Adipose tissue growth and differentiation: view from the chair.
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Adipocytes↗
Biomedical subjects
D C Lau
Publications and source records attributed to D C Lau.
Effect of acarbose on insulin sensitivity in elderly patients with diabetes.
OBJECTIVE: To study the effect of acarbose, an alpha-glucosidase inhibitor, on insulin release and insulin sensitivity in elderly patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Elderly patients with type 2 diabetes were randomly treated in a double-blind fashion with placebo (n = 23) or acarbose (n = 22) for 12 months. Before and after randomization, subjects underwent a meal tolerance test and a hyperglycemic glucose clamp study designed to measure insulin release and sensitivity. RESULTS: After 12 months of therapy there was a significant difference in the change in fasting plasma glucose levels (0.2 +/- 0.3 vs. -0.5 +/- 0.2 mmol/l, placebo vs. acarbose group, respectively; P < 0.05) and in incremental postprandial glucose values (-0.4 +/- 0.6 vs. -3.5 +/- 0.6 mmol/l, placebo vs. acarbose group, P < 0.001) between groups. There was a significant difference in the change in HbA(1c) values in response to treatment (0.4 +/- 0.2 vs. -0.4 +/- 0.1%, placebo vs. acarbose group, P < 0.01). The change in fasting insulin in response to treatment (-2 +/- 2 vs. -13 +/- 4 pmol/l, placebo vs. acarbose group, P < 0.05) and incremental postprandial insulin responses (-89 +/- 26 vs. -271 +/- 59 pmol/l, placebo vs. acarbose group, P < 0.01) was also significantly different between groups. During the hyperglycemic clamps, glucose and insulin values were similar in both groups before and after therapy However, there was a significant difference in the change in insulin sensitivity in response to treatment between the placebo and the acarbose groups (0.001 +/- 0.001 vs. 0.004 +/- 0.001 mg/kg x min(-1) [pmol/l](-1), respectively, P < 0.05) CONCLUSIONS: Acarbose increases insulin sensitivity but not insulin release in elderly patients with diabetes.
Acarbose↗
Call for action: preventing and managing the expansive and expensive obesity epidemic.
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Adult↗
Adipocyte differentiation factor (ADF): a protein secreted by mature fat cells that induces preadipocyte differentiation in culture.
A factor that is released into the culture medium of mature adipocytes and promotes the differentiation (adipogenic conversion) of preadipocytes has been partially characterized. The factor acts in a dose-dependent manner on preadipocytes to produce up to a four-fold increase in triacylglycerol (triglyceride) content and a nine-fold increase in glycerol-3-phosphate dehydrogenase (GPDH) activity, a marker of the late phase of differentiation of preadipocytes. The material appears to be a protein, since it has a molecular weight (Superose-12 gel exclusion chromatography) of about 53 kDa, an isoelectric point (pl) of 4.7-4.9, and is inactivated by the proteases papain and chymotrypsin and extremes of pH (2 and 12). Considerations of molecular weight, isoelectric point, stability to specific proteases, and especially to the action of chemical agents [the adipogenic activity is not affected by either an oxidizing (KIO4) or a reducing agent (DTT)], lead to the conclusion that the differentiation factor is distinct from known cytokines. The authors suggest that the protein be designated adipocyte differentiation factor (ADF). ADF in vivo may act as a cytokine paracrine agent to regulate the differentiation of preadipocytes.
3T3 Cells↗
Arachidonic acid metabolites of the lipoxygenase as well as the cyclooxygenase pathway may be involved in regulating preadipocyte differentiation.
Conditions that trigger preadipocyte differentiation in vivo have yet to be elucidated. To investigate the role of endogenous arachidonic acid (AA) metabolites on adipose tissue growth, rat preadipocytes in primary culture were induced to differentiate using medium conditioned by isolated mature adipocytes (ACM). Differentiation was determined by assay of glycerol-3-phosphate dehydrogenase (GPDH). When collected in the presence of indomethacin (10 nmol/L) to inhibit prostaglandin (PG) synthesis by adipocytes, ACM induced greater differentiation (GPDH activity, 405 +/- 68 nmol NADH used/min/mg protein) than when indomethacin was added postcollection to inhibit preadipocyte PG synthesis (205 +/- 24, P < .05) or ACM alone (304 +/- 55). This suggested that PGs released by adipocytes inhibited differentiation, whereas those released by preadipocytes appeared to act in an autocrine manner to stimulate differentiation. However, 24-hour collections of ACM contained 125 pmol/L PGE2 and 900 pmol/L PGI2, concentrations too low to promote differentiation when added exogenously. Nordihydroguaiaretic acid (NDGA; 10 pmol/L), an inhibitor of lipoxygenase (LOX), stimulated the ACM-induced increase in GPDH activity (ACM, 99 +/- 13; ACM + NDGA, 369 +/- 130). In contrast, when differentiation was induced by a hormonal cocktail (MIX), including insulin and corticosterone, NDGA decreased GPDH activity (MIX, 329 +/- 66; MIX + NDGA, 142 +/- 40; P < .03). We concluded that preadipocyte differentiation within adipose tissue may be subject to both positive and negative regulators derived from AA metabolism resulting from both LOX and cyclooxygenase (COX) activity.
Adipocytes↗
Development of insulin resistance in the JCR:LA-cp rat: role of triacylglycerols and effects of MEDICA 16.
The JCR:LA-cp rat develops an extreme obese/insulin-resistant syndrome such that by 12 weeks of age, there is no longer any insulin-mediated glucose turnover. At 4 weeks of age, obese and lean rats have essentially identical basal and insulin-mediated glucose uptake in skeletal muscle. By 8 weeks of age, however, the obese rats no longer exhibit such intake. Plasma insulin concentrations in the normal fed state show only small increases up to 4 weeks, with a rapid rise to a marked hyperinsulinemia thereafter, with an age at half-development of 5.5 weeks. Plasma triacylglycerol concentrations in fed obese rats are elevated at 3 weeks and rise rapidly thereafter. The triacylglycerol content of skeletal muscle is significantly elevated in the obese rats at 4 weeks of age. Histological examination of Oil Red O-stained muscle tissue and transmission electron microscopy shows the presence of intracellular lipid droplets. Treatment with the potent triacylglycerol-lowering agent MEDICA 16 (beta,beta'-tetramethylhexadecanedioic acid) from 6 weeks of age reduces plasma lipids markedly, but it reduces body weight and insulin resistance only modestly. In contrast, treatment with MEDICA 16 from the time of weaning at 3 weeks of age results in the normalization of food intake and body weight to over 8 weeks of age. The development of hyperinsulinemia is also delayed until 8.5 weeks of age, and insulin levels remain strongly reduced. Plasma triacylglycerol concentrations remain at the same level as in lean rats, and neither an elevated muscle triacylglycerol content nor intracellular lipid droplets are found at 4 weeks of age. The results indicate that insulin resistance develops in the young animals and is not directly due to a genetically determined defect in insulin metabolism. The mechanism of induction instead appears to be related to an exaggerated triacylglycerol metabolism.
Animals↗
Long-term regulation of leptin expression is correlated with adipocyte number in obese rats.
OBJECTIVE: To investigate long-term regulation of leptin expression in adipose tissues of obese JCR:LA-corpulent rats, which have been shown to overexpress leptin. DESIGN: Manipulation of adipose tissue growth in obese rats by dietary restriction. INTERVENTIONS: Weanling female obese rats were maintained on 1 of 3 diets until 8 months old. One group was allowed to feed ad libitum, the second was pair-fed with lean rats, and the third had food intake restricted to maintain weights equal to those of age-matched lean rats. OUTCOME MEASURES: Body and fat pad weights, leptin messenger RNA (mRNA) levels, and size and number of adipocytes in retroperitoneal fat pads. RESULTS: Adipose tissue mass was increased 6-fold in the obese rats compared with the lean ones, despite equal body weight and intake restriction that was sufficient to impair growth. Although leptin mRNA level was down-regulated by intake restriction, it was still twice as elevated in the obese rats as in the lean ones, and was highly correlated with specific fat pad mass and adipocyte number, but not with size. CONCLUSIONS: These data suggest that leptin expression is correlated with adipocyte number within a fat pad, and that there is inappropriate hepatic de novo synthesis and storage of triacylglycerols in obese rats. A role for leptin in nutrient partitioning is proposed.
Adipocytes↗
Effect of progesterone therapy on arginine vasopressin and atrial natriuretic factor in premenstrual syndrome.
OBJECTIVES: To explore the possible role of natriuretic peptides and vasopressin in luteal phase fluid retention in premenstrual syndrome (PMS) and to determine the effect of progesterone therapy on these hormones. DESIGN: Self-controlled prospective study. SETTING: University-based medical research centre. PATIENTS: Six patients with PMS were studied during the symptomatic luteal and asymptomatic follicular phases. The follicular phase response was used as the control for each subject. INTERVENTIONS: An intravenous infusion of 3% saline solution was administered on an early follicular and a late luteal phase day in 2 menstrual cycles. Progesterone was administered orally during the second luteal phase. OUTCOME MEASURES: Osmolality, arginine vasopressin (AVP), atrial natriuretic factor (ANF), and brain natriuretic peptide (BNP) levels in plasma, osmolality, sodium, potassium, cyclic adenosine monophosphate (cAMP) and cyclic guanosine 5'-phosphate (cGMP) concentrations in urine, and thirst sensation. RESULTS: Mean basal plasma ANF and osmolality levels and the threshold for AVP release and thirst were lower, and mean urinary cyclic nucleotide levels and AVP sensitivity (amount of AVP secreted per unit rise in plasma osmolality) were higher, in the luteal phase than in the follicular phase. With saline loading, there was an increase in plasma osmolality, AVP and ANF and in urinary sodium and cyclic nucleotide levels. Plasma ANF and osmolality levels remained lower in the luteal phase compared with the follicular phase, but AVP levels at the end of the saline infusion were higher in the luteal phase than in the follicular phase. Progesterone therapy caused an increase in plasma ANF and osmolality levels and the AVP threshold and a decrease in AVP levels and sensitivity and urinary cyclic nucleotide levels. BNP levels did not change with phase or treatment. The differences in AVP threshold with phase and treatment were statistically significant (p < 0.001). There was a significant phase effect for plasma ANF (p = 0.02) and a significant or near-significant interaction effect of phase and treatment for plasma ANF (p = 0.06) and urinary cAMP (p = 0.047) and cGMP (p = 0.066). The effect of phase and treatment was not significant for the other measurements. CONCLUSIONS: Luteal phase fluid retention may be due to a relative deficiency of ANF and a lower threshold for AVP release. The symptomatic improvement produced by progesterone treatment may be due to its stimulation of ANF and inhibition of AVP release or synthesis.
Adult↗
Paracrine interactions in adipose tissue development and growth.
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Adipocytes↗
A novel method for studying preadipocyte differentiation in vitro.
In vitro differentiation of rat preadipocytes has typically been induced in medium supplemented with pharmacological concentrations of hormonal mixtures. These conditions probably do not reflect the milieu within adipose tissue in vivo. We have developed a new method for inducing differentiation of preadipocytes using culture medium which has been conditioned by isolated adipocytes (ACM). In the presence of ACM, 70%-80% of test preadipocytes contained lipid inclusions compared to < 5% of control. When differentiation was assessed by assay of glycerol-3-phosphate dehydrogenase activity, ACM activity was shown to be reproducible and the consistency of response to ACM by different pools of preadipocytes was comparable to that induced by standard differentiation procedures. We have also demonstrated that the adipogenic activity of ACM may not depend on prostaglandin secretion by adipocytes. We propose that use of paracrine factors produced by components of adipose tissue provides a new approach to preadipocyte differentiation induction which may more closely reproduce the adipose tissue environment.
Adenosine↗
Overexpression of the obese gene in the genetically obese JCR:LA-corpulent rat.
Expression of the obese (ob) gene in JCR:LA-cp rats was examined. A 360 bp fragment of the conserved region of the gene was obtained by RT-PCR using total RNA isolated from adipose tissues of Sprague-Dawley (SD), JCR:LA-cp obese and lean rats. The three gene fragments were sequenced and shown to be identical. They were over 90% identical to the mouse ob gene sequence. The amplified fragments encode for 120 amino acids and have a glutamine residue at position +49. The gene was shown to be expressed only in adipose tissues, both white and brown. A ten-fold increase in ob mRNA was detected in white adipose tissues of obese animals compared to the lean ones of the JCR-LA:cp strain of rat. Ob gene was expressed in adipocytes and preadipocytes from the obese rat whereas in the lean and SD rats, ob gene expression was found in adipocytes only. No ob mRNA was detected in preadipocytes from the lean or SD rats, indicating a differentiation or maturation-dependent expression in normal rats.
Adipocytes↗
Exogenous triacylglycerol inhibits insulin-stimulated glucose transport in L6 muscle cells in vitro.
This study tested the hypothesis using cultured L6 myocytes that insulin resistance in muscle may be the consequence of triacylglycerol accretion in the tissue itself. Exposure of L6 myocytes to triacylglycerol for 4 hours resulted in significant transfer of lipid into the cells compared to control cells treated for only 5 min. Insulin-stimulated 2-deoxyglucose uptake in L6 myocytes was reduced when the cells were preloaded with triacylglycerol. Insulin-independent and insulin-stimulated 2-deoxyglucose uptake were inhibited by cytochalasin B, indicating that both were transporter-mediated. Diacylglycerol mimicked insulin action by increasing 2-deoxyglucose uptake and this was also reduced by triacylglycerol preloading, suggesting that the effect was not mediated at the insulin receptor. Thus, triacylglycerol may exert a direct effect on muscle cell insulin sensitivity possibly at the level of diacylglycerol second messenger pathway.
Analysis of Variance↗
Extracellular matrix components secreted by microvascular endothelial cells stimulate preadipocyte differentiation in vitro.
Paracrine interaction between preadipocytes and microvascular endothelial cells may play a role in the regulation of adipose tissue growth. We report here a study of the effect of extracellular matrix factors secreted by microvascular endothelial cells, derived from adipose tissue, on preadipocyte differentiation in primary culture. Extracellular matrix components (EC) were prepared by differential centrifugation of medium conditioned by microvascular endothelial cells (CM). Preadipocyte differentiation was assessed by enumerating cells containing Oil-Red-O-stainable neutral lipids and by assaying cellular triacylglycerol (TG) content and glycerol-3-phosphate dehydrogenase (GPDH) specific activity. Both supernatant (containing soluble components) and pelleted (containing large complexes of EC) fractions of CM stimulated preadipocyte differentiation. When the supernatant fraction was used, the proportion of cells containing visible lipid droplets was 29% +/- 3% of total preadipocytes in the presence of extracellular complexes, as compared with 6% +/- 1% under control conditions. This differentiation induction was associated with fourfold increases in TG content and GPDH specific activity. Neither the supernatant nor the pelleted fraction of EC affected the maximal differentiation induced by hormonal stimulation in serum-supplemented or serum-free media. The major EC, fibronectin, laminin, and collagen IV, had no effect on differentiation when added individually to culture medium. Collection of CM under hyperglycemic (18 mmol/L glucose) compared with control (6 mmol/L glucose) conditions reduced the stimulatory effect of extracellular complexes by twofold, suggesting decreased or altered production by endothelial cells. The present findings demonstrate that microvascular endothelial cells release EC that promote preadipocyte differentiation.(ABSTRACT TRUNCATED AT 250 WORDS)
Adipocytes↗
Regulation of new fat cell formation in rats: the role of dietary fats.
Factors that stimulate formation of new adipocytes during development of obesity are yet to be identified. We examined whether diet acts directly on preadipocytes to stimulate replication and differentiation or indirectly by interacting with adipocytes to release or modify local growth factors. Male Sprague-Dawley rats were fed chow or diets high in starch (HST), saturated (HFS) or polyunsaturated (HFP) fats until 5-7 months of age. We found that, compared to other diets, HFS induced acceleration of replication of preadipocytes in primary culture (doubling time of retroperitoneal-derived preadipocytes: HFS 17 +/- 1 versus chow 32 +/- 6 and HFP 29 +/- 3 h, P < 0.05). HFS stimulated greater expansion of retroperitoneal fat than HFP even when caloric intake was equal and increased adipocyte number threefold. Preadipocyte pool size in inguinal and retroperitoneal fat pads changed relative to fat pad weight in rats fed all diets compared to chow, suggesting that the balance between the number of cells capable of replicating and those terminally differentiated was perturbed. Differentiation of preadipocytes and release of adipocyte growth factors in vitro were unaffected by diet. We concluded that dietary saturated fats induced expansion of adipose tissue mass more effectively than polyunsaturated fats and that this may, in part, be achieved by acceleration of preadipocyte replication.
Adipocytes↗
Fatty acid synthase and adipsin mRNA levels in obese and lean JCR:LA-cp rats: effect of diet.
In Sprague-Dawley rats, fatty acid synthase (FAS) activity is suppressed by dietary fat. To test the hypothesis that a defect in regulation of de novo fatty acid synthesis exists in massive obesity, we investigated the effect of diet on FAS mRNA levels in genetically obese JCR:LA-corpulent (cp) rats. We also determined levels of mRNA encoding adipsin, a fat cell-derived protein possibly associated with lipid metabolism. Hepatic FAS mRNA levels were elevated five-fold in obese compared to lean cp rats and were unsuppressed by dietary fat. Dietary sucrose increased FAS mRNA levels in lean cp rats, but, in contrast to Sprague-Dawley rats, little deposition of lipid resulted. Adipsin mRNA levels were fivefold lower in obese cp and Sprague-Dawley rats than in lean cp rats and were unaffected by diet. We conclude that exaggerated de novo fatty acid synthesis may play a major role in the pathogenesis of obesity in obese JCR:LA-corpulent rats.
Adipose Tissue↗
Paradoxically slow preadipocyte replication and differentiation in corpulent rats.
We have investigated the in vitro rate of replication and differentiation of preadipocytes derived from lean (+/+) and obese (cp/cp) male JCR:LA-corpulent (cp) rats in an attempt to identify mechanisms that regulate adipose tissue growth. Cp/cp rats were twofold heavier than age-matched lean rats by 9-10 mo. Cp/cp-derived preadipocytes demonstrated an inherently slower rate of replication than +/+ preadipocytes (population doubling time: cp/cp 52.3 +/- 9.6 h vs. +/+ 19.7 +/- 1.6 h), although the preadipocyte pool in the cp/cp was significantly greater. Cp/cp preadipocytes were resistant to hormonally induced differentiation (19.9 +/- 9.4% of cells accumulated lipid) but differentiated when cocultured with mature adipocytes to the same extent as preadipocytes derived from Sprague-Dawley (SD) rats (cp/cp 48.4 +/- 15.2% vs. SD 52.2 +/- 11.9%). In contrast, SD preadipocytes did not differentiate in response to mature adipocytes from +/+ rats (13.8 +/- 5.2%). Our observations suggest that preadipocyte replication and maturation may not be controlled in a coordinated manner.
Adipose Tissue↗
Nature and nurture in adipocyte development and growth.
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Adipose Tissue↗
Influence of paracrine factors on preadipocyte replication and differentiation.
Regional adipose tissue growth may be modulated by paracrine factors that influence preadipocyte replication and/or differentiation. To investigate this hypothesis, we have studied the effects of culture media conditioned by adipose microvascular endothelial cells, preadipocytes, or mature fat cells, on rat preadipocyte replication and differentiation in vitro. Endothelial cell-conditioned medium (ECCM) stimulated preadipocyte replication while medium conditioned by mature fat or preadipocytes had little effect. ECCM contained heat and trypsin sensitive polypeptides, with molecular masses in the 18-35 kDa range. Mature fat-conditioned medium, but not medium enriched with triacylglycerols, induced differentiation in about 50 percent of preadipocytes. This effect was greatly reduced in cells derived from genetically obese JCR:LA-corpulent (cp) rats compared to those derived from lean JCR:LA-cp or Sprague-Dawley rats. The present studies demonstrate the presence of paracrine factors which may play a role in regulating regional adipose tissue growth.
Adipose Tissue↗