Effects of adenosine derivatives on cAMP accumulation and lipolysis in rat adipocytes and on adenylate cyclase in adipocyte plasma membranes.
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Adenosine↗
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Electron microscopical studies on the genesis of white adipocytes: differentiation of immature pericytes into adipocytes in transplanted preadipose tissue.
In order to clarify the relationships between perivascular cells, capillaries and fat cells, with a special reference to the origin of fat cells, we have made a light and electron microscopical study on the developing epididymal adipose tissue of newborn to 5-week-old rats, and also on the differentiating, transplanted epididymal preadipose tissue from 6-day-old rats. Development of epididymal preadipose tissue progressed rapidly 6 or 7 days after birth. The preadipose tissue on the 5th day after transplantation consisted of differentiated areas with many mature fat cells, and of undifferentiated areas in which these cells were scanty. In the differentiated areas of developing epididymal preadipose tissue, both in situ and transplanted, many fat cells seemed to develop in the area immediately adjacent to growing capillaries, but cells intermediate between perivascular cells and preadipocytes were seldom observed. However, in undifferentiated areas of transplanted tissue, we found ultrastructural evidence that immature pericytes of capillaries can differentiate into preadipocytes.
Adipose Tissue↗
Stereochemical aspects of beta-adrenoceptor antagonist-receptor interaction in adipocytes. Differentiation of beta-adrenoceptors in human and rat adipocytes.
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Adipose Tissue↗
Proceedings: Differential effects of prostaglandin E and phenyisopropyl-adenosine on cAMP accumulation in intact adipocytes of rats and adenyl cyclase activity of adipocyte plasma membranes.
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Adenosine↗
Obese adipocytes induce fibroblast-to-myofibroblast transition through TGF-β1 signaling: implications in asthma pathogenesis.
Obesity, a key risk factor for severe asthma, is associated with worsening symptoms and poor responses to conventional therapies. Recent studies have highlighted the presence of adipocytes within airway walls, which correlates positively with body mass index (BMI). However, the role of adipocytes in asthma pathogenesis remains largely unknown. This study aims to explore their potential contribution to airway fibrosis, a progressive form of the disease, through fibroblast-to-myofibroblast transition (FMT). In vitro coculture models were developed to investigate the interactions between adipocytes (derived from patients with and without obesity) and fibroblasts (from patients with and without asthma) on FMT. Proteomic and multiplex analyses were used to identify potential mediators of adipocyte-induced FMT. Our data revealed a significant increase in fibrogenic markers, such as alpha-smooth muscle actin and vimentin, in fibroblasts cocultured with obese (Ob) adipocytes. Notably, this transition was more pronounced in asthmatic fibroblasts compared with healthy fibroblasts. Proteomic profiling of cocultured Ob-adipocytes and asthmatic fibroblasts identified several significantly upregulated proteins linked to the regulation of the transforming growth factor-beta (TGF-β) signaling pathway, including inhibin A, latent TGF-β binding protein 1, thrombospondin 1, and follistatin. The role of TGF-β was further substantiated by multiplex assays, which demonstrated a significant increase in TGF-β and leptin production by Ob-adipocytes following coculture. These findings suggest that Ob-adipocytes may promote FMT in fibroblasts, especially asthmatic fibroblasts, by activating the TGF-β signaling pathway. This highlights a potential mechanism by which obesity exacerbates asthma severity and fibrosis, providing new avenues for therapeutic intervention.NEW & NOTEWORTHY Adipocytes have been found in the airway wall of patients with obesity. This study is the first to show that adipocytes derived from patients with obesity can induce features of airway remodeling that is seen in patients with asthma such as fibroblast-to-myofibroblast transition via the TGF-beta signaling pathway in an indirect mode of cellular communication. This highlights a potential mechanism by which obesity exacerbates asthma severity and fibrosis, providing new avenues for therapeutic intervention.
Humans↗
Decreased insulin binding to adipocytes and circulating monocytes from obese subjects.
UNLABELLED: Insulin binding to isolated adipocytes from 16 normal and 14 obese patients was studied. The data indicated that, as a group, adipocytes from the obese patients bound significantly less insulin than normal. However, of the 14 obese patients, 5 were not hyperinsulinemic and 4 of these 5 subjects had normal insulin binding. These subjects were also younger, and had the onset of obesity in childhood. When these five patients were separated from the original 14 obese patients, enhanced differences in insulin binding to adipocytes were observed when normals and the remaining 9 obese subjects were compared. Similar findings were obtained with isolated circulating mononuclear cells from these same patients. Presumably the five normoinsulinemic obese patients were not insulin-resistant, and, thus, the data indicate that insulin binding to adipocytes was decreased only in insulin-resistant obese patients. This conclusion was strengthened by finding a highly significant correlation (r=-0.71, p less than 0.001) between insulin binding to adipocytes and fasting plasma insulin level, while a weaker correlation (r=-0.49,p less than 0.01) existed between insulin binding and degree of obesity. Finally, when insulin binding to adipocytes and mononuclear cells from the same individual was compared, a significant positive correlation was found (r=0.53,p less than 0.01). IN CONCLUSION: (a) insulin binding to adipocytes and mononuclear cells is decreased in cells from insulin-resistant obese patients; (b) a significant inverse relationship exists between fasting plasma insulin level and insulin binding to adipocytes; and (c) in obesity, events that affect insulin receptors on adipocytes similarly affect insulin receptors on mononuclear cells.
Adipose Tissue↗
Isolation and characterization of cells from rat adipose tissue developing into adipocytes.
To identify cells developing into adipocytes by accumulation of triglyceride, rat epididymal fat pad cells from small rats were exposed to (3)H-labeled chylomicron fatty acids in vivo and then liberated with collagenase. Tissue remnants were removed by filtration and mature fat cells by flotation. Aggregating cells were then removed by filtration through a 25- micro m nylon screen. Further purification of cells labeled in vivo was obtained by removing floating cells from those adhering to the bottom of a culture dish. The adhering cells multiplied to a confluent monolayer when cultured in Medium 199 containing serum, glucose, insulin, and a triglyceride emulsion. The cells then gradually enlarged due to granulation of the cytoplasm by a lipid-staining material. After about 2 weeks these granules had coalesced forming mature adipocytes of typical signet-ring appearance. Free adipocytes could then be recovered from the cultures by collagenase treatment. After about 2 weeks of culture these cells had the same size (about 30 micro m) as adipocytes recovered in the original collagenase preparation of the rat epididymal fat pad. They contained triglyceride lipase activity and incorporated glucose into triglycerides to the same extent as cells developed in vivo but had higher lipoprotein lipase activity. In vitro, heparin in a low concentration, prostaglandin E(1), isobutylmethylxanthine, and cholera toxin markedly promoted the development of these cells into adipocytes. This could be shown to occur almost completely indicating that this fraction of cells was homogeneous and consisted of cells with the capacity to form adipocytes. The duplication time was about 2 days and did not change with subculturing. Preadipocytes could be obtained by density gradient centrifugation, isolating triglyceride-containing cells either directly from the pad or after 3 days in culture. All of these cells developed into adipocytes as described above but did not multiply as readily. It was concluded that cells from the epididymal fat pad from small rats can be isolated in a homogenous fraction that develops in culture into cells of identical morphology and function as adipocytes formed in vivo. The differentiation of these cells into adipocytes may be manipulated in vitro.
Adipose Tissue↗
Influence of genetic obesity in mice on the lipolytic response of isolated adipocytes to isoproterenol and ACTH-(1-24).
The lipolytic response of isolated adipocytes from genetic obese (C57/BL/64 ob/ob) and lean (C57BL/6J +/?) mice to ACTH-(1-24), isoproterenol and glucagon has been studied. The mean cell idameter of adipocytes form ob/ob mice was approximately twice that of lean controls. The adipocytes from obese mice contained on the average approximately six times the amount of triacylglycerol present in the smaller lean mouse adipocyte. Lipolysis was calculated both on a per cell basis (10(5) cells) and per mu mole of triacylglycerol and when expressed on a cell number basis, the larger adipocytes from obese mice showed an ACTH-(1-24) stimulated glycerol release which was quantitatively similar to that of smaller adipocytes from lean mice. When expressed per mu mole of triacylglycerol, the smaller cells from lean animals appeared to be dramatically more responsive to either isoproterenol or ACTH-(1-24). On either basis, ACTH-(1-24) stimulated glycerol release from obese mouse cells was greater than the isoproterenol response. The obese mouse of adipocyte showed selective loss of response to isoproterenol compared to its lean control.
Adipose Tissue↗
Scalable Deep Learning of Histology Images Reveals Genetic and Phenotypic Determinants of Adipocyte Hypertrophy.
BACKGROUND: White adipose tissue dysfunction has emerged as a critical factor in cardiometabolic disease development, yet the cellular microstructure and genetic architecture of adipocyte morphology remain poorly explored. METHODS: We introduce Adipocyte U-Net 2.0, an advanced deep learning method for the semantic segmentation of adipose tissue histology, enabling analysis of over 27 million adipocytes from 2,667 individuals. FINDINGS: Our approach revealed that adipocyte hypertrophy associates with metabolic dysfunction, including increased fasting glucose, glycated hemoglobin, leptin, and triglycerides, with decreased adiponectin and HDL cholesterol levels. Through the largest genome-wide association study of adipocyte size to date (NSubcutaneous = 2,066, NVisceral = 1,878), we identified four genome-wide significant loci: two in sex-combined analysis (rs73184721 in NAALADL2 and rs200047724 in NRXN3) and two female-specific variants (rs140503338 and rs11656704 in ULK2). Notably, these genetic associations showed congruent relationships with cardiometabolic traits, suggesting shared biological mechanisms. INTERPRETATION: Our findings demonstrate the utility of deep learning for adipocyte phenotyping at scale and provide novel insights into the genetic basis of adipocyte morphology and its relationship to metabolic disease.
Journal Article↗
Reductions in glucocorticoid inhibition of glucose oxidation and presumptive glucocorticoid receptor content in rat adipocytes during aging.
Exposure of adipocytes to glucocorticoid hormones in vitro causes inhibition of glucose transport and metabolsim. Maximal inhibition of glucose oxidations is reduced from 42-50 to 22-25 to 5-8% in young, mature, and senescent rat adipocytes, respectively. Percent values also reflect absolute reductions since basal levels of glucose oxidation per cell are constant at all ages. Adipocytes of CD strain rats continue to increase in size throughout their lifespan, while cell size remains constant during the latter 80% of the Wistar adipocyte lifespan. Thus, cellular age, as well as possibly size, seems to be associated with these changes since they occur in adipocytes of both strains. Concentrations as well as absolute numbers of presumptive glucocorticoid receptors per cell are progressively reduced during maturation and aging of adipocytes in both rat strains. Glucocorticoid effects are known to require about 2 h and can be blocked by various antimetabolites during this period, reminiscent of classical steroid receptor-mediated responses. Thus, gradual loss of glucocorticoid receptors from adipocytes during maturation and aging may be related to progressively decreased glucocorticoid responsiveness.
Adipose Tissue↗
Biological properties of antibodies against rat adipocyte intrinsic membrane proteins. Dependence on multivalency for insulin-like activity.
Antisera from rabbits injected with rat adipocyte plasma membranes or intrinsic proteins from such membranes, obtained by a dimethylmaleic anhydride extraction step, mimicked the action of insulin on both glucose transport and lipolysis in intact adipocytes. Biological activity in both types of antisera was mediated by immunoglobulin binding to one or more intrinsic proteins of the adipocyte plasma membrane since fat cells were unresponsive to all antisera absorbed with dimethylmaleic anhydride-extracted membranes. Acid treatment of immunoprecipitates released antibodies which activated glucose uptake and reacted with solubilized adipocyte membranes on immunodiffusion plates. The biologically active immunoglobulin preparations failed to form immunoprecipitin lines when tested against membranes from brain, liver, lung, muscle, kidney, and spleen. Insulin-sensitive glucose uptake in rat soleus muscle did not respond to the antisera. The antibodies activated hexose uptake into fat cells and reacted with solubilized adipocyte membranes on immunodiffusion plates when rat or mouse adipocytes were studied, but not when monkey fat cells were used. The anti-membrane antibody preparations readily activated hexose uptake in trypsinized fat cells which had lost the capacity to bind or respond to insulin. These data are consistent with the concept previously proposed (Pillion, D.J., and Czech, M.P. (1978) J. Biol. Chem. 253, 3761-3764) that the anti-membrane immunoglobulins do not interact with the insulin binding site of the insulin receptor. Monovalent Fab fragments of the biologically active antisera, prepared by papain digestion of the native anti-membrane immunoglobulins, were ineffective in enhancing glucose uptake in adipocytes. However, biological activity of the anti-membrane Fab fragments was restored by the addition of goat anti-rabbit Fab antisera to cells treated with the Fab fraction. Anti-rabbit Fab antisera alone or in combination with Fab fragments prepared from control rabbit sera exhibited no biological activity. These results demonstrate that the ability of anti-membrane antisera to mimic the biological activity of insulin on isolated fat cells is critically dependent on immunoglobulin binding to one or more intrinsic plasma membrane proteins and the multivalent nature of immunoglobulin structure.
Adipose Tissue↗
Acquisition of increased hormone sensitivity during in vitro adipocyte development.
Murine 3T3-L1 fibroblasts enter a differentiation program subsequent to prolonged maintenance in the confluent state and develop into adipocytes. The hormone sensitivity of adenylate cyclase and the physiological responsiveness to insulin were compared in 3T3-L1 preadipocytes and adipocytes. The following observations, comprising several distinct categories of hormone responsiveness, were made. (a) (2.5 micronM) isoproterenol stimulated adenylate cyclase 15-fold in adipocyte homogenates, but only 2.5-fold in preadipocyte preparations, suggesting a considerable magnification in beta-adrenergic responsiveness during development. (b) A totally new control element, adrenocorticotropic hormone responsiveness, was incorporated into the adenylate cyclase system of the adipocytes. (c) Sensitivity to prostaglandin E1 was observed in both preadipocytes and adipocytes, but no change in responsiveness could be detected in the differentiated cells. (d) Glucagon-sensitive adenylate cyclase could not be detected in either preadipocytes or adipocytes. (e) Both preadipocytes and adipocytes possess considerable insulin binding activity, but near physiological levels of insulin stimulate the conversion of glucose to CO2 and lipid only in the differentiated cells.
Adenylyl Cyclases↗
ADH1B, the adipocyte-enriched alcohol dehydrogenase, plays an essential, cell-autonomous role in human adipogenesis.
Alcohol dehydrogenase 1B (ADH1B) is a primate-specific enzyme which, uniquely among the ADH class 1 family, is highly expressed both in adipose tissue and liver. Its expression in adipose tissue is reduced in obesity and increased by insulin stimulation. Interference with ADH1B expression has also been reported to impair adipocyte function. To better understand the role of ADH1B in adipocytes, we used CRISPR/Cas9 to delete ADH1B in human adipose stem cells (ASC). Cells lacking ADH1B failed to differentiate into mature adipocytes manifested by minimal triglyceride accumulation and a marked reduction in expression of established adipocyte markers. As ADH1B is capable of converting retinol to retinoic acid (RA), we conducted rescue experiments. Incubation of ADH1B-deficient preadipocytes with 9-cis-RA, but not with all-transretinol, significantly rescued their ability to accumulate lipids and express markers of adipocyte differentiation. A homozygous missense variant in ADH1B (p.Arg313Cys) was found in a patient with congenital lipodystrophy of unknown cause. This variant significantly impaired the protein's dimerization, enzymatic activity, and its ability to rescue differentiation in ADH1B-deficient ASC. The allele frequency of this variant in the Middle Eastern population suggests that it is unlikely to be a fully penetrant cause of severe lipodystrophy. In conclusion, ADH1B appears to play an unexpected, crucial and cell-autonomous role in human adipocyte differentiation by serving as a necessary source of endogenous retinoic acid.
Humans↗
Adipocyte-derived CRAMP-neutrophil serine protease interaction axis regulates innate cutaneous defense against Staphylococcus aureus.
Dermal adipocytes have emerged as active participants in cutaneous host defense. In parallel, adipocyte hypertrophy and hyperplasia-driven obesity has become a global public health priority and is strongly associated with increased risk and severity of bacterial infections. Here, we established and optimized two complementary S. aureus infection models-epidermal and subcutaneous-and in combination with diet-induced (HFD) and genetic (ob/ob) obesity, to systematically evaluate cathelin-related antimicrobial peptide (CRAMP) expression in adipocytes and its crosstalk with neutrophils. Obese mice displayed impaired cutaneous defense despite marked thickening of the fat layer, characterized by attenuated induction of adipocyte CRAMP and reduced local antibacterial activity. In vitro, CRAMP followed a biphasic pattern during adipocyte differentiation-upregulated at early stages but diminished with advanced maturation and lipid accumulation. Mechanistically, neutrophils processed adipocyte-derived CRAMP via serine proteases to generate shorter peptides with enhanced antibacterial activity. Collectively, these findings identify a CRAMP-neutrophil (serine protease) interaction axis as a key amplifier of cutaneous innate immunity and provide mechanistic insight into obesity-associated susceptibility to skin infection, suggesting potential avenues for targeted intervention.
Animals↗
Insulin binding and glucose metabolism in adipocytes of streptozotocin-diabetic rats.
To investigate the mechanism of the cellular insulin insensitivity of diabetic rats, insulin binding, glucose transport, and glucose oxidation were studied in adipocytes from streptozotocin-diabetic rats. Increased insulin binding was found in cells from diabetic rats, and this was due to an increased number of insulin receptors rather than a change in receptor affinity. Basal and insulin-stimulated glucose oxidation was decreased in adipocytes from diabetic rats when the data are expressed in absolute terms or as percent increased above basal. Although the absolute rate of basal and insulin-stimulated glucose transport was decreased in adipocytes from diabetic rats, the percent increase above basal of insulin-stimulated glucose transport was not decreased. In conclusion, although the cellular insulin insensitivity exists in adipocytes from diabetic rats, the number of insulin receptors was increased, coupling between insulin receptors and the glucose transport system is intact in adipocytes from diabetic rats, and a defect in intracellular glucose metabolism rather than glucose transport plays a major role in the insulin insensitivity of adipocytes from diabetic rats.
Adipose Tissue↗
The effects of spontaneous obesity on insulin binding, glucose transport, and glucose oxidation of isolated rat adipocytes.
UNLABELLED: We have studied insulin, binding, glucose transport, and glucose oxidation, using large adipocytes isolated from older, fatter rats (greater than 12-mo-old, greater than 550 g), and smaller cells obtained from younger, leaner animals (4-5-wk-old, 120-160 g). At media glucose levels less than 5 mM, basal (absence of insulin) rates of glucose oxidation are comparable in both groups of cells. However, in the presence of insulin, the increase in glucose oxidation is much greater in the smaller cells. Maximally effective insulin levels could not overcome the defect in glucose oxidation by larger cells, and thus, even though studies of insulin binding demonstrated a 30-40% decrease in insulin receptors on the larger cells, it is probable that the defect in glucose oxidation is distal to the insulin receptor. Glucose transport was assessed by direct measurement of 2-deoxy glucose uptake. Basal levels of uptake were greater for the larger cells, whereas at maximally effective insulin concentrations, rates of 2-deoxy glucose uptake were the same for both groups of cells. Thus, in the presence of maximally effective levels of insulin, the apparent Km (2.3-2.7 mM) and Vmax values (2.6 and 2.7 nmol/10(5) cells per min) of 2-deoxy glucose uptake were comparable, indicating that the glucose transport system of the larger cells was intact. However, at submaximal levels of insulin, small adipocytes took up more 2-deoxy glucose than larger cells. These findings represent a rightward shift in the insulin dose-response curve in the cells from the older, fatter animals, and this is the predicted functional sequelae of the observed decrease in insulin receptors. Finally, when the amount of insulin bound was plotted as a function of 2-deoxy glucose uptake, no difference was seen between both groups of cells. This indicates that coupling between insulin receptor complexes and the glucose transport system is intact in large adipocytes, and is further evidence that a defect(s) in intracellular glucose metabolism is responsible for the decrease in glucose oxidation of adipocytes from older, fatter rats. IN CONCLUSION: (a) insulin-mediated glucose oxidation is markedly decreased in large adipocytes from older, fatter rats, and since this decrease cannot be corrected by maximally effective insulin levels, the defect is probably distal to the insulin receptor; (b) the glucose transport system is basically normal in large adipocytes; (c) insulin binding to receptors is decreased in large cells and the functional sequelae of this decrease in insulin binding i.e., a rightward shift in the insulin dose-response curve for 2-deoxy glucose uptake, was observed, and (d) since the decreased rates of insulin-mediated glucose oxidation can not be attributed to changes in insulin receptors or to changes in glucose transport, an intracellular defect in glucose metabolism is suggested.
Adipose Tissue↗
Effects of age and obesity on insulin binding to isolated adipocytes.
UNLABELLED: We have measured insulin binding to isolated adipocytes prepared from rats of varying ages and body weights. The ability of adipocytes to bind insulin progressively decreases as animals get older and fatter until about 70 days of age and 300 g body weight are reached. From this point on further decreases in insulin binding to adipocytes were not seen as rats got older and fatter. Analysis of the data indicated that this decrease in insulin binding could be accounted for by decreased numbers of insulin receptor sites per cell. Further studies were conducted in which animals were allowed to age, but obesity was prevented or reversed by hypocaloric diets. In these experiments decreased insulin binding was either prevented or restored to normal by the negative caloric state, indicating that age had no appreciable effect on the ability of adipocytes to bind insulin. The influence of the obesity associated variables-hyperinsulinemia and increased fat cell size-on insulin binding was also examined. These latter studies are consistent with the concept that elevated in vivo plasma insulin levels lead to decreased insulin receptors, and further suggest a role for additonal factors in regulating the adipocyte insulin receptor. IN CONCLUSION: 1. Decreased insulin binding to adipocytes is closely related to the obese state. 2. This decrease in insulin binding can be accounted for by decreased numbers of receptor sites per cell, and 3. The mecahnism(s) underlying this decreased insulin binding are complex and probably represents an effect of more than one variable.
Adipose Tissue↗
Effects of antiinsulin receptor autoantibody on the metabolism of rat adipocytes.
We have studied the effects of the serum from a patient with an unusual form of diabetic syndrome with extreme insulin resistance on the metabolism of rat adipocytes in vitro. This serum and IgG fractions from it inhibited the [125I]insulin binding to isolated adipocytes and stimulated the 2-deoxyglucose uptake, glucose oxidation, and the incorporation of amino acids into protein. In addition, these fractions inhibited the lipolysis induced by beta 1-24 ACTH in isolated adipocytes. The insulin-like effects of this serum and the effects of insulin were not additive at their maximal concentrations. The inhibition of [125I]insulin binding was due to a decrease in receptor affinity rather than to a change in receptor number by Scatchard plot analysis. Both the inhibition of insulin binding and the insulin-like effects on rat adipocytes were neutralized by antihuman IgG. In addition, these insulin-like effects were abolished by trypsin treatment of adipocytes. These facts suggest that this serum has a circulating antibody directed at or near the insulin receptor itself and that this antibody mimics the insulin effect on rat adipocytes by binding to the insulin receptor in vitro.
Adipose Tissue↗