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Department of Internal Medicine, Divisions of Endocrinology and Cardiovascular Disease, University of Iowa and the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa 52246
Address all correspondence and requests for reprints to: Dr. William Sivitz, Department of Internal Medicine, The University of Iowa Hospitals and Clinics, 3E-17 VA, Iowa City, Iowa 52246. E-mail: William-Sivitz{at}uiowa.edu
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Abstract |
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Subcutaneous leptin was administered at 10.0 and 1.0 µg/h. To avoid confounding effects of differences in food intake, both leptin- and vehicle-treated rats were fasted during the 48-h period of infusion. Infusion of leptin, 10 µg/h, significantly reduced both plasma glucose and insulin. Leptin, 1.0 µg/h, also decreased plasma glucose and insulin, although the effects on insulin did not achieve statistical significance. Leptin at either dose did not alter body weight or epididymal fat mass compared with vehicle treated controls. Leptin, 10 µg/h, decreased circulating insulin-like growth factor-1 levels. No differences in GLUT-4 content in either in brown or epididymal fat were observed as a result of leptin-treatment. Leptin, 10 µg/h, significantly decreased urine osmolality, increased water intake, and reduced renal potassium excretion compared with vehicle-infused rats. In additional rats, we measured the acute effect of iv leptin on insulin sensitivity determined as whole body glucose utilization during hyperinsulinemic glucose clamps performed at glucose targets of 60 and 90 mg/100 ml. Glucose utilization was increased by 29% during the last 135 min of glycemia clamped at 60 mg/100 ml (P < 0.05) and by 30% during the last 135 min of glycemia clamped at 90 mg/dl (P < 0.01) in rats infused with leptin compared with vehicle.
In summary, leptin increased insulin sensitivity in normal rats both under fasting conditions and in the presence of hyperinsulinemia at clamped glucose. These effects did not appear dependent on altered body weight. Leptin also altered salt and water metabolism under fasting conditions resulting in increased water intake and more dilute urine.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The effects of leptin on insulin sensitivity are less clear. Leptin treatment of ob/ob mice, which lack a functional leptin protein, resulted in weight loss and reduced circulating insulin and glucose concentrations, suggesting improved insulin sensitivity (1). Insulin concentrations were also reduced (without altered glycemia) in normal rats subject to hyperleptinemia as a result of adenoviral transfection (16). However, in both the ob/ob mice and adenoviral-treated rats, leptin markedly reduced adipose mass so independent effects on insulin-sensitivity could not be determined.
The actions of leptin on appetite and energy dissipation appear to be mediated through a central effect at the hypothalamus wherein leptin receptors are abundant (17). However, leptin receptors are also expressed in several other tissues, suggesting peripheral effects as well (17). The abundance of leptin receptor mRNA in the kidney suggests possible effects on urine composition and fluid volume, a notion further suggested by the association of hyperleptinemia with the insulin resistance syndrome (18, 19), an important component of which includes hypertension.
To determine whether leptin alters basal (fasting) glucose metabolism as well as fluid and electrolyte balance in genetically normal rats, we treated rats with either leptin or vehicle for 48 h using continuous sc infusion of two doses delivered by osmolar infusion pumps. To avoid confounding effects of leptin on food intake, all rats, both leptin- and vehicle-treated, were fasted during these experiments. Plasma glucose, insulin, insulin-like growth factor-1 (IGF-1), and leptin concentrations; epididymal and brown adipose tissue GLUT-4 content; and parameters of salt and water metabolism were measured. In additional studies, we examined the acute effect of iv leptin infusion on insulin sensitivity under hyperinsulinemic conditions at constant (clamped) glycemia.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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sc leptin infusion experiments
Animals were fed and maintained according to standard NIH
guidelines. Mouse leptin (1 µg/µl) or vehicle (PBS, pH 7.4) were
infused using sc osmolar pumps delivering either 10 µl/h (2 ml pump)
or 1 µl/h (200 µl pump). In this fashion, male Sprague-Dawley rats
were treated for 48 h with continuous sc leptin 10 µg/h or 1.0
µg/h. Rats treated with each dose of leptin were compared with
vehicle treated rats infused at the same rate using the same volume
infusion pump. All rats were placed in individual metabolic cages
24 h before insertion of the infusion pumps. Leptin- and
vehicle-infused rats were treated at the same time and maintained in
adjacent metabolic cages. For insertion of the pumps, rats were
anesthetized with methoxyflorane by inhalation. An approximately 1.0 cm
incision was made in the skin over the back, and the infusion pump with
flow moderator was inserted into the sc space. The wound was then
closed with two nylon sutures and the animals allowed to recover. Food
was removed and water intake and urine output monitored for the next
48 h. Urine was collected separate from feces. Sodium, potassium,
and osmolality were determined on urine collected during the final
24 h of infusion. After 48 h, rats were anesthetized by
methoxyflurane inhalation and blood collected in heparinized tubes by
open chest cardiac puncture for plasma analysis. Epididymal fat pads
and all identifiable interscapular adipose tissue were excised,
weighed, and immediately processed as described below.
Glycemic clamp procedures
Male Sprague-Dawley rats were prepared as previously described
(20). Food was removed from all rats at 0730, 3–4 h before time 0 of
the glycemic clamp period. Anesthesia was induced with ip methohexital
sodium (40 mg/kg) and a polyethylene catheter inserted into the right
femoral vein for maintenance of anesthesia with iv chloralose (50 mg/kg
initially, then 25 mg/kg·h). To prevent upper respiratory tract
obstruction and hypoxia, the trachea was cannulated for spontaneous
respiration of O2 enriched air. Sodium bicarbonate (0.1
mmol) was administered iv every 60 min. Rectal temperature was
monitored continuously and maintained at 37.5 C using a heated surgical
table and lamps. Polyethylene catheters were inserted into the left
femoral vein for infusion of insulin and leptin or vehicle, left
femoral artery for continuous arterial pressure measurement and blood
sampling, and left jugular vein for infusion of glucose.
Insulin and leptin or PBS (vehicle) were administered using a dual roller pump (Biorad) to control flow. At the onset of the clamp period (time 0), an iv bolus dose of leptin (500 µg/kg), or equivalent volume of PBS, were administered and followed by a continuous infusion of leptin (133 µg/kg·h) or PBS, for the next 3 h. Immediately after bolus leptin injection, a continuous infusion of human regular insulin (Lilly, Indianapolis, IA) was initiated and maintained at 125 mU/h. Whole blood glucose was maintained at 60 or 90 mg/100 ml using a variable rate infusion of 20% dextrose controlled by a Rainen peristaltic pump with tubing of id 0.02 mm calibrated to deliver a range of glucose infusion rates. Whole blood (30 µl) was sampled every 15 min and glucose determined using a Yellow Springs Instruments (Yellow Springs, OH) analyzer (YSI). To assist in maintaining target glycemia, glucose was also determined every 5 min on a drop of blood using a reagent strip and meter (Glucometer Elite, Bayer Diagnostics, Tarrytown, NY) calibrated previously to approximate the YSI readings.
Plasma and urine assays
Rat insulin, rat C-peptide, mouse leptin, and rat leptin were
determined by RIA using kits purchased from Linco, Inc. (St. Louis,
MO). For rat insulin, interassay CV in our hands was 11% over six
assays at a mean of 0.55 ng/ml and 10% at a mean of 2.05 ng/ml and the
assay range was 0.1–10 ng/ml. For rat C peptide, interassay CV in our
hands was 8% over five assays at a mean of 0.151 nM and
13% at a mean value of 0.484 nM and the assay range was
0.050–1.600 nM. For mouse leptin, interassay CV in our
hands was 2% over five assays at a mean of 1.19 ng/ml and 9% at a
mean value of 5.35 ng/ml and the assay range was 0.2 to 20 ng/ml. For
rat leptin, interassay CV in our hands was 9% over five assays at a
mean of 1.77 ng/ml and 12% at a mean value of 6.27 ng/ml, and the
assay range was 0.5–50 ng/ml. Plasma leptin measurements reported
herein were performed using the mouse leptin kit since the purpose was
to document effective infusion of the mouse peptide. However, we
measured rat leptin in addition to mouse leptin on plasma samples from
untreated normal rats to determine the degree of cross-reactivity and
normal plasma levels. Plasma glucose was measured using the YSI
analyzer. Plasma samples frozen in dry ice were sent to Linco, Inc.,
for RIA of IGF-1 using acid-ethanol extraction to minimize interference
by IGF binding proteins. As reported by Linco, Inc., assay sensitivity
is 0.31 ng/ml, linearity using the log/logit function extends to 10
ng/ml, and quality control requires two control samples within 2
SD of the mean. Urine sodium, potassium, and osmolality
were determined using standard methods by the clinical chemistry
laboratory at the Iowa City VA Medical Center.
Adipose tissue glucose transporter content
GLUT-4 content was determined as previously described (21) with
certain modifications. Epididymal and interscapular brown adipose
tissue was homogenized for 5 seconds using a polytron probe (Tekmar,
Cincinnati, OH) in ice-cold TES buffer (20 mM Tris-HCl, 250
mM sucrose, 1 mM EDTA, pH 7.4, containing 1
mM PMSF, 0.01 mM leupeptin, and 5 µg/ml
aprotinin). The homogenate was spun twice at 3000 x g
for 10 min, the supernatant spun again at 100,000 x g
for 90 min at 4 C, and the resultant precipitate suspended in ice-cold
TES by shearing using 22, 25, and 30-gauge needles. Protein was
determined by the Bradford method using a kit purchased from Bio-Rad
(Hercules, CA). Ten micrograms protein per lane was separated on 10%
polyacrylamide and electroblotted to Hybond-ECL nitrocellulose
membranes (Amersham, Arlington Heights, IL). Blots were blocked with
10% dry milk in PBS with 0.01% Tween-20 (PBS-Tween) for 10 min and
incubated with rabbit anti-GLUT-4 at 1:1000 dilution for 1 h at
room temperature, washed twice with PBS-Tween for 15 min each, and
exposed to antirabbit IgG (Amersham) at 1:2000 dilution for 15 min at
room temperature. Blots were again twice washed in PBS-Tween and
developed by electrochemoluminescence using a standard kit (ECL-Kit,
Amersham). GLUT-4 protein was quantified by densitometry using a
Hewlett-Packard Scan Jet 4c scanner equipped with a transiluminator and
image analysis software (SigmaGel, Jandel Scientific, San Rafael, CA).
Results were normalized to the mean of two control samples included on
all blots. Even loading was confirmed by amido black staining of the
blots.
Statistics
Numerical parameters measured in the leptin-infused rats were
compared with vehicle-treated controls by unpaired, two-tailed
t test. Four of eleven rat insulin levels measured in the
high dose sc leptin-treated rats were below 0.1 ng/ml, the limit of
assay sensitivity. Therefore, insulin concentrations were compared by
nonparametric analysis using the Mann-Whitney test ranking insulin
values below 0.1 ng/ml as equivalent.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Leptin
infusion at either dose did not change body weight compared with
vehicle-infused controls. However, the high dose leptin-treated rats
and their respective controls weighed more at baseline and lost more
weight during the 48-h period of fasting than the low dose
leptin-treated rats and their controls. Mouse leptin levels were
greater than control in both leptin-infused groups and considerably
higher in the high dose compared with low dose leptin-treated rats.
However, it should be noted that mouse leptin measurements do not
accurately reflect endogenous rat leptin secretion which represents the
only source of leptin in the noninfused control rats. In this regard,
we carried out measurements of rat leptin in five rat plasma samples
previously assayed for mouse leptin and found 49% cross-reactivity
(mean mouse leptin/mean rat leptin). Also, we measured rat leptin at
1100 h (3 h after removal of food) in four normal male rats
(272 ± 2 g) and found a mean (± SEM)
concentration of 1.70 ± 0.19 ng/ml in plasma obtained by cardiac
puncture after anesthesia by methoxyflurane inhalation.
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). Brown adipose tissue weight was not significantly
different in the lower dose leptin-treated rats compared with their
controls. No differences were noted in epididymal fat mass between the
leptin (at either dose) and vehicle-infused rats. Rats treated with the
lower dose of leptin and their controls weighed less at baseline and,
not surprisingly, had less epididymal fat mass at sacrifice.
Plasma glucose and insulin were measured after 2 days of infusion of
both doses of leptin and compared with respective vehicle-infused
controls (Fig. 1). Plasma glucose concentrations were
significantly reduced in both the high and low dose leptin-infused rats
compared with controls. Plasma insulin was reduced in the high dose
leptin-infused rats (Fig. 1). Plasma insulin was also reduced in the
low dose leptin-infused rats; however, this difference fell short of
statistical significance.
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). These IGF-1
studies were performed in a subgroup of 6 of the 11 rats from each
(leptin or vehicle) group. The leptin and control rats within this
subgroup were treated side by side at the same time and, like the
overall group, did not differ in initial body weight (mean ±
SEM, 332 ± 2 g and 331 ± 3 g,
leptin-infused compared with control, respectively) or weight loss
after treatment (mean ± SEM, 35.2 ± 1.2 g
and 37.0 ± 1.3 g, leptin-infused compared with control,
respectively).
GLUT-4 protein content was measured by immunoblot analysis in brown
adipose tissue and epididymal fat of the high dose leptin-infused rats
and their respective vehicle controls (Fig. 2). We could detect no
difference in GLUT-4 content in either tissue between these two groups.
As expected, based on prior studies of GLUT-4 expression in our
laboratory and others (22, 23, 24, 25), GLUT-4 signal intensity in epididymal
adipose tissue of these fasted rats (both leptin- and vehicle-treated)
was low. GLUT-4 expression is also reduced in brown adipose tissue as a
result of fasting (26) although the magnitude of that effect is
probably not as great accounting for the higher signal to noise ratio
in the brown fat samples (Fig. 2A).
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). Consistent with
this observation, urine output was greater in the high dose leptin
treated rats compared with controls; however, this difference missed
significance (P = 0.08). We also observed a significant
decrease in potassium excretion by the high dose leptin-infused rats
compared with vehicle controls. In contrast to the high dose leptin
experiments, no significant differences in the above parameters were
observed between the low dose leptin-infused rats and there respective
vehicle controls.
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.
There were no significant differences between the leptin- and
vehicle-infused rats in body weight, insulin or C-peptide in plasma
obtained at the end of the clamp period, or in mean arterial pressure
and heart rate during the clamp period. Plasma leptin, measured as the
mouse protein, was markedly increased in the leptin infused rats
compared with vehicle.
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, A and D). Leptin infusion
increased insulin sensitivity measured as whole body glucose
utilization (infusion rate), an effect evident as early as 45 min in
rats targeted at both levels of glycemia (Fig. 3, B and E). Glucose
utilization (area under the curve of glucose infusion rate
vs. time) in the leptin-treated rats at either glycemic
target was significantly greater than vehicle from time 45 min to the
end of the clamp period (Fig. 3, C and F).
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), suggesting no difference in endogenous insulin secretion.
However, ideally, endogenous insulin secretion should be very low or
entirely suppressed relative to infused insulin. Therefore, we studied
an additional group of leptin- and vehicle-infused rats targeted to 60
mg/100 ml, a glycemic level seen at baseline (time 0). Under these
conditions C-peptide was suppressed to the low limit of assay
sensitivity (Table 3) and, on a molar basis, to <3% of insulin
concentrations. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cohen et al. (27) recently reported that leptin modulates several steps involved in insulin mediated signaling in hepatoma cell lines suggesting multiple intracellular mechanisms by which leptin might have both positive or negative effects on insulin action. Although the bulk of these effects could be interpreted as evidence for leptin-mediated insulin resistance, our in vivo results, under the conditions we studied, imply enhancement of net whole body insulin action.
Chen et al. (16) recently reported lower insulin with similar glucose values in normal rats made hyperleptinemic for 28 days through infusion of recombinant adenovirus expressing the rat leptin transgene and suggested that leptin increased insulin sensitivity in these rats. In these studies, the adenovirus-transfected rats contained far less body fat than pair-fed controls, so the effect on insulin sensitivity may have been secondary to reduced fat mass. However, in our studies, the 2-day leptin infused rats were of the same weight and had equal epididymal fat mass to vehicle-treated controls. Hence, our results suggest that leptin has effects on insulin sensitivity independent of altered fat mass. Our glycemic clamp data showing an acute effect (45–180 min) of leptin on insulin-sensitivity further support this notion. Our sc leptin infusion studies also differ from the studies of Chen et al. in that we examined insulin sensitivity in the fasted state, as opposed to the pair-feeding experiments performed by Chen et al.
The effect of leptin to regulate body fat mass and energy storage is not explained on the basis of food intake alone, suggesting that leptin also increases energy expenditure (28). One way this may might occur is through increased brown adipose tissue energy metabolism with consequent thermogenesis. Although, not directly examined, certain observations support this concept. First, we observed a consistent hyperemic appearance to brown adipose tissue in our sc leptin-infused rats, suggesting increased blood flow that could facilitate metabolic activity. Second, brown adipose tissue of the high dose sc leptin-infused rats weighed less than vehicle control. Although speculative, this could be the result of accelerated fat metabolism and consequent reduced lipid mass. Third, we recently observed that leptin infusion to anesthetized rats increased brown adipose tissue sympathetic nerve activity measured by direct recording from nerves inervating interscapular fat (29). Increased sympathetic activity could activate ß3-adrenoreceptors that consequently could increase metabolic activity (30). Consistent with this concept, Collins et al. (31) recently reported that leptin increased brown adipose tissue norepinephrine turnover.
The above considerations led us to examine the expression of the GLUT-4 glucose transporter in brown and epididymal adipose tissue. GLUT-4 is expressed specifically in fat and muscle and is considered the major insulin-sensitive glucose transporter (32). However, we observed no difference in GLUT-4 content in these tissues, suggesting that the expression of this transporter in the tissues examined is not important in mediating the effects of leptin on insulin sensitivity. Nonetheless, leptin could still alter glucose transport in these tissues because intrinsic transporter activity, GLUT-4 translocation, and/or transporter recycling rate can alter glucose uptake independent of transporter expression (33). Of course there are a myriad of other potential biochemical or physiological mechanisms by which leptin might enhance insulin sensitivity without directly altering glucose transport, and these remain to be explored.
We also measured IGF-1 levels in sc leptin-infused rats compared with vehicle controls. Plasma IGF-1 concentrations, as well as the function of certain hormonal axes including reproductive, are impaired in nutritionally deplete states. Because leptin enhances reproductive function (34), we sought to determine whether leptin might maintain plasma IGF-1 during fasting. However, contrary to this hypothesis, plasma IGF-1 was actually lower in the leptin-infused rats, suggesting that leptin enhances the effect of fasting to deplete plasma IGF-1. However, in this regard, we point out that, although plasma samples for IGF-1 were subject to acid-ethanol extraction, it is difficult to exclude confounding effects of one or more IGF-1 binding proteins.
Ahima et al. (35) examined 48 h fasted mice treated
with ip leptin injections every 12 h (during fasting) compared
with saline injected fasted mice and untreated ad lib fed
mice. These investigators found insulin and glucose levels did not
differ between the leptin- and saline-treated fasted mice. Hence, these
findings are in contrast to our data and to the adenoviral data of Chen
et al. (16). The discrepancy could reflect different routes
of leptin administration; however, we suspect that the explanation lies
in the different leptin concentrations achieved. Leptin concentrations
in the leptin-treated mice of Ahima et al., although greater
than saline-treated fasted mice, did not differ from nonfasted,
untreated controls. In contrast, our leptin-infused, fasted rats had
higher circulating leptin concentrations (Table 1) than untreated
normal rats (described in Results) and the adenoviral
transfected rats of Chen et al. achieved leptin
concentrations far higher than vector treated controls. Ahima et
al. also found that leptin substantially blunted fasting-induced
alterations in the gonadal, adrenal, and thyroid axes of male mice, and
prevented the starvation-induced delay in ovulation in female mice.
Given these hypothalamic-pituitary effects, it is possible that the
effect of leptin observed in our experiments to lower IGF-1
concentrations might be secondary to reduced GH secretion. Of course,
this remains to be determined.
In contrast to our results, Schwartz, et al. (36) reported that intracerebral ventricular administration of 3.5 µg human leptin to normal male Long-Evans rats at the onset and 16 h before the conclusion of a 40 h fast did not affect glucose or insulin levels. These differences may be attributable to several factors. First, systemic leptin, which should have been present in far higher concentrations in our experiments, could be important in enhancing insulin sensitivity. In addition, the concentrations of leptin in the CNS may have been substantially different between our studies and those of Schwartz et al. Third, the pharmacokinetics of leptin action may be modulated by circulating leptin binding proteins. In this regard, it is also possible that leptin interactions with choroid plexus binding proteins (17), which would likely be bypassed by direct CNS administration, could alter leptin action. Finally, Schwartz et al. administered human leptin whereas we used mouse leptin and we cannot rule out species differences in ligand-receptor interactions.
In addition to leptin effects on insulinemia and glycemia, we observed that high dose leptin-infused rats drank significantly more water and produced more dilute urine than vehicle treated rats. Urine output was greater in the leptin-treated rats, although this fell short of statistical significance. Hence, these data suggest that leptin may inhibit either central ADH release or its renal tubular action. Jackson et al. (37) examined the effect of human leptin directly administered into left renal arteries of anesthetized rats. Consistent with our observations, these authors reported a diuretic effect. They also noted an increase in the ratio of sodium to potassium excretion, a ratio that was not affected in our experiments. Of course, comparison to our results is difficult because we examined a much different route and time course of leptin administration and we studied fasted rats.
Leptin concentrations in the rats we examined were clearly above physiologic, especially for the fasting state. Nonetheless, the concentrations in the high dose sc infused rats were within the range found in obese humans (4, 5, 6). Consequently, our results have potential therapeutic implications. It is possible that leptin treatment may improve glycemia in some insulin-resistant diabetic individuals even without accompanying weight loss. Potentially, this could be useful in treating noninsulin-dependent diabetes mellitus. The observed effects of leptin on urine composition may also have implications toward the clinical use of leptin. Our results suggest that trials of leptin therapy consider effects on water intake and output, circulating fluid volume, and electrolytes.
In summary, sc leptin infusion increases insulin sensitivity under basal (fasting) conditions. Also, iv leptin acutely increases insulin sensitivity in rats subject to hyperinsulinemia at constant glucose. This occurs in genetically normal rats and does not appear to require altered body weight or fat mass. Additional study will be needed to determine whether the effect of leptin on insulin sensitivity originates in the CNS or in peripheral tissues, to further define the mechanism(s) of this effect, and to determine if leptin may improve fasting glycemia and insulin action in states of underlying insulin resistance. Leptin also alters salt and water metabolism in fasted rats resulting in potassium retention, greater water intake, and more dilute urine.
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Footnotes |
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Received January 2, 1997.
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P. D. G. Miles, Y. Barak, R. M. Evans, and J. M. Olefsky Effect of heterozygous PPARgamma deficiency and TZD treatment on insulin resistance associated with age and high-fat feeding Am J Physiol Endocrinol Metab, March 1, 2003; 284(3): E618 - E626. [Abstract] [Full Text] [PDF]
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R. B.S. Harris, T. D. Mitchell, and S. Hebert Leptin-Induced Changes in Body Composition in High Fat-Fed Mice Experimental Biology and Medicine, January 1, 2003; 228(1): 24 - 32. [Abstract] [Full Text] [PDF]
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 M. Z. Strowski, M. Kohler, H. Y. Chen, M. E. Trumbauer, Z. Li, D. Szalkowski, S. Gopal-Truter, J. K. Fisher, J. M. Schaeffer, A. D. Blake, et al. Somatostatin Receptor Subtype 5 Regulates Insulin Secretion and Glucose Homeostasis Mol. Endocrinol., January 1, 2003; 17(1): 93 - 106. [Abstract] [Full Text] [PDF]
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M. Bagnasco, M. G. Dube, P. S. Kalra, and S. P. Kalra Evidence for the Existence of Distinct Central Appetite, Energy Expenditure, and Ghrelin Stimulation Pathways as Revealed by Hypothalamic Site-Specific Leptin Gene Therapy Endocrinology, November 1, 2002; 143(11): 4409 - 4421. [Abstract] [Full Text] [PDF]
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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]
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C.-Y. Lin, D. A. Higginbotham, R. L. Judd, and B. D. White Central leptin increases insulin sensitivity in streptozotocin-induced diabetic rats Am J Physiol Endocrinol Metab, May 1, 2002; 282(5): E1084 - E1091. [Abstract] [Full Text] [PDF]
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 M. Amstalden, M.R. Garcia, R.L. Stanko, S.E. Nizielski, C.D. Morrison, D.H. Keisler, and G.L. Williams Central Infusion of Recombinant Ovine Leptin Normalizes Plasma Insulin and Stimulates a Novel Hypersecretion of Luteinizing Hormone after Short-Term Fasting in Mature Beef Cows Biol Reprod, May 1, 2002; 66(5): 1555 - 1561. [Abstract] [Full Text]
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J. Wang, S. Obici, K. Morgan, N. Barzilai, Z. Feng, and L. Rossetti Overfeeding Rapidly Induces Leptin and Insulin Resistance Diabetes, December 1, 2001; 50(12): 2786 - 2791. [Abstract] [Full Text] [PDF]
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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]
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P. Concannon, K. Levac, R. Rawson, B. Tennant, and A. Bensadoun Seasonal changes in serum leptin, food intake, and body weight in photoentrained woodchucks Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2001; 281(3): R951 - R959. [Abstract] [Full Text] [PDF]
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M. Wauters, I. Mertens, T. Rankinen, M. Chagnon, C. Bouchard, and L. Van Gaal Leptin Receptor Gene Polymorphisms Are Associated with Insulin in Obese Women with Impaired Glucose Tolerance J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3227 - 3232. [Abstract] [Full Text] [PDF]
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H. Yamashita, J. Shao, T. Ishizuka, P. J. Klepcyk, P. Muhlenkamp, L. Qiao, N. Hoggard, and J. E. Friedman Leptin Administration Prevents Spontaneous Gestational Diabetes in Heterozygous Leprdb/+ Mice: Effects on Placental Leptin and Fetal Growth Endocrinology, July 1, 2001; 142(7): 2888 - 2897. [Abstract] [Full Text] [PDF]
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 M. L. G. Correia, D. A. Morgan, W. I. Sivitz, A. L. Mark, and W. G. Haynes Leptin Acts in the Central Nervous System to Produce Dose-Dependent Changes in Arterial Pressure Hypertension, March 1, 2001; 37(3): 936 - 942. [Abstract] [Full Text] [PDF]
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N. Matsuoka, Y. Ogawa, H. Masuzaki, K. Ebihara, M. Aizawa-Abe, N. Satoh, E. Ishikawa, Y. Fujisawa, A. Kosaki, K. Yamada, et al. Decreased triglyceride-rich lipoproteins in transgenic skinny mice overexpressing leptin Am J Physiol Endocrinol Metab, February 1, 2001; 280(2): E334 - E339. [Abstract] [Full Text] [PDF]
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B. B. Yaspelkis III, J. R. Davis, M. Saberi, T. L. Smith, R. Jazayeri, M. Singh, V. Fernandez, B. Trevino, N. Chinookoswong, J. Wang, et al. Leptin administration improves skeletal muscle insulin responsiveness in diet-induced insulin-resistant rats Am J Physiol Endocrinol Metab, January 1, 2001; 280(1): E130 - E142. [Abstract] [Full Text] [PDF]
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 B. Winters, Z. Mo, E. Brooks-Asplund, S. Kim, A. Shoukas, D. Li, D. Nyhan, and D. E. Berkowitz Reduction of obesity, as induced by leptin, reverses endothelial dysfunction in obese (Lepob) mice J Appl Physiol, December 1, 2000; 89(6): 2382 - 2390. [Abstract] [Full Text] [PDF]
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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]
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K. Matsumura, I. Abe, T. Tsuchihashi, and M. Fujishima Central effects of leptin on cardiovascular and neurohormonal responses in conscious rabbits Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2000; 278(5): R1314 - R1320. [Abstract] [Full Text] [PDF]
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R. Buettner, C. B. Newgard, C. J. Rhodes, and R. M. O'Doherty Correction of diet-induced hyperglycemia, hyperinsulinemia, and skeletal muscle insulin resistance by moderate hyperleptinemia Am J Physiol Endocrinol Metab, March 1, 2000; 278(3): E563 - E569. [Abstract] [Full Text] [PDF]
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T. J. Kieffer and J. F. Habener The adipoinsular axis: effects of leptin on pancreatic beta -cells Am J Physiol Endocrinol Metab, January 1, 2000; 278(1): E1 - E14. [Abstract] [Full Text] [PDF]
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 E. K. Jackson and W. A. Herzer A comparison of the natriuretic/diuretic effects of rat vs. human leptin in the rat Am J Physiol Renal Physiol, November 1, 1999; 277(5): F761 - F765. [Abstract] [Full Text] [PDF]
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M. Ozata, I. C. Ozdemir, and J. Licinio Human Leptin Deficiency Caused by a Missense Mutation: Multiple Endocrine Defects, Decreased Sympathetic Tone, and Immune System Dysfunction Indicate New Targets for Leptin Action, Greater Central than Peripheral Resistance to the Effects of Leptin, and Spontaneous Correction of Leptin-Mediated Defects J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3686 - 3695. [Abstract] [Full Text] [PDF]
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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]
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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]
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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]
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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]
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N. Barzilai, L. She, L. Liu, J. Wang, M. Hu, P. Vuguin, and L. Rossetti Decreased visceral adiposity accounts for leptin effect on hepatic but not peripheral insulin action Am J Physiol Endocrinol Metab, August 1, 1999; 277(2): E291 - E298. [Abstract] [Full Text] [PDF]
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 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]
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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]
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 C. S. Mantzoros The Role of Leptin in Human Obesity and Disease: A Review of Current Evidence Ann Intern Med, April 20, 1999; 130(8): 671 - 680. [Abstract] [Full Text] [PDF]
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W. I. Sivitz, B. D. Fink, and P. A. Donohoue Fasting and Leptin Modulate Adipose and Muscle Uncoupling Protein: Divergent Effects Between Messenger Ribonucleic Acid and Protein Expression Endocrinology, April 1, 1999; 140(4): 1511 - 1519. [Abstract] [Full Text]
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D.L. Foster and S. Nagatani Physiological Perspectives on Leptin as a Regulator of Reproduction: Role in Timing Puberty Biol Reprod, February 1, 1999; 60(2): 205 - 215. [Abstract] [Full Text] [PDF]
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A. L. Mark, M. Correia, D. A. Morgan, R. A. Shaffer, and W. G. Haynes Obesity-Induced Hypertension : New Concepts From the Emerging Biology of Obesity Hypertension, January 1, 1999; 33(1): 537 - 541. [Abstract] [Full Text] [PDF]
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 L. Liu, G. B. Karkanias, J. C. Morales, M. Hawkins, N. Barzilai, J. Wang, and L. Rossetti Intracerebroventricular Leptin Regulates Hepatic but Not Peripheral Glucose Fluxes J. Biol. Chem., November 20, 1998; 273(47): 31160 - 31167. [Abstract] [Full Text] [PDF]
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G. S. Tannenbaum, W. Gurd, and M. Lapointe Leptin Is a Potent Stimulator of Spontaneous Pulsatile Growth Hormone (GH) Secretion and the GH Response to GH-Releasing Hormone Endocrinology, September 1, 1998; 139(9): 3871 - 3875. [Abstract] [Full Text] [PDF]
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K. Arvaniti, Y. Deshaies, and D. Richard Effect of leptin on energy balance does not require the presence of intact adrenals Am J Physiol Regulatory Integrative Comp Physiol, July 1, 1998; 275(1): R105 - R111. [Abstract] [Full Text] [PDF]
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M. C. Flynn, T. R. Scott, T. C. Pritchard, and C. R. Plata-Salaman Mode of action of OB protein (leptin) on feeding Am J Physiol Regulatory Integrative Comp Physiol, July 1, 1998; 275(1): R174 - R179. [Abstract] [Full Text] [PDF]
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W. G. Haynes, W. I. Sivitz, D. A. Morgan, S. A. Walsh, and A. L. Mark Sympathetic and Cardiorenal Actions of Leptin Hypertension, September 1, 1997; 30(3): 619 - 623. [Abstract] [Full Text]
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 G. A. Brockmann, J. Kratzsch, C. S. Haley, U. Renne, M. Schwerin, and S. Karle Single QTL Effects, Epistasis, and Pleiotropy Account for Two-thirds of the Phenotypic F2 Variance of Growth and Obesity in DU6i x DBA/2 Mice Genome Res., December 1, 2000; 10(12): 1941 - 1957. [Abstract] [Full Text]
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