This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ranganathan, S. Articles by Kern, P. A. Search for Related Content PubMed PubMed Citation Articles by Ranganathan, S. Articles by Kern, P. A.

Lack of Effect of Leptin on Glucose Transport, Lipoprotein Lipase, and Insulin Action in Adipose and Muscle Cells¹

Department of Medicine, Division of Endocrinology, University of Arkansas for Medical Sciences, and The John L. McClellan VA Medical Center (S.R., P.A.K.), Little Rock, Arkansas 72205; and Veterans Administration Medical Center and Department of Medicine (T.P.C., R.R.H., S.M.), University of California, San Diego, California 92023

Address all correspondence and requests for reprints to: Philip A. Kern, M.D., Associate Chief of Staff-Research, John L. McClellan Memorial Veterans’ Hospital, 4300 West 7th Street, Little Rock, Arkansas 72205. E-mail: kernphilipa{at}exchange.uams.edu

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
The effect of leptin on glucose transport, lipogenesis, and lipoprotein lipase activity was studied in cultured rat adipocytes and 3T3-L1 adipocytes. Leptin had no effect on basal and insulin stimulated glucose transport in isolated adipocytes from the rat and the genetically obese mouse. The incorporation of glucose into lipids was also unaffected. Lipoprotein lipase (LPL) activity remained unchanged in response to leptin in these cells, as well as in minced adipose tissue. Leptin also had no effect on both basal and insulin-stimulated glucose transport in cultured rat and human skeletal muscle cells. These studies showed that leptin had no effect on glucose transport, lipoprotein lipase activity, and insulin action in fat and muscle cells in vitro.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
LEPTIN is the peptide product of the obese (ob) gene, and leptin secretion by adipocytes plays a key role in the regulation of energy metabolism and body weight. The genetically obese ob/ob mouse produces a defective leptin, resulting in massive obesity and hyperphagia (1). In addition to obesity, the ob/ob mouse has insulin resistant diabetes and defects in fat metabolism, thermogenesis, and reproduction. Whether the diabetes found in ob/ob mice is related to obesity alone, or to some other consequence of the defective leptin, is not known.

When ob/ob mice were treated ip with recombinant leptin, they not only ate less food and lost weight, but were also found to have decreased plasma insulin and glucose levels (2, 3, 4). It was also observed that very low doses of leptin were able to normalize blood glucose and body temperature without having any effect on food intake and body weight. Together with data demonstrating that the leptin receptor is found in many tissues, these results suggested that leptin may also have peripheral effects not related to satiety.

Several other reports have suggested that leptin has direct metabolic effects on cells. Emilsson et al. (5) have reported that leptin inhibited insulin secretion when added to culture of isolated pancreatic islet cells. In HEPG-2 cells, leptin inhibited insulin-stimulated insulin receptor substrate (IRS-1) tyrosine phosphorylation (6). In contrast to the inhibition of IRS-1 tyrosine phosphorylation, Takahashi et al. (7) have reported that leptin induced tyrosine phosphorylation of several proteins, including STAT-1, in renal adenocarcinoma cells. In cultured adipocytes, Bai et al. (8) demonstrated that leptin inhibited the insulin and dexamethasone-stimulated synthesis of fatty acids and total lipids. All these studies clearly indicate that leptin has direct effects on other metabolic pathways, in addition to its effect on the hypothalamus in regulating food intake.

In this report, we studied the direct effects of leptin on insulin action by examining glucose transport and lipoprotein lipase in differentiated preadipocytes from rat and 3T3-L1 cells, as well as in isolated adipocytes from the rat and the ob/ob mouse. We found no effect of leptin on insulin action, even in the ob/ob adipocytes, which would be expected to be very sensitive to exogenous leptin. Leptin also did not have any effect on the basal and insulin-stimulated glucose transport in rat and human skeletal muscle cells.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
Chemicals and supplies
Recombinant leptin was obtained from Amgen (Thousand Oaks, CA) and Research Diagnostics, Inc. (Flanders, NJ). Both of these products were shown to be biologically active in two different obese mouse models, by the suppliers. Deoxyglucose, 3-isobutyl 1-methylxanthine, BSA, and dexamethasone were obtained from Sigma Chemicals (St. Louis, MO). 2-Deoxy (³H)glucose and U-(¹⁴C)-D-glucose were obtained from Dupont NEN (Boston, MA). Media, FBS, and all reagents for tissue culture were purchased from GIBCO (Grand Island, NY). Human recombinant insulin (Novolin) was obtained from Novo Nordisk (Princeton, NJ). All other reagents were of the best available grade.

Animals and adipocyte cultures
Male Sprague-Dawley rats, weighing between 180 and 220 g, were killed after an overnight fast, and the epididymal adipose tissue was removed immediately. Adipocytes were isolated from the adipose tissue by a collagenase digestion and were cultured for up to 24 h, as described previously (9). The same methods were used to obtain adipocytes from ob/ob mice, which were purchased from Jackson labs and were killed at 6–8 weeks of age.

Cell culture and differentiation
3T3-L1 cells were grown on 75-cm² culture flasks (Costar, Irvine, CA), in DMEM (Gibco BRL), supplemented with 10% FCS and an antibiotic mixture containing penicillin and streptomycin. For the experiments, cells were cultured in 12-well dishes, were grown to confluence, and were differentiated by incubation in DMEM medium with 10% FBS containing 1 µg/ml insulin, 0.5 mM isobutylmethylxanthine, and 0.25 µM dexamethasone for 48 h, according to the methods described by Clancy and Czech (10). Cells were then maintained in DMEM, containing 10% serum and 1 µg/ml insulin, for 3–4 days. Medium was then changed to DMEM, containing 10% FBS, for 2–3 days.

The stromal vascular fraction containing the preadipocytes was prepared from the collagenase digestion of the adipose tissue, as described previously (11), cultured in 12-well dishes, and differentiated using the methods described for 3T3-L1 cells.

The L6 cell culture was a gift from Dr. Amira Klip (The Hospital for Sick Children, Toronto, Ontario, Canada). These cells were maintained in MEM, supplemented with 2% FBS, and an antibiotic mixture containing penicillin, streptomycin, and amphotericin, according to previous methods (12). For experiments, the cells were seeded in 12-well dishes and grown for 5–7 days, when they became differentiated into myotubes.

The procedures for culturing the muscle cells from human muscle biopsies and for the measurement of glucose transport were the same as those described by Ciaraldi et al. (13).

Glucose transport
3T3-L1 cells. The differentiated cells were treated with leptin (0.5 µg/ml) for 24 h before the day of the experiment. Before glucose transport assay, the cells were preincubated with 1 mL serum-free DMEM for 4 h. The cells were then washed twice with Krebs-Ringer phosphate buffer and incubated in the same buffer for 30 min. To determine insulin-stimulated glucose transport, insulin (10 nM) was added, and the incubation was continued for another 30 min. 2-Deoxy (³H)glucose was added to produce a final concentration of 0.1 mM (1 µCi/100 nmol) and incubated for 10 min at room temperature. Leptin was added back to the respective wells during the transport assay. The medium was aspirated, and the cells were washed three times with PBS and dissolved in 0.5 ml of 0.2 N NaOH. Radioactivity in the lysate was determined by scintillation counting. Cell protein content was determined using BioRad reagent. Non-carrier-mediated transport of deoxyglucose was determined in the presence of 10 µM cytochalasin B.

Isolated mature adipocytes. Glucose transport in adipocytes, isolated from fat pads from rat and ob/ob mouse, was determined using the procedure described by Foley et al. (14). In this method, the uptake of (U-¹⁴C)-D-glucose was measured at very low glucose concentration (300 nM). One ml of the cell suspension (5% lipocrit in DMEM) was incubated with leptin (0.5 µg/ml) for 1–24 h, as specified in the table or figure legends. At the end of this incubation, the cells were washed three times with PBS and incubated with 10 nM insulin for 60 min and then with 0.1 µCi of (¹⁴C)-glucose (300 nM) for another 60 min at 37 C with shaking. Leptin was added back to the respective tubes of cells during these incubations. Then, 200 µl of the reaction mixture was transferred to a long microfuge tube containing 100 µl silicone oil. The tubes were then centrifuged for 20 sec, and top phase, containing the adipocytes, was cut and transferred to a scintillation vial to determine the radioactivity. Glucose transport was expressed as nanomoles of glucose.

L6 cells. Deoxy (³H)glucose transport was assayed in these cells using the same method described for 3T3 cells, except that the concentration of deoxyglucose used was 10 µM.

Measurement of lipoprotein lipase (LPL)
LPL was measured, in the medium, after release with heparin, as described previously (15). The culture medium was removed from the dishes, and 1 ml of fresh medium containing heparin (10 u/ml) was added and incubated for 60 min at room temperature.

LPL catalytic activity was measured using an emulsified ³H-triolein substrate, as described previously (16). After incubation of 100 µl of sample with 100 µl of substrate for 60 min, liberated ³H-fatty acids were separated from the reaction mixture using the method of Belfrage (17). The LPL activity is expressed as nanomoles of fatty acids released in 60 min.

Glucose incorporation into lipids. Incorporation of ¹⁴C-D-glucose into lipids was determined using the methods described by Lima et al. (9). Briefly, the adipocytes were washed and resuspended to 5% lipocrit. One ml of the cell suspension was incubated in a 20-ml plastic scintillation vial with leptin for 3 h and then with 0.1 µCi of (U-¹⁴C)D-glucose (5 mM), with or without insulin (10 nM), for 1 or 2 h, as indicated, at 37 C with shaking. At the end of this incubation, the reaction mixture was treated with 5 ml Dole’s reagent (isopropanol:n-heptane:H₂SO₄, 4:1:0.1, vol/vol) for lipid extraction (18).

Statistics. Data are presented as the mean ±SD. Student’s t test was used to assess the significance of effects of leptin on the various parameters studied. P < 0.05 was the accepted level of significance.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Glucose transport. To determine whether leptin affected glucose transport, 3T3-L1 cells were differentiated as described under Materials and Methods and were treated with leptin (0.5 µg/ml) for 24 h, after which, glucose transport was measured in the presence and absence of insulin. As shown in Fig. 1, insulin stimulated a 3- to 4-fold increase in glucose transport. In the cells treated with leptin, there was no effect on either basal or insulin-stimulated glucose transport.

View larger version (28K): [in this window] [in a new window]   Figure 1. Effect of leptin on 2-deoxyglucose transport in 3T3-L1 adipocytes. The cells were plated in 12-well dishes and allowed to differentiate using dexamethasone, isobutyl dimethylxanthine, and insulin. The differentiated cells were treated with leptin (0.5 µg/ml) for 24 h, and then the basal and insulin-stimulated transport of 2-deoxy(3H)glucose were determined (, basal; , insulin-stimulated). All the experimental details are as described in Materials and Methods. The values are expressed as picomoles of deoxyglucose per well. The protein concentration in the cells did not change after treatment with leptin. Each value is an average and SD from six determinations.

View larger version (32K): [in this window] [in a new window]   Figure 2. Effect of leptin on (14C)-D-glucose transport in rat adipocytes. Adipocytes were isolated from epididymal fat pads using collagenase digestion, then washed and resuspended in DMEM, to give a lipocrit of 5%. One milliliter of this suspension was incubated with or without leptin (0.5 µg/ml) for the indicated time period at 37 C in an incubator. At the end of this period, the cells were washed three times with PBS and incubated with 10 nM insulin for 60 min and then with 0.1 µCi of (14C) glucose (300 nM) for another 60 min at 37 C with shaking. Leptin was added back to the respective tubes during this incubation. Further details of the procedure are described in the text. Each value is the mean and SD from triplicate determinations.

View larger version (35K): [in this window] [in a new window]   Figure 3. Effect of leptin on 2-deoxyglucose transport in L6 muscle cells. The cells were cultured in 12-well dishes, and after differentiation, they were treated with leptin (0.5 µg/ml) for 24 or 48 h, as indicated. The uptake of 2-deoxyglucose was determined at the end of this period. All the experimental details are as described in Materials and Methods. The values are expressed as picomoles of 2-deoxyglucose per milligram of cell protein.

View larger version (37K): [in this window] [in a new window]   Figure 4. Effect of leptin on LPL activity differentiated rat preadipocytes. The preadipocytes from rat adipose tissue were isolated, cultured in 12-well dishes, and allowed to differentiate using dexamethasone, isobutyl dimethylxanthine, and insulin, as described in Materials and Methods. The cells were then treated with leptin (0.5 µg/ml) for 24 h and 10 nM insulin overnight. Heparin-releasable LPL activity was determined, and the results are expressed as nanomoles of fatty acids released per milligram of cell protein. Each value represents the mean and SD from triplicate determinations.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

Several reports have suggested that leptin has direct effects on peripheral cells. Cohen et al. (6) found that leptin (48 ng/ml) inhibited insulin-stimulated IRS-1 tyrosine phosphorylation in HEPG-2 cells. This inhibitory effect would be expected to impair insulin action in liver, leading to elevated hepatic glucose output. In another study, Takahashi et al. (7) showed that leptin induced tyrosine phosphorylation of several proteins, including STAT-1, in renal adenocarcinoma cells. In adipocytes, Bai et al. (8) showed that leptin inhibited the insulin and dexamethasone-stimulated synthesis of fatty acids and total lipids. Such an inhibition of lipid synthesis would go against a role for leptin as an anabolic hormone. Emilsson et al. (5) described a leptin-mediated inhibition of insulin secretion by isolated pancreatic islet cells. Leptin also serves as the adipose-brain signal for the onset of sexual maturation (19, 20) and is part of the signal for the pulsatile release of gonadotropins. In a recent study, it was reported that leptin inhibited the FSH and IGF-I-stimulated progesterone production by rat ovarian granulosa cells (21). These studies provide evidence that leptin may have direct effects on other metabolic pathways, in addition to its effect on the hypothalamus in regulating food intake.

In this study, we searched for an effect of leptin on both basal and insulin-stimulated glucose or lipid metabolism in adipocytes and muscle cells, but found no effect. Because the cell lines, such as 3T3-L1 cells, are sometimes not representative of primary cultures, we examined glucose transport, [¹⁴C]-incorporation into lipids, and LPL activity in rat adipocytes. In addition, we examined the effects of leptin on ob/ob cells. Because these cells are not exposed to leptin in vivo, they would likely be most sensitive to leptin, just as the ob/ob mouse is much more sensitive to the appetite-suppression effects of injected leptin. The lack of effect of leptin on insulin, glucose transport on LPL activity in adipocytes in our studies indicates that leptin-mediated partial reversal of diabetes is probably mediated through the hypothalamus, involving decreased food intake and stimulation of the autonomous nervous system. In different studies reported in the literature, the time required to detect the metabolic changes in response to leptin varied from 10 min to 2 days. In our studies, we have incubated the cells with leptin for up to 48 h, wherever possible. In the case of isolated adipocytes, we used 3–24 h incubation because it was difficult to keep them functionally intact beyond 24 h.

A recent study described a leptin-mediated inhibition of insulin action in adipocytes (22). In another recent report, leptin was shown to increase basal glucose transport and glycogen synthesis in C₂C₁₂ muscle cells (23). In both these studies, the source of leptin was different from that used by us, although it is not clear why this should be important, given that both preparations are recombinant and pure and have been tested for bioactivity. In the study by Müller et al. (22), adipocytes were cultured with leptin in a medium containing high glucose (25 mM) and adenosine, an insulin agonist, and this may have affected the data. In another recent study, Mick et al. (24) have observed that leptin has no effect on glucose transport and insulin action in isolated rat adipocytes.

Leptin receptors exist in two major forms, the long one with the complete intracellular domain and the short one with truncated intracellular domain. The long form is thought to mediate the biological effects of leptin and is expressed in large amounts in the choroid plexus and the hypothalamus and, to a smaller extent, in lung and kidney. Using PCR, Lee et al. (25) demonstrated the presence of several forms of the leptin receptor in adipose tissue. Although the short form of the leptin receptor is predominant (26) in the adipose tissue, detectable levels of the long functional form have been reported in one study (25) but not in another (5). Yamashita et al. (27) have recently reported that the short form of the leptin receptor can also perform signal transduction, when expressed in Chinese hamster ovary cells, although (to a lesser extent, compared with the long form). The physiological significance of this finding in these genetically altered cells needs to be determined. Therefore, it is not clear whether adipocytes have adequate levels of functional leptin receptors to interact with leptin and to be metabolically regulated.

Although Ghilardi et al. (26) have shown that skeletal muscle does not express the functional form of leptin receptor, Liu et al. (28) have reported that leptin inhibited glycogen synthesis in soleus muscle from ob/ob mice in vitro. On the contrary, Berti et al. (23) have shown that leptin increased glycogen synthesis in cultured muscle cells. Muoio et al. (29) have found that leptin stimulated fatty acid oxidation and inhibited triglyceride synthesis in isolated muscle preparation. Therefore, the peripheral effect of leptin on the metabolism in muscle is uncertain.

In summary, we examined the effects of leptin on glucose transport, glucose metabolism, and LPL activity in adipocytes and cultured muscle cells, and we found no effect. These data suggest that the predominant effects of leptin are mediated through its action on the hypothalamus and not through direct effects on muscle or adipose tissue.

	Acknowledgments

 
We thank Ms. Leslie Carter for assistance in the experiments with human skeletal muscle cells.

	Footnotes

 
¹ This work was supported by a Merit Review Grant from the Veterans Administration, Grant DK-39176 from the National Institutes of Health, and support from the Research Services of the Veterans Administration Medical Center, San Diego, CA.

Received August 6, 1997.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM 1994 Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432[CrossRef][Medline]
2. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM 1995 Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269:543–546[Abstract/Free Full Text]
3. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P 1995 Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269:546–549[Abstract/Free Full Text]
4. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F 1995 Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269:540–543[Abstract/Free Full Text]
5. Emilsson V, Liu Y-L, Cawthorne MA, Morton NM, Davenport M 1997 Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion. Diabetes 46:313–316[Abstract]
6. Cohen B, Novick D, Rubinstein M 1996 Modulation of insulin activities by leptin. Science 274:1185–1188[Abstract/Free Full Text]
7. Takahashi Y, Okimura Y, Mizuno I, Takahashi T, Kaji H, Uchiyama T, Abe H, Chihara K 1996 leptin induces tyrosine phosphorylation of cellular proteins including STAT-1 in human renal adenocarcinoma cells, ACHN. Biochem Biophys Res Commun 228:859–864[CrossRef][Medline]
8. Bai Y, Zhang S, Kim K, Lee J, Kim K-H 1996 Obese gene expression alters the ability of 30A5 preadipocytes to respond to lipogenic hormones. J Biol Chem 271:13939–13942[Abstract/Free Full Text]
9. Lima FB, Bao S, Garvey WT 1994 Biological actions of insulin are differentially regulated by glucose and insulin in primary cultured adipocytes, chronic ability to increase glycogen synthase activity. Diabetes 43:53–62[Abstract]
10. Clancy BM, Czech MP 1990 Hexose transport stimulation and membrane redistribution of glucose transporter isoforms in response to cholera toxin, dibutyryl cyclic AMP and insulin 3T3–L1 adipocytes. J Biol Chem 265:12434–12443[Abstract/Free Full Text]
11. Kern PA, Eckel RH 1984 Absence of lipoprotein lipase in cultured human adipose stromal cells. Arteriosclerosis 4:232–237[Abstract/Free Full Text]
12. Mitsumoto Y, Klip A 1992 Developmental regulation of the subcellular distribution and glycosylation of GLUT1 and GLUT4 glucose transporters during myogenesis of L6 muscle cells. J Biol Chem 267:4957–4962[Abstract/Free Full Text]
13. Ciaraldi TP, Abrams L, Nikoulina S, Mudaliar S, Henry RR 1995 Glucose transport in cultured human skeletal muscle cells. Regulation by insulin and glucose in nondiabetic and non-insulin-dependent diabetes mellitus subjects. J Clin Invest 96:2820–2827
14. Foley JE, Kashiwagi A, Verso MA, Reaven G, Andrews J 1983 Improvement in in vitro insulin action after one month of insulin therapy in obese noninsulin-dependent Diabetics. J Clin Invest 72:1901–1909
15. Kern PA, Marshall S, Eckel RH 1985 Regulation of lipoprotein lipase in primary cultures of isolated human adipocytes. J Clin Invest 75:199–208
16. Nilsson-Ehle P, Schotz MC 1976 A stable radioactive substrate emulsion for assay of lipoprotein lipase. J Lipid Res 17:536–541[Abstract]
17. Belfrage P, Vaughn M 1969 Simple liquid-liquid partition system for isolation of labeled oleic acid from mixture with glycerides. J Lipid Res 10:341–344[Abstract]
18. Dole VP, Meinertz H 1960 Microdetermination of long chain fatty acids in plasma and tissues. J Biol Chem 235:2595–2599[Free Full Text]
19. Mantzoros CS, Flier JS, Rogol AD 1997 A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. 5. Rising leptin levels may signal the onset of puberty. J Clin Endocrinol Metab 82:1066–1070[Abstract/Free Full Text]
20. Ahima RS, Dushay J, Flier SN, Prabakaran D, Flier JS 1997 Leptin accelerates the onset of puberty in normal female mice. J Clin Invest 99:391–395[Medline]
21. Zachow RJ, Magoffin DA 1996 Direct intraovarian effects of leptin: impairment of the synergistic action of insulin-like growth factor-I on follicle-stimulating hormone-dependent estradiol-17b production by rat ovarian granulosa cells. Endocrinology 138:847–850[Abstract/Free Full Text]
22. Müller G, Ertl J, Gerl M, Preibisch G 1997 Leptin impairs metabolic actions of insulin in isolated rat adipocytes. J Biol Chem 272:10585–10593[Abstract/Free Full Text]
23. Berti L, Kellerer M, Capp E, Haring HU 1997 Leptin stimulates glucose transport and glycogen synthesis in C₂C₁₂ myotubes: evidence for a PI3-kinase mediated effect. Diabetologia 40:606–609[CrossRef][Medline]
24. Mick G, Vanderbloomer T, Fu CL, McCormick K 1997 Leptin does not effect acute adipocyte glucose metabolism. Diabetes [Suppl 1] 46:863 (Abstract)
25. Lee G-H, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM 1997 Abnormal splicing of the leptin receptor in diabetic mice. Nature 379:632–635
26. Ghilardi N, Ziegler S, Wiestner A, Stoffel R, Heim MH, Skoda RC 1996 Defective STAT signaling by the leptin receptor in diabetic mice. Proc Natl Acad Sci USA 93:6231–6235[Abstract/Free Full Text]
27. Yamashita T, Murakami T, Iida M, Kuwajima M, Shima K 1997 Leptin receptor of Zucker fatty rat performs reduced signal transduction. Diabetes 46:1077–1080[Abstract]
28. Liu Y, Emilsson V, Cawthorne MA 1997 Leptin inhibits glycogen synthesis in the isolated soleus muscle of obese (ob/ob)mice. FEBS Lett 411:351–355[CrossRef][Medline]
29. Muoio DM, Dohn GL, Fiedorek FT, Tapscott EB, Coleman RA 1997 Leptin directly alters lipid partitioning in skeletal muscle. Diabetes 46:1360–1363[Abstract]

This article has been cited by other articles:

				M.-J. Lee, H. Lin, C.-W. Liu, M.-H. Wu, W.-J. Liao, H.-H. Chang, H.-C. Ku, Y.-S. Chien, W.-H. Ding, and Y.-H. Kao Octylphenol stimulates resistin gene expression in 3T3-L1 adipocytes via the estrogen receptor and extracellular signal-regulated kinase pathways Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1542 - C1551. [Abstract] [Full Text] [PDF]

				H. Bays, L. Mandarino, and R. A. DeFronzo Role of the Adipocyte, Free Fatty Acids, and Ectopic Fat in Pathogenesis of Type 2 Diabetes Mellitus: Peroxisomal Proliferator-Activated Receptor Agonists Provide a Rational Therapeutic Approach J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 463 - 478. [Full Text] [PDF]

				C. Perez, C. Fernandez-Galaz, T. Fernandez-Agullo, C. Arribas, A. Andres, M. Ros, and J. M. Carrascosa Leptin Impairs Insulin Signaling in Rat Adipocytes Diabetes, February 1, 2004; 53(2): 347 - 353. [Abstract] [Full Text]

				G. Brabant, H. Nave, B. Mayr, M. Behrend, V. van Harmelen, and P. Arner Secretion of Free and Protein-Bound Leptin from Subcutaneous Adipose Tissue of Lean and Obese Women J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3966 - 3970. [Abstract] [Full Text] [PDF]

				R. B. CEDDIA, H. A. KOISTINEN, J. R. ZIERATH, and G. SWEENEY Analysis of paradoxical observations on the association between leptin and insulin resistance FASEB J, August 1, 2002; 16(10): 1163 - 1176. [Abstract] [Full Text] [PDF]

				G. Sweeney, J. Keen, R. Somwar, D. Konrad, R. Garg, and A. Klip High Leptin Levels Acutely Inhibit Insulin-Stimulated Glucose Uptake without Affecting Glucose Transporter 4 Translocation in L6 Rat Skeletal Muscle Cells Endocrinology, November 1, 2001; 142(11): 4806 - 4812. [Abstract] [Full Text] [PDF]

				K. Arvaniti, D. Richard, F. Picard, and Y. Deshaies Lipid deposition in rats centrally infused with leptin in the presence or absence of corticosterone Am J Physiol Endocrinol Metab, October 1, 2001; 281(4): E809 - E816. [Abstract] [Full Text] [PDF]

				R. Lau, W. D. Blinn, A. Bonen, and D. J. Dyck Stimulatory effects of leptin and muscle contraction on fatty acid metabolism are not additive Am J Physiol Endocrinol Metab, July 1, 2001; 281(1): E122 - E129. [Abstract] [Full Text] [PDF]

				L. O’Rourke, S. J. Yeaman, and P. R. Shepherd Insulin and Leptin Acutely Regulate Cholesterol Ester Metabolism in Macrophages by Novel Signaling Pathways Diabetes, May 1, 2001; 50(5): 955 - 961. [Abstract] [Full Text]

				T. J. Kowalski, S.-M. Liu, R. L. Leibel, and S. C. Chua Jr. Transgenic Complementation of Leptin-Receptor Deficiency: I. Rescue of the Obesity/Diabetes Phenotype of LEPR-Null Mice Expressing a LEPR-B Transgene Diabetes, February 1, 2001; 50(2): 425 - 435. [Abstract] [Full Text]

				G. R. Steinberg and D. J. Dyck Development of leptin resistance in rat soleus muscle in response to high-fat diets Am J Physiol Endocrinol Metab, December 1, 2000; 279(6): E1374 - E1382. [Abstract] [Full Text] [PDF]

				Y.-B. Kim, S. Uotani, D. D. Pierroz, J. S. Flier, and B. B. Kahn In Vivo Administration of Leptin Activates Signal Transduction Directly in Insulin-Sensitive Tissues: Overlapping but Distinct Pathways from Insulin Endocrinology, July 1, 2000; 141(7): 2328 - 2339. [Abstract] [Full Text] [PDF]

				J. M. Bryson, J. L. Phuyal, V. Swan, and I. D. Caterson Leptin has acute effects on glucose and lipid metabolism in both lean and gold thioglucose-obese mice Am J Physiol Endocrinol Metab, September 1, 1999; 277(3): E417 - E422. [Abstract] [Full Text] [PDF]

				R. M. O'Doherty, P. R. Anderson, A. Z. Zhao, K. E. Bornfeldt, and C. B. Newgard Sparing effect of leptin on liver glycogen stores in rats during the fed-to-fasted transition Am J Physiol Endocrinol Metab, September 1, 1999; 277(3): E544 - E550. [Abstract] [Full Text] [PDF]

				L. Poretsky, N. A. Cataldo, Z. Rosenwaks, and L. C. Giudice The Insulin-Related Ovarian Regulatory System in Health and Disease Endocr. Rev., August 1, 1999; 20(4): 535 - 582. [Abstract] [Full Text] [PDF]

				J. Rouru, I. Cusin, K. E. Zakrzewska, B. Jeanrenaud, and F. Rohner-Jeanrenaud Effects of Intravenously Infused Leptin on Insulin Sensitivity and on the Expression of Uncoupling Proteins in Brown Adipose Tissue Endocrinology, August 1, 1999; 140(8): 3688 - 3692. [Abstract] [Full Text]

				P. R. Shepherd and B. B. Kahn Glucose Transporters and Insulin Action -- Implications for Insulin Resistance and Diabetes Mellitus N. Engl. J. Med., July 22, 1999; 341(4): 248 - 257. [Full Text] [PDF]

				H. H. Zhang, S. Kumar, A. H. Barnett, and M. C. Eggo Intrinsic Site-Specific Differences in the Expression of Leptin in Human Adipocytes and Its Autocrine Effects on Glucose Uptake J. Clin. Endocrinol. Metab., July 1, 1999; 84(7): 2550 - 2556. [Abstract] [Full Text]

				J.-l. Wang, N. Chinookoswong, S. Scully, M. Qi, and Z.-Q. Shi Differential Effects of Leptin in Regulation of Tissue Glucose Utilization in Vivo Endocrinology, May 1, 1999; 140(5): 2117 - 2124. [Abstract] [Full Text]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ranganathan, S. Articles by Kern, P. A. Search for Related Content PubMed PubMed Citation Articles by Ranganathan, S. Articles by Kern, P. A.