help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rouru, J.
Right arrow Articles by Rohner-Jeanrenaud, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rouru, J.
Right arrow Articles by Rohner-Jeanrenaud, F.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*GLUCOSE
Endocrinology Vol. 140, No. 8 3688-3692
Copyright © 1999 by The Endocrine Society

ARTICLES

Effects of Intravenously Infused Leptin on Insulin Sensitivity and on the Expression of Uncoupling Proteins in Brown Adipose Tissue1

Juha Rouru, Isabelle Cusin, Katerina E. Zakrzewska, Bernard Jeanrenaud and Françoise Rohner-Jeanrenaud

Laboratoires de Recherches Métaboliques (J.R., I.C., K.E.Z., B.J., F.R.-J.), Hôpital Cantonal Universitaire de Genève, 24, CH-1211 Genève 14, Switzerland; and Department of Pharmacology and Clinical Pharmacology (J.R.), University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland

Address all correspondence and requests for reprints to: Juha Rouru, Department of Pharmacology and Clinical Pharmacology, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland. E-mail: juha.rouru{at}orion.fi


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Centrally administered leptin has been shown to increase insulin-stimulated glucose utilization and to favor the expression of uncoupling proteins (UCPs). To study if leptin also has direct peripherally mediated effects on these processes, this hormone (1 mg/day) or its vehicle was infused iv for 4 days to lean rats and insulin-stimulated glucose utilization in skeletal muscle and adipose tissue as well as the expression of UCP messenger RNAs (mRNAs) in brown adipose tissue were measured. Iv leptin administration resulted in decreases in food intake (31%), body weight gain, and plasma insulin levels (45%), in increases in overall (23%) as well as brown adipose tissue and muscle glucose utilization, and in decreases in white adipose tissue glucose uptake. Most of these changes were mimicked, in control rats, by giving them the same amount of food as that consumed by the leptin-infused group (pair-feeding). Iv leptin infusion also favored the expression of UCPs in brown adipose tissue, either by increasing their expression or preventing the fall occurring during the pair-feeding regimen. Relative UCP expression levels were 100, 104, and 33 for UCP1, 100, 191, and 125 for UCP2 and 100, 107, and 29 for UCP3 in ad libitum fed control rats, in leptin-treated rats and in pair-fed control rats, respectively. These results suggest that the overall effect of leptin on glucose utilization and on the expression of UCPs may be mediated through central mechanism.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
LEPTIN is released into the circulation from adipose tissue and sends signals regarding the size of body fat stores to hypothalamic centers regulating both appetite and energy expenditure (1). Thus, after its binding to the long receptor isoform within the hypothalamus (2, 3), leptin decreases food intake and presumably increases energy dissipation (4, 5, 6). Leptin receptors are also expressed in peripheral tissues (2, 3), although their role in mediating physiological responses to increased plasma leptin concentrations is not clear. Furthermore, leptin itself has recently been shown to be synthesized in skeletal muscle under certain conditions (7).

The net effect of leptin on glucose metabolism is still a matter of debate. In most in vitro studies, no effect of leptin was found on glucose uptake in muscles (8, 9, 10, 11) nor in adipocytes (9, 10), although an inhibitory effect on glucose uptake in adipocytes (12) and a stimulatory one in isolated muscles and cultured myotubes have been reported (13, 14). In in vivo studies, stimulatory effects of leptin on whole body insulin sensitivity (15, 16), basal glucose turnover and glucose uptake by skeletal muscles (17) have been reported, although these findings have not been confirmed by others (18, 19).

Recently, it has been shown that a 4-day intracerebroventricular (icv) leptin infusion increased the insulin-stimulated overall glucose uptake as well as glucose uptake by skeletal muscles when compared with ad libitum fed control animals, but not when compared with rats pair-fed to the amount of food ingested by the leptin-treated group (20). This suggested that the effect of leptin on glucose metabolism was mediated centrally and caused by the reduced food intake and body weight gain. In the same study, icv leptin infusion has been shown to favor the expression of the three uncoupling proteins (UCPs) described, namely UCP1 (21), UCP2 (22), and UCP3 (23, 24) by preventing the decrease that was observed in pair-fed animals. This is in keeping with other data suggesting that these three uncoupling proteins may play a role in the increased energy dissipation caused by leptin (20, 24, 25, 26, 27, 28).

As leptin is secreted into the peripheral blood, as its receptors are expressed in the periphery (2, 3) and as the existence of peripheral effects of leptin remains conceivable, the aim of the present study was to investigate the effects of peripheral (iv) leptin administration on glucose metabolism and on the expression of UCPs in brown adipose tissue, the main energy dissipating organ in rodents.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Lean (Fa/?) male rats of the Zucker strain were used in this study to allow comparison with our recent study, where leptin was administered icv (20). Part of the animals carry a mutation in the leptin receptor gene (fa) (29), but they represent adequate controls, as it has been shown that the normal leptin receptor functions as a dominant negative toward the mutated receptor (30).

The animals were housed in individual cages under conditions of controlled temperature (23 C) and illumination (0700–1900 h). The rats were allowed ad libitum access to water and standard laboratory chow, unless otherwise stated. Food intake and body weight were measured daily. All procedures used were approved by the "Office vétérinaire fédéral et cantonal," Geneva, Switzerland.

In vivo glucose utilization during euglycemic hyperinsulinemic clamps following chronic iv infusion of leptin
At 11–12 weeks of age, rats were anesthetized with isoflurane (Forene, Abbot Laboratories, Inc., Cham, Switzerland) and equipped with a catheter positioned in the femoral vein. After a 1-day recovery period, 1 mg of recombinant mouse leptin (Novartis Pharma, Basle, Switzerland) per day or its vehicle (Krebs-Ringer solution) was infused for four days to freely moving rats. Three groups of rats were investigated: one group of rats iv infused with leptin, one group of control rats iv infused with the vehicle and allowed to eat ad libitum and one group of control rats iv infused with the vehicle but pair-fed to the amount of food consumed by leptin-infused animals. The pair-feeding regimen was performed as follows: average daily food intake for the leptin-treated group was calculated; one third of this amount of food was given in the morning (0900 h), whereas the remaining two thirds were given before the extinction of the light (1800 h), based on a preliminary study of food consumption during the day and the night.

Blood was collected daily from the tip of the tail into EDTA tubes for the determination of plasma insulin concentrations. After 4 days of iv leptin infusion, 5-hour fasted rats were anesthetized with sodium pentobarbital (55 mg/kg ip) and euglycemic-hyperinsulinemic clamps were performed as previously described (31). Mean ± SEM steady-state values of insulinemia during the clamps were 21.9 ± 1.7, 18.7 ± 0.9 and 23.4 ± 2.2 ng/ml and mean ± SEM steady-state values of glycemia were 6.5 ± 0.3, 6.1 ± 0.1 and 6.0 ± 0.2 mmol/liter, in ad libitum fed, in leptin-treated and in pair-fed rats, respectively. Such insulinemia values enabled to study the half maximal stimulation of glucose utilization by insulin (31). The in vivo insulin-stimulated glucose utilization index by individual tissues was measured during euglycemic-hyperinsulinemic clamps associated with the labeled 2-deoxy-D-glucose technique (2-deoxy-D [1-3H] glucose, Amersham Pharmacia Biotech, Aylesbury, UK), as previously described and validated (32, 33). Different muscle types such as white quadriceps (WQ), red gastrocnemius (RG), white gastrocnemius (WG) as well as epididymal white adipose tissue (WAT) and brown adipose tissue (BAT) were sampled.

Plasma glucose was determined by the glucose oxidase method [Beckman Coulter, Inc. (Fullerton, CA) glucose analyzer 2]. Plasma insulin levels were measured by RIA as described earlier (34). Plasma leptin levels were determined using a commercial RIA kit for rat leptin having 100% cross-reactivity with mouse leptin (Linco Research, Inc., St. Louis, MO).

State of uncoupling protein 1, 2 and 3 expression in brown adipose tissue following iv infusion of leptin
The iv infusion of leptin, or of vehicle with or without the pair-feeding regimen was carried out as described above. At the end of the respective infusions, the rats were decapitated, brown adipose tissue removed and frozen in liquid nitrogen. Total RNA was extracted (35), aliquots of 10 µg were size-fractionated on 1.5% agarose gels, and blots were hybridized (Quikhyb, Stratagene, Basel, Switzerland) to random primed labeled cDNAs hybridizing with UCP1 and UCP3 (23) and with UCP2 (22) as well as with ß-actin (CLONTECH Laboratories, Inc. Laboratory, Palo Alto, CA). Autoradiographs (X-Omat-AR, Eastman Kodak Co., Rochester, NY) were quantified by densitometry with the Image Quant Software (Molecular Dynamics, Sunnyvale, CA). Abundance of UCP1, UCP2, and UCP3 mRNA relative to that of ß-actin was expressed as a percentage of corresponding ad libitum fed vehicle-infused controls.

Statistical analysis
For daily measurements of food intake, changes in body weight and plasma insulin concentrations, statistical analysis was carried out using one-way ANOVA for repeated measurements. In case of significant treatment x time interaction effects, groups at each time point were compared separately by one-way ANOVA followed by Tukey procedure for multiple comparisons. For other analysis, one-way ANOVA followed by Tukey procedure was used. If the data were not normally distributed, logarithmic transformation was performed before calculations. If the requirements of parametric ANOVA were not reached even after logarithmic transformation, as was the case for plasma leptin concentrations, Kruskal-Wallis ANOVA followed by Mann-Whitney U test was used. The calculations were performed by Statistica software (version 4.5 for Windows, StatSoft Inc., Tulsa, OK).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Values of food intake and body weight changes are presented in Fig. 1Go. When compared with ad libitum fed controls, chronically iv leptin-infused rats (4 days) had reduced food intake during the whole experimental period. Pair-fed vehicle-infused rats obviously had a food intake that was identical to that of iv leptin-infused animals (data not shown). Ad libitum fed control rats gained weight during the 4-day experimental period, whereas both the chronically iv leptin-infused rats and their respective pair-fed controls lost weight in a similar fashion during the same period.



View larger version (19K):
[in this window]
[in a new window]
  		Figure 1. Daily food intake and body weight change in iv vehicle-infused ad libitum fed controls, iv leptin-infused (1 mg/day) rats and iv vehicle-infused pair-fed controls. Values are means ± SEM of five to six animals per group. For each time point *, P < 0.05 for pair-fed rats vs. ad libitum fed controls and **, P < 0.05 for leptin-treated and pair-fed rats vs. ad libitum fed controls.

 
Plasma leptin concentrations were considerably higher in chronically iv leptin-infused than in either ad libitum fed or pair-fed control rats, being 41.0 ± 27.3, 2.4 ± 0.3 and 0.7 ± 0.09 ng/ml, respectively (leptin-infused rats vs. either pair-fed or ad libitum fed controls, P < 0.005, pair-fed vs. ad libitum fed controls P < 0.005). As shown by Fig. 2Go, basal plasma insulin levels were lower in both leptin-infused and vehicle-infused pair-fed rats, than in ad libitum fed controls. When compared with ad libitum fed control rats, iv leptin-infused rats and pair-fed animals had higher insulin-stimulated glucose infusion rates (GIR), although statistical significance was reached only for the iv leptin-infused group (27.0 ± 0.8 mg/kg/min for ad libitum fed controls, 33.1 ± 1.2 mg/kg·min for leptin-infused rats, P < 0.005, and 29.9 ± 1.1 mg/kg/min for pair-fed controls). Additional data on glucose handling showed that hepatic glucose production was normally suppressed by insulin in the three groups of animals (data not shown).



View larger version (19K):
[in this window]
[in a new window]
  		Figure 2. Plasma insulin levels in iv vehicle-infused ad libitum fed controls, iv leptin-infused (1 mg/day) rats and iv vehicle-infused pair-fed controls. Values are means ± SEM of five to six animals per group. For each timepoint: *, P < 0.05 for pair-fed rats vs. ad libitum fed controls, **, P < 0.05 for leptin-treated and pair-fed rats vs. ad libitum fed controls.

 
Glucose utilization index by individual tissues was measured using euglycemic-hyperinsulinemic clamps associated with the labeled 2-deoxy-glucose (2DG) technique. For different muscle types, it was observed that when compared with insulin-stimulated glucose utilization indices obtained in ad libitum fed control rats, those of iv leptin-infused animals were significantly higher (Fig. 3Go). A similar pattern was observed for muscles of pair-fed animals that exhibited higher glucose utilization indices than those of ad libitum fed controls, although this difference did not always reach statistical significance. In brown adipose tissue (BAT), the glucose utilization index of leptin-treated rats was higher than that of the pair-fed controls and had a trend to be higher than that of the ad libitum fed control animals (Fig. 4Go). In epididymal white adipose tissue, the insulin-stimulated glucose utilization index was lower in iv leptin-infused animals than in both ad libitum fed and pair-fed controls (Fig. 4Go).



View larger version (28K):
[in this window]
[in a new window]
  		Figure 3. In vivo glucose utilization index of various muscles measured by the labeled 2-deoxyglucose technique during euglycemic-hyperinsulinemic clamps in iv vehicle-infused ad libitum fed controls, iv leptin-infused (1 mg/day) rats and iv vehicle-infused pair-fed controls. WQ, White quadriceps; RG, red gastrocnemius; WG, white gastrocnemius. Means ± SEM of five to six animals per group. *, P < 0.05 vs. ad libitum fed controls.

 


View larger version (33K):
[in this window]
[in a new window]
  		Figure 4. In vivo glucose utilization index of brown adipose tissue (BAT) and epididymal white adipose tissue (WAT) measured by the labeled 2-deoxyglucose technique during euglycemic-hyperinsulinemic clamps in iv vehicle-infused ad libitum fed controls, iv leptin-infused (1 mg/day) rats and iv vehicle-infused pair-fed controls. Means ± SEM of five to six animals per group (BAT) or 4–6 animals per group (WAT). *, P < 0.05 vs. ad libitum fed controls, * *, P < 0.05 vs. pair-fed controls.

 
Brown adipose tissue weights were 281 ± 22, 150 ± 8 and 195 ± 11 mg in ad libitum fed, leptin treated and pair-fed rats, respectively (P < 0.05, ad libitum fed vs. leptin treated and pair-fed animals). UCP1 and UCP3 mRNA levels in brown adipose tissue from pair-fed animals were markedly decreased when compared with ad libitum fed controls, a decrease that was prevented to occur in the iv leptin-infused group (Fig. 5Go). Brown adipose tissue UCP2 mRNA levels were increased by iv leptin infusion compared with ad libitum fed controls, whereas there was no difference in UCP2 expression between the two control groups (Fig. 5Go). UCP expression results were qualitatively similar when expressed without correction by ß-actin (data not shown).



View larger version (22K):
[in this window]
[in a new window]
  		Figure 5. UCP1, UCP2 and UCP3 mRNA levels in brown adipose tissue of iv vehicle-infused ad libitum fed controls, iv leptin-infused (1 mg/day) rats and iv vehicle-infused pair-fed controls. Means ± SEM of four to six animals per group, *, P < 0.05 vs. ad libitum fed controls; **, P < 0.05 vs. pair-fed controls.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, the decreases in body weight and plasma insulin levels produced by 4 days iv leptin infusion in normal rats were mimicked by a pair-feeding regimen, indicating that they were due to the actual decrease in incoming nutrients. The loss of body weight caused by leptin treatment is proposed to be mainly due to loss of white adipose tissue, as reported earlier (16). This phenomenon was also noted at the level of brown adipose tissue in the present study. Plasma leptin concentrations were lower in pair-fed than in ad libitum fed controls, in keeping with the observation that leptin and body mass are correlated (36).

In skeletal muscles of leptin-infused rats, the increase in insulin sensitivity was similar to that of pair-fed controls and thus appeared to be a consequence of reduced caloric intake, rather than a direct insulin sensitizing action of leptin per se. In brown adipose tissue of leptin-infused rats, the increased insulin sensitivity compared with the two control groups appeared to be a genuine effect of leptin (37). At the level of white adipose tissue, the mechanism for the markedly decreased insulin-stimulated glucose uptake after leptin administration is not clear. However, it has been proposed that leptin depletes triglyceride levels in cells exhibiting leptin receptors via a mechanism involving both an increase in FFA oxidation and a decrease in esterification (27, 38). Such a decreased leptin-induced esterification of fatty acids is in keeping with a lesser glucose demand and therefore with the decrease in glucose uptake observed in white adipose tissue of leptin-infused rats.

It should be noted that the effects of iv leptin treatment on glucose metabolism at the level of skeletal muscles and white adipose tissue in the present study are strikingly similar to the results that we obtained by administering leptin centrally with an otherwise similar protocol (20). This suggests that these effects of leptin may be mediated through central mechanisms, without necessarily resulting from the decrease in food intake, as was the case for white adipose tissue. The concept of a centrally mediated mechanism in the effect of leptin on glucose metabolism is in agreement with a study of acute leptin infusion (17).

The observation that leptin prevented the drop in brown adipose tissue UCP1 and UCP3 expression brought about by the pair-feeding regimen is in keeping with a study in which a reduction of 24 h energy expenditure was observed in pair-fed animals but prevented to occur in icv leptin-infused mice (39). It is also in agreement with another study in which oxygen consumption and UCP1 mRNA expression in brown fat were decreased by food restriction and increased by peripheral leptin treatment (40). Furthermore, and in keeping with the study of Zhou et al. (27), UCP2 expression in adipose tissue was clearly increased in the leptin-infused group when compared with ad libitum fed control rats. When comparing UCP mRNA expression levels between leptin-treated and ad libitum fed control rats, the only difference between iv and icv leptin-infused rats appears to be that here UCP2 expression was increased in brown fat, whereas after icv leptin (20) this happened rather to UCP3. Unfortunately, we do not have any obvious explanation for this. However, the present results are fitting with the concept that leptin is able to increase energy expenditure and/or prevent a decrease thereof (4, 5, 6, 39).

It is concluded that iv administered leptin enhances insulin-stimulated glucose metabolism. This effect, at least at the level of skeletal muscle, is due to reduced energy intake and consequent reduction in body weight. Iv leptin treatment also favors the expression of uncoupling proteins, either by increasing their expression or by preventing the fall occurring due to reduced energy intake. These effects of leptin are suggested to be mediated via hypothalamic leptin receptors, because the effects of iv and icv administered leptin are qualitatively similar.


   Acknowledgments
 
We thank Dr. D. Riquier for providing the UCP2 probe and Dr. O. Boss for the probe recognizing UCP1 and UCP3. Dr. M. Chiesi (Novartis, Basle, Switzerland) is acknowledged for providing recombinant mouse leptin. We are indebted to Ms. P. Arboit for excellent technical assistance.


   Footnotes
 
1 This work has been supported by Grant 31–53719.8 from the Swiss National Science Foundation, Bern, Switzerland and by grant from Novartis, Basle, Switzerland. The postdoctoral fellowship of Juha Rouru was financed by the Academy of Finland, Helsinki, Finland, Yrjö Jahnsson Foundation, Helsinki, Finland and Turku University Foundation, Turku, Finland, which are gratefully acknowledged. Back

Received December 4, 1998.


   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 327:425–432
  2. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Woolf EA, Monroe CA, Tepper RI 1995 Identification and expression cloning of a leptin receptor, OB-R. Cell 83:1263–1271[CrossRef][Medline]
  3. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM 1996 Abnormal splicing of the leptin receptor in diabetic mice. Nature 379:632–635[CrossRef][Medline]
  4. Peleymounter 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. 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]
  6. 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]
  7. Wang J, Liu R, Hawkins M, Barzilai N, Rossetti L 1998 A nutrient-sensing pathway regulates leptin gene expression in muscle and fat. Nature 393:684–688[CrossRef][Medline]
  8. Muoio DM, Dohm GL, Fiedorek FTJ, Tapscott EB, Coleman RA 1997 Leptin directly alters lipid partitioning in skeletal muscle. Diabetes 46:1360–1363[Abstract]
  9. Ranganathan S, Ciaraldi TP, Henry RR, Mudaliar S, Kern PA 1996 Lack of effect of leptin on glucose transport, lipoprotein lipase, and insulin action in adipose and muscle cells. Endocrinology 139:2509–2513[Abstract/Free Full Text]
  10. Zierath JR, Frevert EU, Ryder JW, Berggren P-O, Kahn BB 1998 Evidence against a direct effect of leptin on glucose transport in skeletal muscle and adipocytes. Diabetes 47:1–4[Abstract]
  11. Fürnsinn C, Brunmair B, Furtmüller R, Roden M, Englisch R, Waldhäusl W 1998 Failure of leptin to affect basal and insulin-stimulated glucose metabolism of rat skeletal muscle in vitro. Diabetologia 41:524–529[CrossRef][Medline]
  12. 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]
  13. Berti L, Kellerer M, Capp E, Häring 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]
  14. Harris RBS 1998 Acute and chronic effects of leptin on glucose utilization in lean mice. Biochem Biophys Res Commun 245:502–509[CrossRef][Medline]
  15. Sivitz WI, Walsh SA, Morgan DA, Thomas MJ, Haynes WG 1997 Effects of leptin on insulin sensitivity in normal rats. Endocrinology 138:3395–3401[Abstract/Free Full Text]
  16. Barzilai N, Wang J, Massilon D, Vuguin P, Hawkins M, Rossetti L 1997 Leptin selectively decreases visceral adiposity and enhances insulin action. J Clin Invest 100:3105–3110[Medline]
  17. Kamohara S, Burcelin R, Halaas JL, Friedman JM, Charron MJ 1997 Acute stimulation of glucose metabolism in mice by leptin treatment. Nature 389:374–377[CrossRef][Medline]
  18. Widdowson PS, Upton R, Pickavance L, Buckingham R, Tadayyon M, Arch J, Williams G 1998 Acute hyperleptinemia does not modify insulin sensitivity in vivo in the rat. Horm Metab Res 30:259–262[Medline]
  19. Rossetti L, Massilon D, Barzilai N, Vuguin P, Chen W, Hawkins M, Wu J, Wang J 1997 Short term effects of leptin on hepatic gluconeogenesis and in vivo insulin action. J Biol Chem 272:27758–27763[Abstract/Free Full Text]
  20. Cusin I, Zakrzewska KE, Boss O, Muzzin P, Giacobino JP, Ricquier D, Jeanrenaud B, Rohner-Jeanrenaud F 1998 Chronic central leptin infusion enhances insulin-stimulated glucose metabolism and favors the expression of uncoupling proteins. Diabetes 47:1014–1019[Abstract]
  21. Bouillaud F, Weissenbach J, Ricquier D 1986 Complete cDNA-derived amino acid sequence of rat brown fat uncoupling protein. J Biol Chem 261:1487–1490[Abstract/Free Full Text]
  22. Fleury C, Neverova M, Collins S, Raimdault S, Champigny O, Levi-Meyrueis C, Boillaud F, Seldin MF, Surwit RS, Riquier D, Warden CH 1997 Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet 15:269–272[CrossRef][Medline]
  23. Boss O, Samec S, Paoloni-Giacobino A, Rossier C, Dulloo A, Seydoux J, Muzzin P, Giacobino JP 1997 Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression. FEBS Lett 408:39–42[CrossRef][Medline]
  24. Gong DW, He Y, Karas M, Reitman M 1997 Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, ß3-adrenergic agonists, and leptin. J Biol Chem 272:24129–24132[Abstract/Free Full Text]
  25. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP 1996 Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84:491–495[CrossRef][Medline]
  26. Liu Q, Bai C, Chen F, Wang R, MacDonald T, Gu M, Zhang Q, Morsy MA, Caskey CT 1998 Uncoupling protein-3: a muscle-specific gene upregulated by leptin in ob/ob mice. Gene 207:1–7[CrossRef][Medline]
  27. Zhou YT, Shimabukuro M, Koyama K, Lee Y, Wang MY, Trieu F, Newgard CB, Unger RH 1997 Induction by leptin of uncoupling protein-2 and enzymes of fatty acid oxidation. Proc Natl Acad Sci USA 94:6386–6390[Abstract/Free Full Text]
  28. Sarmiento U, Benson B, Kaufman S, Ross L, Qi M, Scully S, DiPalma C 1997 Morphologic and molecular changes induced by recombinant human leptin in the white and brown adipose tissues of C57BL/6 mice. Lab Invest 77:243–256[Medline]
  29. Phillips MS, Liu Q, Hammond HA, Dugan V, Hey PJ, Caskey CT, Hess JF 1996 Leptin receptor missense mutation in the fatty Zucker rat. Nat Genet 13:18–19[CrossRef][Medline]
  30. White DW, Wang Y, Chua SC, Morgenstern JP, Leibel RL, Baumann H, Tartaglia LA 1997 Constitutive and impaired signaling of leptin receptors containing the Gln-Pro extracellular domain fatty mutation. Proc Natl Acad Sci USA 94:10657–10662[Abstract/Free Full Text]
  31. Terrettaz J, Assimacopoulos-Jeannet F, Jeanrenaud B 1986 Severe hepatic and peripheral insulin resistance as evidenced by euglycemic clamps in genetically obese fa/fa rats. Endocrinology 118:674–678[Abstract]
  32. Ferré P, Leturque A, Burnol AF, Pénicaud L, Girard J 1985 A method to quantify glucose utilization in vivo in skeletal muscle and white adipose tissue of the anaesthetized rat. Biochem J 228:103–110[Medline]
  33. James DE, Burleigh KM, Kraegen EW 1986 In vivo glucose metabolism in individual tissues of the rat. J Biol Chem 261:6366–6374[Abstract/Free Full Text]
  34. Herbert V, Lau KS, Gottlieb CW, Bleicher SJ 1965 Coated charcoal immunoassay of insulin. J Clin Endocrinol Metab 25:1375–1384[Medline]
  35. Chomczynski P, Sacci N 1987 Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159[Medline]
  36. Caro JF, Sinha MK, Kolaczynski JW, Zhang PL, Considine RV 1996 Leptin: the tale of an obesity gene. Diabetes 45:1455–1462[Medline]
  37. Siegrist-Kaiser CA, Pauli V, Juge Aubry CE, Boss O, Pernin A, Chin WW, Cusin I, Rohner-Jeanrenaud F, Burger AG, Zapf J, Meier CA 1997 Direct effects of leptin on brown and white adipose tissue. J Clin Invest 100:2858–2864[Medline]
  38. Shimabukuro M, Koyama K, Chen G, Wang MY, 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]
  39. Halaas JF, Boozer C, Blair-West J, Fidahusein N, Denton DA, Friedman JF 1997 Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc Natl Acad Sci USA 94:8878–8883[Abstract/Free Full Text]
  40. Scarpace PJ, Matheny M, Pollock BH, Tümer N 1997 Leptin increases uncoupling protein expression and energy expenditure. Am J Physiol 273:E226–E230



This article has been cited by other articles:


Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
R. B. S. Harris, T. D. Mitchell, E. W. Kelso, and W. P. Flatt
Changes in environmental temperature influence leptin responsiveness in low- and high-fat-fed mice
Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2007; 293(1): R106 - R115.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J. Ukropec, R. V. P. Anunciado, Y. Ravussin, and L. P. Kozak
Leptin Is Required for Uncoupling Protein-1-Independent Thermogenesis during Cold Stress
Endocrinology, May 1, 2006; 147(5): 2468 - 2480.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
A. Varma, J. He, B.-C. Shin, L. A. Weissfeld, and S. U. Devaskar
Postnatal intracerebroventricular exposure to leptin causes an altered adult female phenotype
Am J Physiol Endocrinol Metab, December 1, 2004; 287(6): E1132 - E1141.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
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]

Home page
 Physiol. Rev.Home page
B. CANNON and J. NEDERGAARD
Brown Adipose Tissue: Function and Physiological Significance
Physiol Rev, January 1, 2004; 84(1): 277 - 359.
[Abstract] [Full Text] [PDF]

Home page
 J ANIM SCIHome page
T. G. Ramsay
Porcine leptin inhibits lipogenesis in porcine adipocytes
J Anim Sci, December 1, 2003; 81(12): 3008 - 3017.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
A. M. Rodriguez, P. Roca, M. L. Bonet, C. Pico, P. Oliver, and A. Palou
Positive correlation of skeletal muscle UCP3 mRNA levels with overweight in male, but not in female, rats
Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2003; 285(4): R880 - R888.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
P. Cettour-Rose and F. Rohner-Jeanrenaud
The Leptin-Like Effects of 3-d Peripheral Administration of a Melanocortin Agonist Are More Marked in Genetically Obese Zucker (fa/fa) than in Lean Rats
Endocrinology, June 1, 2002; 143(6): 2277 - 2283.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
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]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
K. Arai, K. Kim, K. Kaneko, M. Iketani, A. Otagiri, N. Yamauchi, and T. Shibasaki
Nicotine infusion alters leptin and uncoupling protein 1 mRNA expression in adipose tissues of rats
Am J Physiol Endocrinol Metab, June 1, 2001; 280(6): E867 - E876.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
Y. Chen and M. L. Heiman
Increased weight gain after ovariectomy is not a consequence of leptin resistance
Am J Physiol Endocrinol Metab, February 1, 2001; 280(2): E315 - E322.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
J. R. Levy, J. Lesko, R. J. Krieg Jr., R. A. Adler, and W. Stevens
Leptin responses to glucose infusions in obesity-prone rats
Am J Physiol Endocrinol Metab, November 1, 2000; 279(5): E1088 - E1096.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rouru, J.
Right arrow Articles by Rohner-Jeanrenaud, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rouru, J.
Right arrow Articles by Rohner-Jeanrenaud, F.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*GLUCOSE

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals