Rat Fat Cells Research Articles

WITHDRAWN: The impact of chromium supplementation on carbohydrates, liver function, kidney function and testosterone levels in diabetic rats

Trivalent chromium (Cr III) can improve glucose absorption in fat cells of rats, and chromium supplementation may have therapeutic value for type II diabetes. In this study the impact of chromium supplementation on biochemical including carbohydrates, lipids, kidney function, liver function, and testosterone was examined in a diabetic rat. Wistar albino rats were divided into three groups of 10 rats each. Rats in Group A were untreated and served as the non-diabetic control. Rats in Group B and C were treated with a 60 mg/kg streptozotocin intraperitoneally injection to induce diabetes and those in Group C also received 120 mcg chromium picolinate. Induction of diabetes 3 days after streptozotocin (STZ) treatment was confirmed in Groups B and C by measurement of fasting blood suger levels with a glucometer. Animals having blood sugar levels >200 mg/dL were considered to be diabetic. rats with diabetes also exhibited other diabetes symptoms such as polyuria, polydipsia and glycosuria. The control Group A non-diabetic and diabetic STZ Group B had average glucose levels of 139.0±27.0 mg/dl and 460.9±122.0 mg/dl, respectively. Chromium supplementation substantially decreased glucose levels relative to the diabetes group to 251.9±30.0 mg/dl. For lipid profiles, chromium supplementation was associated with significant reductions in HDL levels and in potassium levels in kidney function tests. Testosterone levels were significantly increased with chromium supplementation. Taken together, chromium supplementation acts at various levels to mitigate diabetes symptoms as reflected by reduced glucose levels, HDL levels and potassium levels, as well as increased testosterone levels.

The correlation between percent liver weight (PLW) and percent fat cells (PFC) of liver in HFD-STZ induced diabetic rats in comparison with insulin, metformin and combination treated diabetic rats.

Background: The study was designed to evaluate short term effects of commonly used antidiabetic drugs on liver. The objective of the study is to observe and analyze the correlation between percent liver weight and percent liver fat cells in control rats and diabetic, insulin, metformin and insulin-metformin combination treated high fat diet (HFD) / Streptozotocin (STZ) induced diabetic albino rats. Study Design: Experimental comparative study. Setting: Institute of Bio Medical Sciences (IBMS), Dow University of Health Sciences (DUHS), Ojha Campus, Karachi. Period: December 2014 to May 2015. Materials and Methods: The experimental study was conducted on 50 albino wistar rats. 10 rats served as control rats while rest of the rats were experimentally induced for diabetes type 2 and were then randomized into 5 groups. One group was treated with insulin, one with metformin, and the one group with insulin-metformin combination for 4 weeks. All the treated groups were compared with untreated and control group. At the end of experiment, all the rats were sacrificed and livers were isolated and weighed. Percent liver weight calculated. Liver cut sections were processed and stained to analyze the correlation in percent fat cells in liver percent liver weight and in each treated and untreated diabetic groups, then the results were compared with control rats. Results: Data is analyzed by using SPSS Version 22. Pearson correlation was used to identify correlation between the percent liver weight and percent fat cells in liver of control, treated and untreated diabetic groups. Significant and positive correlation (p-value < 0.01) in insulin treated group of diabetic rats was observed indicating that insulin has a role in causing fatty liver. Conclusion: Insulin treated diabetic group shows a significant positive correlation between percent fat cells of liver and percent liver weight.

Peran kecambah kacang hijau (Phaseolus radiatus (L.)) pada sel lemak retroperitoneal tikus Sprague Dawley yang diberi diet tinggi lemak

The role of mung bean sprouts (Phaseolus radiatus (L.)) on retroperitoneal fat cells of Sprague Dawley rats fed a high-fat dietBackground: The tendency of current lifestyles with high consumption patterns of fat is one of the factors causing obesity which is a risk of cardiovascular disease. Prevention of cardiovascular disease can be done by adopting a dietary pattern that is rich in antioxidants including consumption of sources of vitamin E. Sprouts from mung beans contain vitamin E and phytochemicals rich in antioxidants, so they can be used as an alternative to prevent hyperlipidemia sourced from daily functional food.Objective: To assess the effects of mung bean sprouts on retroperitoneal fat weight, cell number and cell diameter in rats fed high-fat feed.Method: This research is an experimental study with a post-test design with the control group. Thirty-four male Sprague Dawley rats ± 2 months old were divided into five groups, group I (standard feed), group II (high-fat feed), group III (high-fat feed and intervention of feeding tube of mung bean sprout 0.67 g/ 200 g BW), group IV (high fat feed and intervention of feeding tube of mung bean sprout 1.34 g / 200 g BW), and group V (high-fat feed and 23 IU dose of vitamin E supplement with feeding tube). After adaptation for three days, the intervention was carried out for four weeks. Analysis of fat weight, fat cell number, and fat cell diameter were done after the treatments. Data analysis using the One-Way ANOVA test. Results: Mung bean sprout dose of 1.34 g given for 4 weeks did not significantly decrease fat weight and cell number, but it decreased the diameter of retroperitoneal fat cells.Conclusion: Mung bean sprouts dose 1.34 g was better than a dose of 0.67 g and vitamin E supplementation in reducing the diameter of retroperitoneal fat cells in rats fed a high-fat diet.

Insulin Controls Triacylglycerol Synthesis through Control of Glycerol Metabolism and Despite Increased Lipogenesis.

Under normoxic conditions, adipocytes in primary culture convert huge amounts of glucose to lactate and glycerol. This “wasting” of glucose may help to diminish hyperglycemia. Given the importance of insulin in the metabolism, we have studied how it affects adipocyte response to varying glucose levels, and whether the high basal conversion of glucose to 3-carbon fragments is affected by insulin. Rat fat cells were incubated for 24 h in the presence or absence of 175 nM insulin and 3.5, 7, or 14 mM glucose; half of the wells contained 14C-glucose. We analyzed glucose label fate, medium metabolites, and the expression of key genes controlling glucose and lipid metabolism. Insulin increased both glucose uptake and the flow of carbon through glycolysis and lipogenesis. Lactate excretion was related to medium glucose levels, which agrees with the purported role of disposing excess (circulating) glucose. When medium glucose was low, most basal glycerol came from lipolysis, but when glucose was high, release of glycerol via breakup of glycerol-3P was predominant. Although insulin promotes lipogenesis, it also limited the synthesis of glycerol-3P from glucose and its incorporation into acyl-glycerols. We assume that this is a mechanism of adipose tissue defense to avoid crippling fat accumulation which has not yet been described.

Effects of short-term fasting and pharmacological activation of AMPK on metabolism of rat adipocytes

AMP-activated protein kinase (AMPK) is a key intracellular energy sensor and regulates processes associated with energy metabolism. In the present study, effects of AICAR, a pharmacological activator of AMPK, on metabolism of adipocytes of non-fasted and 12-h fasted rats were compared. It was shown that in fat cells of control rats, epinephrine- and dibutyryl-cAMP-induced lipolysis was markedly reduced in the presence of AICAR. However, in adipocytes of fasted animals, the lipolytic response was not significantly affected by AICAR. Moreover, in cells of control rats, the inhibitory effect of insulin on epinephrine-induced lipolysis was markedly deepened in the presence of AICAR. However, this effect was not shown in fat cells of fasted rats. This indicates that pharmacological activation of AMPK by AICAR influences metabolism of adipocytes of non-fasted rats, however, AICAR fails to affect metabolism of these cells under conditions of fasting.

Antilipolytic effects of 1,8-naphthyridine derivatives β-adrenoceptor antagonists in rat white adipocytes.

The rat fat cell β-adrenoceptors were investigated by studying the effects of new 1,8-naphthyridine derivatives synthesized starting from 7-amino-2-chloro-3-phenyl-1,8-naphthyridine on lipolysis induced by isoprenaline, and alprenolol. Lipolysis induced by isoprenaline agonist was competitively antagonized by the 1,8-naphthyridine analogue with a 7-hydroxy-2-(4'-methoxybenzylamine)-6-nitro-3-phenyl substituent designated as 3. In contrast, 10, 50, and 100μm of 7-methoxy and 7-ethoxy derivatives did not modify the concentration-response curve of isoprenaline. A rightward shift of the curve was, however, observed with 50μm of a 7-methoxy-2-(4'-methoxybenzylamine)-6-amino-3-phenyl substituent designated as 10. The selective β1 -AR antagonist, 7-hydroxy-4-morpholinomethyl-2-piperazino-1,8-naphthyridine slightly reduced isoprenaline-induced lipolysis only at high doses. Alprenolol-mediated lipolytic effect was antagonized by derivative 3, 10 and the selective β3 -AR antagonist SR 59,230A, but resistant to the selective β1 -AR antagonist 7-hydroxy-4-morpholinomethyl-2-piperazino-1,8-naphthyridine. The results provide preliminary pharmacological evidence for the antilipolytic effect of the newly synthesized 1,8-naphthyridine derivatives on rat fat cells. The analogues designated as 3 and 10 were the most potent antagonists of this series.

Dietary fructo-oligosaccharides improve insulin sensitivity along with the suppression of adipocytokine secretion from mesenteric fat cells in rats

Short-chain fructo-oligosaccharides (FOS) are known to have beneficial effects on health. However, the effects of FOS on insulin resistance have not been fully clarified. We observed the effects of FOS feeding on insulin sensitivity and adipocytokine release from abdominal adipocytes in weaning rats. Male Sprague-Dawley rats, 3 weeks old, were divided into three groups and fed a sucrose-based American Institute of Nutrition (AIN)-93 growth diet (control), the control diet containing 5% FOS for 5 weeks (FOS-5wk) or the control diet for 2 weeks followed by the 5% FOS diet for 3 weeks (FOS-3wk). Tail blood was collected after fasting for 9h on day 33 of feeding, and glucose and insulin levels were measured. On the last day, rats were anaesthetised and killed after the collection of aortic blood. Small- and large-intestinal mesenteric fat tissues were immediately excised, and the release of adiponectin, leptin and TNF-α was evaluated from the subsequently isolated adipocytes. The weight of the large-intestinal mesenteric fat, fasting blood insulin level and homeostatic model assessment for insulin resistance decreased in a time-dependent manner, and were much lower in the FOS-5wk group than in the control group. These values were correlated with aortic blood leptin levels. The secretion rate of leptin from the isolated mesenteric adipocytes in the small intestine, but not in the large intestine, was lower in the FOS-fed groups than in the control group. In conclusion, FOS feeding improved insulin sensitivity accompanied by the reduction in large-intestinal fat mass and leptin secretion from the mesenteric adipocytes of the small intestine.

Lipogenic enzyme activities and glucose uptake in fat tissue of dyslipemic, insulin-resistant rats: Effects of fish oil

Objective The purposes of the present work were twofold: (1) investigate same mechanisms involved in the development of fat cell hypertrophy in the experimental model of dyslipidemia and whole-body insulin resistance induced in rats chronically fed a sucrose-rich diet (SRD); and (2) analyze the possible beneficial effect of fish oil on these mechanisms. Methods For 6 mo, male Wistar rats received a sucrose-rich diet (62.5% w/w sucrose, 8% corn oil) or a control diet in which sucrose was replaced by starch. After this period, the sucrose-fed animals were divided randomly into two groups: the first one continued with the same diet up to 8 mo and the second one received the same diet, but with corn oil replaced by 7% fish oil + 1 % corn oil. Rats were fed with this diet for the next 2 mo. Results Although an enlarged fat cell lipolysis and an impaired insulin-stimulated glucose uptake were present in the fat cells of SRD-fed rats, an increase of several key enzymes of the novo lipogenesis could be one of the possible mechanisms involved in visceral adiposity. The addition of dietary fish oil restored or improved the above abnormalities. Conclusion This study shows possible mechanisms conditioning the influence of nutrients on the development and management of dyslipidemia, insulin sensitivity, and fat cell accretion, all abnormalities present in the metabolic syndrome.

Hormonal sensitivity of brown fat cells of fetal rats in monolayer culture.

The primary monolayer culture of brown fat cells was performed with the brown adipose tissue of fetal rats as the material. Brown fat cells in the culture were highly sensitive to some hormones. Insulin had a marked effect of lipogenesis and it made the cells contain large multilocular lipid droplets. Lipolysis is also mediated by hormones, e.g., epinephrine or ACTH etc., and lipolytic process was controlled through cyclic AMP system. Brown fat cells of fetal rats in monolayer culture seem to be a suitable material for long-term experiment of lipogenesis and lipolysis.

Effect of antibody-mediated crosslinking of insulin on its bioactivity and receptor binding.

Precipitating anti-insulin antibodies or anti-insulin IgG/anti-IgG complexes bind insulin in a highly aggregated form and thus should preferably be capable of inducing receptor aggregation, which has recently been suggested to be a precondition for insulin bioactivity. We, therefore, studied the influence of antibody-mediated crosslinking of insulin on the glucose conversion into CO2 in rat fat cells and glycogen synthesis in rat liver cells. As far as possible receptor-bound insulin was measured in parallel. Insulin bound to antibodies with low insulin precipitating capacity had no or little bioactivity and receptor reactivity on fat cells. The bioactivity, however, could be restored in part by addition of a second antibody. On liver cells, second antibody-mediated crosslinking of insulin-antibody complexes resulted in an enhancement of receptor reactivity, and insulin bioactivity of such crosslinked immune complexes was demonstrable. An insulin-precipitating antiserum was shown to form insulin-antibody complexes with significant bioactivity in fat cells which correlated with their receptor binding. In each case antibodies had no or little effect in the absence of insulin. Our data suggest that insulin neutralization by antibodies can be compensated by crosslinking the insulin-antibody complexes or by formation of big complexes precipitating by themselves. This is probably due to the induction of receptor aggregation.

Anti-lipase and lipolytic activities of ursolic acid isolated from the roots of Actinidia arguta

The aim of this study was to investigate the anti-obestic effects of ursolic acid isolated from the roots of Actinidia arguta, as well as the mechanism of action of this compound. This was conducted by testing whether ursolic acid inhibited the elevation of the rat plasma triacylglycerol levels after oral administration of a lipid emulsion containing corn oil in rats. Ursolic acid prevented the elevation of plasma triacylglycerol levels 2 h after oral administration of the lipid emulsion at a dose of 100 mg/kg. Furthermore, ursolic acid inhibited phosphodiesterase activity in vitro with an IC(50) of 51.21 muM and enhanced lipolysis in rat fat cells. We suggest that the inhibitory effects of ursolic acid, isolated from the roots of A. arguta, on obesity, might be attributable to the inhibition of lipid absorption through the inhibition of pancreatic lipase and by enhancing lipolysis in fat cells.

Fat redistribution and adipocyte transformation in uninephrectomized rats

Dyslipidemia complicates renal function leading to disturbances of major homeostatic organs in the body. Here we examined the effect of chronic renal dysfunction induced by uninephrectomy on fat redistribution and lipid peroxidation in rats treated with an angiotensin-converting enzyme (ACE) inhibitor (lisinopril) for up to 10 months. Uninephrectomized rats developed fat redistribution and hypercholesterolemia typical of chronic renal failure when compared with sham-operated rats or lisinopril-treated uninephrectomized rats. The weight of the peri-renal fat was significantly less in the untreated compared to the lisinopril-treated uninephrectomized rats or those rats with a sham operation. We also found that there was a shift of heat-protecting unilocular adipocytes to heat-producing multilocular fat cells in the untreated uninephrectomized rats. Similarly in these rats we found a shift of subcutaneous and visceral fat to ectopic fat with excessive lipid accumulation and lipofuscin pigmentation. Lisinopril treatment prevented fat redistribution or transformation and lipid peroxidation. This study shows that ACE inhibition may prevent the fat anomalies associated with chronic renal dysfunction.

Iodohydroxybenzylpindolol binding to beta-adrenergic receptors of diabetic and control rat adipocytes' crude membrane.

We have characterized the binding of [125I]-Iodohydroxybenzylpindolol to rat adipocytes' crude membrane. The binding was rapid, reaching equilibrium within 19 min. Binding of [125I]-Iodohydroxybenzylpindolol was saturable with 9 nM. Half-maximal saturation provided an estimated Kd of 2.42 nM. The order for 125IHYP displacement by various compounds was (-)-propranolol (-)-isoproterenol greater than (-)-epinephrine greater than (-)-norepinephrine. [125I]-Iodohydroxybenzylpindolol binding was more sensitive to L-propranolol inhibition in crude membrane prepared from diabetic rat fat cells than in those prepared from controls. The basal cAMP level was identical in diabetic and control rat crude membrane. Isoproterenol increased the cAMP level in diabetic more than in control rats.

Lipolysis Induced by Segment Wall Extract from Satsuma Mandarin Orange (Citrus unshu Mark)

The lipolysis induced by Satsuma mandarin orange (Citrus unshu Mark) was investigated using rat fat cells. Peel or segment wall extract from Satsuma mandarin orange induced the lipolysis in a concentration-dependent manner, whereas juice sac extract did not induce the lipolysis. High concentration of synephrine, which is an adrenergic amine, was detected in the peel or segment wall extract, whereas it was not detected in the juice sac extract. The segment wall extracts from Iyokan and orange had high lipolytic activity, whereas the extracts from grapefruit and lemon did not have lipolytic activity. The beta-antagonist inhibited the lipolysis elicited by the segment wall extract from Satsuma mandarin orange, whereas alpha-antagonist did not inhibit the lipolysis induced by the segment wall. The lipolysis induced by the segment wall was considerably higher in the visceral fat cells when compared to the subcutaneous fat cells. These results suggest that the segment wall, an edible fraction, from Satsuma mandarin orange might be useful as a functional food, especially as a fat-reducing material.

Lack of the effect of mycotoxins–aflatoxin B 1 and ochratoxin A on some functions of rat adipocytes

Mycotoxins–aflatoxin B 1 (AFB 1) and ochratoxin A (OTA)—compounds which are strong carcinogenic, mutagenic and cytotoxic factors—are also known to evoke a decrease of food intake and body weight gains. The purpose of our study was to determine the direct influence of AFB 1 and OTA incubated with isolated rat fat cells on the lipogenesis, lipolysis and leptin secretion. Adipocytes were isolated from the epididymal fat tissue by the collagenase digestion. Toxins used at concentrations 1, 10 and 100 μM were incubated for 90 min with adipocytes. Basal and insulin-stimulated lipogenesis—determined by the measure of [U– 14C]glucose conversion to total lipids—was abated by AFB 1 only at the highest concentration. At two lower ones, AFB 1 did not affect the process. OTA at all used concentrations decreased insulin-stimulated lipogenesis but the effect was not dose-dependent. The lipolysis was determined by the measure of glycerol release from adipocytes. The basal lipolysis was unchanged by both toxins. The epinephrine-stimulated lipolysis was intensified by AFB 1 only at the highest concentration, however, the process was not altered by OTA. The antilipolytic action of insulin was unaffected by both compounds (10 μM). To determine the influence of the tested toxins on leptin secretion, adipocytes were incubated for 120 min in the presence of glucose and insulin as stimulators of hormone secretion. AFB 1 and OTA added to the incubation medium (1, 10 and 100 μM) had no significant influence on the leptin release. The results obtained in this experiment demonstrate that adipocytes are susceptible to the direct action of AFB 1 and OTA. This susceptibility is, however, rather weak and is exhibited by a slight restriction of the lipogenesis (in the case of both toxins) and by a slight increase of the lipolysis (in the case of AFB 1).

NoIn VitroEffects of Fatty Acids on Glucose Uptake, Lipolysis or Insulin Signaling in Rat Adipocytes

Elevated plasma levels of free fatty acids (FFA) can produce insulin resistance in skeletal muscle tissue and liver and, together with alterations in beta-cell function, this has been referred to as lipotoxicity. This study explores the effects of FFAs on insulin action in rat adipocytes. Cells were incubated 4 or 24 h with or without an unsaturated FFA, oleate or a saturated FFA, palmitate (0.6 and 1.5 mM, respectively). After the culture period, cells were washed and insulin effects on glucose uptake and lipolysis as well as cellular content of insulin signaling proteins (IRS-1, PI3-kinase, PKB and phosphorylated PKB) and the insulin regulated glucose transporter GLUT4 were measured. No significant differences were found in basal or insulin-stimulated glucose uptake in FFA-treated cells compared to control cells, regardless of fatty acid concentration or incubation period. Moreover, there were no significant alterations in the expression of IRS-1, PI3-kinase, PKB and GLUT4 following FFA exposure. Insulin's ability to stimulate PKB phosphorylation was also left intact. Nor did we find any alterations following FFA exposure in basal or cAMP-stimulated lipolysis or in the ability of insulin to inhibit lipolysis. The results indicate that oleate or palmitate does not directly influence insulin action to stimulate glucose uptake and inhibit lipolysis in rat fat cells. Thus, lipotoxicity does not seem to occur in the fat tissue itself.

Measurement in vivo of the survival rate in autologous adipocyte transplantation.

Up until now, research on fat cells has been unable to prove their survival rate objectively in vivo. In this article, the first application of the cell surface marker PKH26 in the fat cells of rats is reported. In a study of 48 Lewis rats, this method enabled the objective stereometry of viable and necrotic grafts after variable follow-up times in groups of eight animals each. The best survival rate was 30.41 percent, and the best implantation site was the interscapular subcutis. During follow-up, a characteristic change in size of the viable fat cells matched the in vitro findings of various investigators. Because of the surface marking, it could be proved that the viable cells found after 6 months were transplanted cells that had undergone a cycle of fat deprivation and regaining. This is proof of the cell survival theory postulated by Peer in 1950.

Characterization of semicarbazide-sensitive amine oxidase in human subcutaneous adipocytes and search for novel functions.

Numerous studies have characterized semicarbazide-sensitive amine oxidase activity (SSAO) in rat fat cells but this oxidase is scarcely documented in human adipose tissue. Our aim was to further characterize SSAO in human adipose tissue (activity, mRNA and protein abundance) and to investigate whether SSAO activity can interplay with glucose and lipid metabolism in human adipocytes via the hydrogen peroxide it generates. Polyclonal antibodies directed against bovine lung SSAO allowed the detection of a substantial amount of immunoreactive protein (apparent molecular mass 100 kDa) in human subcutaneous adipocytes from either mammary or abdominal fat depots. A 4-kb mRNA was detected in fat depots using a cDNA probe designed from the placenta SSAO sequence. Almost all the oxidation of benzylamine found in adipose tissue homogenates was due to fat cells and was located in the adipocyte membrane fraction. The oxidation of benzylamine and methylamine were similar and totally inhibited by semicarbazide or hydralazine but resistant to pargyline. Histamine was poorly oxidized. Benzylamine and methylamine dose-dependently stimulated glucose transport in intact adipocytes. This insulin-like effect of amines did not increase in the presence of 0.1 mM vanadate but was inhibited by semicarbazide and antioxidants. Benzylamine and methylamine also exhibited antilipolytic effects, with complete inhibition of lipolysis at 1 mM. These results show that fat cells from non-obese subjects express a membrane-bound SSAO which readily oxidizes exogenous amines, generates hydrogen peroxide and exerts short-term insulin-like actions on glucose and lipid metabolism.

Inhibition of rat fat cell lipolysis by monoamine oxidase and semicarbazide-sensitive amine oxidase substrates

It has been demonstrated that amine oxidase substrates stimulate glucose transport in cardiomyocytes and adipocytes, promote adipogenesis in pre-adipose cell lines and lower blood glucose in diabetic rats. These insulin-like effects are dependent on amine oxidation by semicarbazide-sensitive amine oxidase or by monoamine oxidase. The present study aimed to investigate whether amine oxidase substrates also exhibit another insulin-like property, the inhibition of lipolysis. We therefore tested the influence of tyramine and benzylamine on lipolytic activity in rat adipocytes. These amines did not modify basal lipolysis but dose-dependently counteracted the stimulation induced by lipolytic agents. The response to 10 nM isoprenaline was totally inhibited by tyramine 1 mM. The blockade produced by inhibition of amine oxidase activity or by 1 mM glutathione suggested that the generation of oxidative species, which occurs during amine oxidation, was involved in tyramine antilipolytic effect. Among the products resulting from amine oxidation, only hydrogen peroxide was antilipolytic in a manner that was potentiated by vanadate, as for tyramine or benzylamine. Antilipolytic responses to tyramine and to insulin were sensitive to wortmannin. These data suggest that inhibition of lipolysis is a novel insulin-like effect of amine oxidase substrates which is mediated by hydrogen peroxide generated during amine oxidation.

Epidermal Growth Factor and Transforming Growth Factor α Mimic the Effects of Insulin in Human Fat Cells and Augment Downstream Signaling in Insulin Resistance

The ability of the growth factors epidermal growth factor (EGF), transforming growth factor alpha, and platelet-derived growth factor to exert insulin-like effects on glucose transport and lipolysis were examined in human and rat fat cells. No effects were found in rat fat cells, whereas EGF (EC(50) for glucose transport approximately 0.02 nm) and transforming growth factor alpha (EC(50) approximately 0.2 nm), but not platelet-derived growth factor, mimicked the effects of insulin (EC(50) approximately 0.2 nm) on both pathways. EGF receptors, but not EGF, were abundantly expressed in human fat cells as well as in human skeletal muscle. EGF increased the tyrosine phosphorylation of several proteins (the EGF receptor, insulin receptor substrate (IRS)-1, IRS-2, and Grb2-associated binder 1), whereas Shc and Gab2 were only weakly and inconsistently phosphorylated. p85, the regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase), was also found to associate with all of these docking molecules, showing that EGF activated PI 3-kinase pools that were additional to those of insulin. EGF and/or insulin increased protein kinase B/Akt serine phosphorylation to a similar extent, whereas mitogen-activated protein kinase phosphorylation was more pronounced for EGF than for insulin. The impaired insulin-stimulated downstream signaling, measured as protein kinase B/Akt serine phosphorylation, in insulin-resistant cells (Type 2 diabetes) was improved by the addition of EGF. Thus, EGF receptors, but not EGF, are abundantly expressed in human fat cells and skeletal muscle. EGF mimics the effects of insulin on both the metabolic and mitogenic pathways but utilize in part different signaling pathways. Both insulin and EGF increase the tyrosine phosphorylation and activation of IRS-1 and IRS-2, whereas EGF is also capable of activating additional PI 3-kinase pools and, thus, can augment the downstream signaling of insulin in insulin-resistant states like Type 2 diabetes.