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Endocrinology Vol. 142, No. 11 4827-4830
Copyright © 2001 by The Endocrine Society

ARTICLES

Leptin Increases the Viability of Isolated Rat Pancreatic Islets by Suppressing Apoptosis

Shigeru Okuya, Katsuya Tanabe, Yukio Tanizawa and Yoshitomo Oka

Third Department of Internal Medicine, Yamaguchi University School of Medicine, Ube, Yamaguchi 755-8505, Japan

Address all correspondence and requests for reprints to: Dr. S. Okuya, Third Department of Internal Medicine, Yamaguchi University School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan. E-mail: okuya{at}po.cc.yamaguchi-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
To test the hypothesis that leptin secreted from adipose tissue is a mediator linking obesity and pancreatic islet hypertrophy, we examined the effects of leptin on proliferative and apoptotic responses in rat islet cells. Rat pancreatic islets were isolated and incubated with 0, 1, 5, or 75 nM leptin for 24 h under serum-deprived conditions. Cell viability was assessed with 2,5-diphenyltetrazolium bromide and trypan blue dye exclusion tests. Cell proliferation and apoptosis were evaluated with 5-bromo-2'-deoxyuridine incorporation into DNA and DNA ladder formation, respectively. Incubation for 24 h with 1 and 5 nM leptin, the concentrations observed in obese subjects, increased the viability of isolated pancreatic islet cells. Five nanomolar concentrations of leptin did not stimulate 5-bromo-2'-deoxyuridine incorporation into incubated islet cells, indicating no influence on cell proliferation, but did inhibit DNA ladder formation, a hallmark of cell apoptosis. Moreover, 5 nM leptin reduced the triglyceride content and suppressed inducible nitric oxide synthase mRNA expression in incubated islets. These results suggest that leptin increased viable cell numbers via suppression of apoptosis in isolated pancreatic islet cells under these experimental conditions. This mechanism might account at least in part for an obesity-induced increase in pancreatic ß-cell mass.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE ob GENE product, leptin, is expressed primarily in adipose tissue and is secreted into the circulation, serving as a satiety factor for the hypothalamus. The amount of leptin mRNA and serum levels of leptin are highly correlated with body fat volume (1). In addition to regulating body weight, leptin influences reproductive, hemopoietic, and metabolic systems (1, 2), suggesting that leptin also has extrahypothalamic, peripheral actions. We and others have reported that leptin receptors are expressed in pancreatic ß-cells and that leptin influences insulin secretion (1, 3, 4). Moreover, we have demonstrated that leptin activates both the MAPK and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) cascade in the pancreatic ß-cell line MIN6, and that leptin increases MIN6 cell proliferation (5). On the other hand, it is well documented that obesity induces hyperinsulinemia and pancreatic ß-cell mass expansion (6). We hypothesized that leptin could be an important, and perhaps distinct, regulator of pancreatic ß-cell mass.

To test the hypothesis that leptin secreted from adipose tissue is a mediator linking obesity and increased pancreatic islet mass, we employed primary rat islets in this study, because the results obtained with the clonal cell line described above might not have physiological relevance. Cell mass size is determined and regulated by cell proliferation and/or apoptosis (6). Leptin has been reported to be involved in the regulation of cell proliferation as well as apoptosis (2, 5, 7, 8). Moreover, leptin reportedly has a lowering effect on triglyceride (TG) content and inducible nitric oxide synthase (iNOS) mRNA expression in islets, both of which are thought to be related to ß-cell apoptosis (9, 10, 11, 12). Herein, we examined the effects of leptin on proliferative and apoptotic responses, TG content, and iNOS mRNA expression of isolated rat islet cells under serum-deprived conditions, as serum contains a variety of cytokines, including leptin.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Pancreatic islet isolation and incubation
Pancreatic islets were isolated from 10-wk-old male Wistar rats using a collagenase digestion technique. Isolated islets were incubated in serum-free RPMI 1640 medium (Life Technologies, Inc., Grand Island, NY) containing 0.5% BSA with or without mouse recombinant leptin (R & D Systems, Inc., Minneapolis, MN) for 24 h at 37 C in a 5% CO2 incubator. Islets were also treated with 1 mM FFA (2:1, oleate/palmitate; Sigma, St. Louis, MO) for 24 h and used as a positive control for apoptosis (12). Our institution’s guidelines for animal care were followed, as well as specific national laws where applicable.

Cell culture
3T3-L1 fibroblasts were routinely cultured in DMEM (Sigma) supplemented with 10% donor calf serum (Tissue Culture Biologicals, Tulare, CA) in an atmosphere of 10% CO2 at 37 C.

Determination of cell viability
Two different methods were used to confirm the effects of leptin or FFA on the viability of isolated pancreatic islet cells.

Colorimetric 2,5-diphenyltetrazolium bromide (MTT) assay. Isolated pancreatic islet cell viability was measured using the MTT assay (5). This assay is based on the cleavage of MTT (Sigma) to form formazan by mitochondrial respiration in viable cells. After 24-h treatment with 0, 1, 5, or 75 nM leptin or 1 mM FFA, cells were incubated with MTT (final concentration, 0.2 mg/ml) for 4 h. After being mixed with HCl-isopropanol, the OD was measured at 570 and 630 nm as test and reference wavelengths, respectively.

Dye exclusion assay. Viable cell ratios were determined using the dye exclusion assay (13). This assay is based on the exclusion of trypan blue dye (Sigma) from viable cells. After 24-h treatment, pancreatic islet cells were dispersed with trypsin/EDTA, then incubated with trypan blue (final concentration, 0.2 mg/ml) for 1 min. Cells were observed under a microscope and counted as stained and nonstained cells separately, and the viable cell ratio was calculated.

Cell proliferation assay
Cell proliferation was assessed by an immunocytochemical system using a Cell Proliferation Kit (Amersham Pharmacia Biotech, Little Chalfont, UK) to detect 5-bromo-2'-deoxyuridine (BrdU) incorporated into cellular DNA. Isolated pancreatic islet cells were incubated as described above. After 18-h treatment, cells were incubated with BrdU for an additional 6 h at 37 C. After the total 24-h incubation, cells were dispersed with trypsin/EDTA, fixed in acid-ethanol, and incubated with anti-BrdU/nuclease solution. After a brief wash, the cells were incubated with peroxidase antimouse IgG, washed, and detected with diaminobenzidine. The cells were observed under a microscope and photographed. Meanwhile, 3T3-L1 fibroblasts were also treated with BrdU for 6 h and used as a positive control for cell proliferation.

DNA fragmentation assay
The DNA fragmentation nucleosomal ladder is a widely recognized hallmark of apoptotic cell death (14). Nucleosomal ladder detection of apoptotic cells was performed using an ApoAlert ligation-mediated PCR (LM-PCR) (14) ladder assay kit (CLONTECH Laboratories, Inc., Palo Alto, CA), because the number of apoptotic cells was presumed to be small. Among its advantages, the LM-PCR assay is said to be semiquantitative, allowing comparison of the relative extent of apoptosis in different samples. Isolated pancreatic islet cells were incubated as described above. After 24-h treatment, genomic DNA was routinely extracted and quantified. The assay was initiated with equal amounts of DNA, originating from different samples. Dephosphorylated adaptors were ligated to the 5'-phosphorylated blunt ends of the DNA fragments generated during apoptosis; the 5'-protruding ends of the molecules were filled in using a DNA polymerase. The adaptor then serves as a primer for PCR in which the fragments with adaptors on both ends are exponentially amplified. The resulting nucleosomal ladder was visualized on an agarose/ethidium bromide gel, digitally scanned, and quantified using NIH Image 1.62.

TG content of islets
After 24-h treatment under each condition, 250 islets were sonicated in 50 µl sodium phosphate buffer. The homogenate was then mixed with isopropyl alcohol for the extraction of lipids. TGs were measured by the acetyl-acetone method using TG-Test Wako (Wako Pure Chemical Industries, Ltd., Osaka, Japan).

Semiquantitation of iNOS mRNA by RT-PCR
Total RNA was extracted from 250 islets cultured under each condition. First strand cDNA was obtained using oligo(deoxythymidine)12–18-primed RT of each total RNA sample. Primers used to amplify iNOS cDNA were 5'-CGT GTG CCT GCT GCC TTC CTG CTG T-3' and 5'-GTA ATC CTC AAC CTG CTC CTC ACT C-3' (nucleotides 2679–2703 and 3326–3350, 672-bp fragment) (9). As an internal standard, ß-actin cDNA was also amplified using primers 5'-TTG TAA CCA ACT GGG ACG ATA TGG-3' and 5'-GAT CTT GAT CTT CAT GGT GCT AGG-3' (nucleotides 1552–1575 and 2991–2844, 764-bp fragment) (9). A mixture of synthesized first strand cDNA mixture was employed for PCR amplification using the amplification conditions described previously (9). The amplification products were analyzed on an agarose/ethidium bromide gel, digitally scanned, and quantified using NIH Image 1.62. iNOS mRNA levels were expressed as the ratio of iNOS to ß-actin band signal intensities.

Statistical analysis
The statistical significance of differences in measured quantities was determined by t test. P < 0.05 was considered statistically significant. Average values were expressed as the mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
In this study we used serum-deprived conditions because serum contains a variety of cytokines and growth factors, including leptin. Cell viability, as assessed by MTT assay and trypan blue dye exclusion tests, was significantly increased in isolated islet cells incubated with 1 and 5 nM leptin for 24 h (Fig. 1Go, A and B). After a 24-h incubation with 5 nM leptin, viable cells were increased by 15 ± 2% (P < 0.05) in the MTT assay and by 19 ± 8% (P < 0.05) in the trypan blue dye exclusion test compared with the results obtained in the absence of leptin. At 75 nM leptin, a nearly supraphysiological concentration, no stimulatory effects on cell viability were seen (Fig. 1Go, A and B). We also employed treatment with 1 mM FFA, which reportedly induces ß-cell apoptosis (12). After a 24-h incubation with 1 mM FFA, viable cells were decreased by 15 ± 3% (P < 0.05) in the MTT assay and by 20 ± 5% (P < 0.05) in the trypan blue dye exclusion test. We then assessed BrdU incorporation into DNA in cells incubated for 24 h with or without 5 nM leptin. No BrdU incorporation was detected in either the absence or presence of 5 nM leptin (Fig. 1CGo). Using the same detection method, BrdU incorporation into DNA in 3T3-L1 fibroblasts cultured in DMEM with 10% donor calf serum was clearly demonstrated, i.e. the nucleus was stained blue-black (Fig. 1DGo). Thus, the experimental procedure was confirmed to have been performed properly.



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  		Figure 1. Leptin increased and FFA decreased the viability of isolated islet cells, as assessed by MTT assay (A) and trypan blue dye exclusion test (B). Isolated rat islet cells were incubated with 0, 1, 5, or 75 nM leptin or 1 mM FFA in serum-free RPMI 1640 medium containing 0.5% BSA for 24 h. The results, expressed as fold increases above the value obtained in the absence of both leptin and FFA, are the mean ± SEM of eight experiments, with each measurement performed in triplicate. *, P < 0.05. C, Cell proliferation assay, evaluating BrdU incorporation into DNA in isolated islet cells during 24-h incubation with or without 5 nM leptin. No BrdU incorporation was detected in either the absence or presence of 5 nM leptin. Essentially the same results were obtained in three other experiments. D, BrdU incorporation into DNA of 3T3-L1 fibroblasts was clearly demonstrated in parallel experiments; the nucleus was stained blue-black. The arrowheads indicate positive cells.

 
While performing these experiments, we observed, using a phase contrast microscope, that some incubated cells exhibited intranuclear chromatin condensation and cell surface blebbing, morphological characteristics of apoptosis (15) (Fig. 2AGo). Therefore, we attempted to detect the DNA fragmentation nucleosomal ladder as an index of apoptosis. Under the above experimental conditions, we had expected that only a small percentage of cells would be apoptotic, or that apoptosis would occur asynchronously, making genomic DNA ladders undetectable by direct electrophoresis. We therefore employed the LM-PCR assay (14), which uses PCR to specifically amplify the nucleosomal ladder, such that apoptosis, even that occurring in a small percentage of cells, would be readily detectable. This sensitive assay demonstrated 5 nM leptin to significantly inhibit DNA ladder formation by 33 ± 4% (P < 0.01), whereas 1 mM FFA accelerated it by 40 ± 8% (P < 0.01; Fig. 2Go, B and C). Similar results were obtained with 1 nM leptin.



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  		Figure 2. A, Phase contrast microscopic examination of isolated pancreatic islet cells incubated with or without leptin for 24 h. The cell, indicated by an arrowhead, exhibited intranuclear chromatin condensation and cell surface blebbing, morphological changes characteristic of apoptosis. B, LM-PCR DNA ladder assay. Representative DNA ladders are shown. A 5-nM concentration of leptin inhibited DNA fragmentation of isolated pancreatic islet cells during serum-deprived incubation, whereas 1 mM FFA increased DNA fragmentation. C, LM-PCR DNA ladder assay. The DNA ladder density was quantitated using NIH Image 1.62, and the results, expressed as fold change compared to the value in control cells (in the absence of both leptin and FFA), are the mean ± SEM of five experiments. *, P < 0.01.

 
In addition, we attempted to determine whether the antiapoptotic effect of this leptin is mediated by lipopenia and/or a reduction in NO production. Therefore, the effects of 5 nM leptin on TG content and iNOS mRNA expression in islets cultured for 24 h were also examined. We observed a significant decline in TG content in the leptin-cultured islets and a significant TG increment in the FFA-cultured islets (Table 1Go). The semiquantitative RT-PCR analysis of iNOS mRNA expression in incubated islets showed the iNOS/ß-actin mRNA ratios in 5 nM leptin- and 1 mM FFA-cultured islets to be 52% and 147% of the control value (without effectors), respectively (Fig. 3Go, A and B). Namely, leptin decreased the iNOS message, whereas FFA increased it significantly. The ß-actin PCR product amounts were used as an RNA loading control. (Fig. 3AGo).


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  		Table 1. TG contents of isolated pancreatic islets incubated for 24 h

 


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  		Figure 3. RT-PCR analysis of iNOS and ß-actin mRNA expression. A, Representative iNOS and ß-actin RT-PCR products are shown. Leptin (5 nM) inhibited iNOS mRNA expression in isolated pancreatic islet cells during serum-deprived incubation, whereas 1 mM FFA increased the iNOS mRNA level. B, Mean iNOS/ß-actin mRNA ratios. The RT-PCR product density was quantitated using NIH Image 1.62, and the results are expressed as the mean ± SEM of three experiments. *, P < 0.05 vs. no effector.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present results demonstrate that adding recombinant leptin at 1 and 5 nM increases the viability of isolated rat pancreatic islet cells. Furthermore, this greater viability was not associated with increased cell proliferation, but, rather, with suppressed DNA fragmentation under serum-deprived conditions. Leptin also reduced TG content and suppressed iNOS mRNA expression in rat pancreatic islet cells. It has been reported that serum starvation per se induces cell apoptosis (15). We, however, employed serum-deprived conditions, because serum contains various cytokines, including leptin, and our goal was to verify the effects of leptin itself on proliferation and/or apoptosis of isolated rat islet cells. The experimental condition does not necessarily represent the in vivo condition, and the possibility that the effects we observed did not represent physiological changes cannot be ruled out. The present results, however, suggest that leptin at the concentrations reported in obese subjects increases viable cell number by suppressing apoptosis of pancreatic islet cells.

We previously demonstrated that the long form of the leptin receptor, Ob-Rb, thought to be the fully functional form (4), is expressed in both isolated pancreatic islets and the pancreatic ß-cell line MIN6 (3), and that leptin activates both the MAPK and the JAK-STAT cascade in MIN6 cells (5). Several reports have indicated that MAPK and JAK-STAT activation are involved in antiapoptotic responses to some cytokines, such as granulocyte-macrophage colony-stimulating factor (16) and erythropoietin (17). These findings and our results suggest that leptin exerts antiapoptotic effects on the pancreatic ß-cell line MIN6 through the MAPK and/or the JAK-STAT cascade. In the present study we observed apoptosis to have a remarkable relationship with both TG content and iNOS mRNA expression in pancreatic islets. Several reports revealed the TG content in pancreatic ß-cells to correlate strongly with cell apoptosis, i.e. lipoapoptosis (8, 12). An increase in TG content up-regulates iNOS, and the resulting increased production of NO induces the apoptosis of islet cells (9, 10). A high TG content was reported to increase de novo ceramide synthesis (12), which perhaps increases iNOS expression and lowers expression of the antiapoptotic factor Bcl-2 (8), thereby leading to apoptosis. These reports and our present results suggest that the antiapoptotic effect of leptin on pancreatic islet cells is mediated at least in part by reduction of endogenous TG. Further studies are needed to elucidate the precise mechanism underlying the antiapoptotic effects of leptin.

Although we and others have reported that leptin induces proliferation of MIN6 (5) and fetal pancreatic islet (7) cells, the present study showed leptin to exert no detectable proliferative effects on cells isolated from 10-wk-old rat islets. This might be due to the lower replicative activity of adult rat pancreatic ß-cells (7) and/or the lack of growth factors under our experimental conditions. Leptin reportedly potentiates leukemic cell proliferation induced by growth factors, such as granulocyte colony-stimulating factor, IL-3, and stem cell factor (2).

Kieffer and Habener (4) proposed the existence of an adipoinsular axis, a dual hormonal feedback loop involving insulin and leptin produced by pancreatic ß-cells and adipose tissue, respectively. They described leptin as suppressing insulin secretion as part of a bidirectional adipoinsular axis. The antiapoptotic effects of leptin, demonstrated herein, appear to be in opposition to this concept. Our results may, however, be attributable to the process of creating the conditions necessary to show the inhibitory effects of leptin; the adipoinsular axis constitutes a positive feedback loop operating at the initiation of obesity, but once obesity is established and the leptin concentration exceeds a certain level, leptin exerts a negative feedback effect on ß-cells. In this context it is noteworthy that no antiapoptotic effects were observed at a very high leptin concentration (75 nM). Thus, our results are not necessarily inconsistent with the concept of an adipoinsular axis.

In conclusion, leptin at 1 and 5 nM, concentrations observed in obese subjects, increases the number of viable pancreatic islet cells by suppressing apoptosis. This mechanism might account at least in part for the obesity-induced increase in pancreatic ß-cell mass.


   Acknowledgments
 


   Footnotes
 
This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (11671119, to S.O.) and Health Sciences Research Grants (Research on Human Genome and Gene Therapy) from the Ministry of Health and Welfare of Japan (to Y.O.).

Abbreviations: BrdU, 5-Bromo-2'-deoxyuridine; iNOS, inducible nitric oxide synthase; JAK, Janus kinase; LM-PCR, ligation-mediated PCR; MTT, 2,5-diphenyltetrazolium bromide; STAT, signal transducer and activator of transcription; TG, triglyceride.

Received April 10, 2001.

Accepted for publication July 30, 2001.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Frübeck G, Salvador J 2000 Relation between leptin and the regulation of glucose metabolism. Diabetologia 43:3–12[CrossRef][Medline]
  2. Konopleva M, Mikhail A, Estrov Z, Zhao S, Harris D, Sanchez-Williams G, Kornblau SM, Dong J, Kliche KO, Jiang S, Snodgrass HR, Estey EH, Andreeff M 1999 Expression and function of leptin receptor isoforms in myeloid leukemia and myelodysplastic syndromes: proliferative and anti-apoptotic activities. Blood 93:1668–1676[Abstract/Free Full Text]
  3. Tanizawa Y, Okuya S, Ishihara H, Asano T, Yada T, Oka Y 1997 Direct stimulation of basal insulin secretion by physiological concentrations of leptin in pancreatic ß cells. Endocrinology 138: 4513–4516
  4. Kieffer TJ, Habener JF 2000 The adipoinsular axis: effects of leptin on pancreatic ß-cells. Am J Physiol 278:E1–E14
  5. Tanabe K, Okuya S, Tanizawa Y, Matsutani A, Oka Y 1997 Leptin induces proliferation of pancreatic beta cell line MIN6 through activation of mitogen-activated protein kinase. Biochem Biophys Res Commun 241:765–768[CrossRef][Medline]
  6. Pick A, Clark J, Kubstrup C, Levisetti M, Pugh W, Bonner-Weir S, Polonsky KS 1998 Role of apoptosis in failure of ß-cell mass compensation for insulin resistance and ß-cell defects in the male Zucker diabetic fatty rat. Diabetes 47:358–364[Abstract]
  7. Islam MS, Sjöholm Å, Emilsson V 2000 Fetal pancreatic islets express functional leptin receptors and leptin stimulates proliferation of fetal islet cells. Int J Obesity 24:1246–1253
  8. Shimabukuro M, Wang M-Y, Zhou Y-T, Newgard CB, Unger RH 1998 Protection against lipoapoptosis of ß cells through leptin-dependent maintenance of Bcl-2 expression. Proc Natl Acad Sci USA 95:9558–9561[Abstract/Free Full Text]
  9. Shimabukuro M, Ohneda M, Lee Y, Unger RH 1997 Role of nitric oxide in obesity-induced ß cell disease. J Clin Invest 100:290–295[Medline]
  10. Shimabukuro M, Koyama K, Lee Y, Unger RH 1997 Leptin- or troglitazone-induced lipopenia protects islets from interleukin 1 ß cytotoxicity. J Clin Invest 100:1750–1754[Medline]
  11. Shimabukuro M, Koyama K, Chen G, Wang M-Y, Trieu F, Lee Y, Newgard CB, Unger RH 1997 Direct antidiabetic effect of leptin through triglyceride depletion of tissues. Proc Natl Acad Sci USA 94:4637–4641[Abstract/Free Full Text]
  12. Shimabukuro M, Zhou YT, Levi M, Unger RH 1998 Fatty acid-induced ß cell apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci USA 95:2498–2502[Abstract/Free Full Text]
  13. Altman SA, Randers L, Rao G 1993 Comparison of trypan blue dye exclusion and fluorometric assays for mammalian cell viability determinations. Biotechnol Prog 9:671–674[CrossRef][Medline]
  14. MacManus JP, Fliss H, Preston E, Rasquinha I, Tuor U 1999 Cerebral ischemia produces laddered DNA fragments distinct from cardiac ischemia and archetypal apoptosis. J Cereb Blood Flow Metab 19:502–510[CrossRef][Medline]
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  16. Simon HU, Yousefi S, Dibbert B, Levi-Schaffer F, Blaser K 1997 Antiapoptotic signals of granulocyte-macrophage colony-stimulating factor are transduced via Jak2 tyrosine kinase in eosinophils. Eur J Immunol 27:3536–3539[Medline]
  17. Bittorf T, Seiler J, Zhang Z, Jaster R, Brock J 1999 SHP1 protein tyrosine phosphatase negatively modulates erythroid differentiation and suppression of apoptosis in J2E erythroleukemic cells. Biol Chem 380:1201–1209[CrossRef][Medline]



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