. We found that similar to aging men, male BN rats demonstrate both primary and secondary testicular failure with aging without confounding age-related tumors, hormonal changes and systemic illnesses. With aging, these animals have blunted circadian variations in luteinizing hormone (LH) and T, and decreased hypothalamic gonadotropin-releasing hormone (GnRH) synthetic capacity with preserved pituitary gonadotropin responses to GnRH. We found that aging male BN rats have increased peripheral and visceral adiposity associated with increased insulin and leptin levels, and decreased relative lean body mass and muscle mass. We found that these rats exhibit reduced food intake and body weight gain associated with decreased hypothalamic neuropeptide Y (NPY) gene expression in the arcuate nucleus (ARC), both during ad-libitum feeding and after a 72-h fast. Recently, we found that old male BN rats treated chronically with troglitazone, an insulin sensitizer, lowered high insulin and leptin levels, decreased body fat, and corrected the blunted food intake and body weight gain response to fasting without affecting basal ARC NPY gene expression. These findings suggested that hyperinsulinemia and/or hyperleptinemia associated with aging may contribute to the age-related impairment in energy and weight regulation. Our studies suggest that the aging male BN rat is an excellent model to investigate the mechanisms underlying the age-associated changes in the neuroendocrine control of body composition, energy intake and body weight.
Aging↗
The nuclear lamina and inherited disease.
Inherited disorders of the nuclear lamina present some of the most intriguing puzzles in cell biology. Mutations in lamin A and lamin C - nuclear intermediate filament proteins that are expressed in nearly all somatic cells - cause tissue-specific diseases that affect striated muscle, adipose tissue and peripheral nerve or skeletal development. Recent studies provide clues about how different mutations in these proteins cause either muscle disease or partial lipodystrophy. Although the precise pathogenic mechanisms are currently unknown, the involvement of lamins in several different disorders shows that research on the nuclear lamina will shed light on common human pathologies.
Animals↗