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Division of Endocrinology, Metabolism, and Clinical Nutrition, Department of Medicine, and General Clinical Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
Address all correspondence and requests for reprints to: G. E. Sonnenberg, M.D., Division of Endocrinology, Metabolism, and Clinical Nutrition, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, Wisconsin 53226. E-mail: gsonnen{at}mcw.edu
Abstract
Despite numerous studies, the in vivo regulation of plasma leptin levels in response to nutritional factors continues to remain unclear. We investigated temporal and dose-response relationships of plasma leptin in response to physiological changes in insulin/glucose. After an overnight fast of 10 h, lean, healthy subjects were investigated for an additional 16 h of either extended fasting or one of three levels of glycemia/insulinemia induced by stepwise increasing iv glucose infusions. During extended fasting, plasma leptin values declined steadily and significantly. Plasma leptin levels remained constant at glucose concentrations between 5.8–6.5 mmol/liter, which maintained normoinsulinemia at 41.5–45.4 pmol/liter and FFA at 106–123 mg/liter, but leptin concentrations were increased at higher rates of glucose infusion (with plasma glucose rising to 8.7 mmol/liter). Concentrations of serum leptin were inversely related to FFA levels during extended fasting and at all levels of glycemia. Our data indicate that in lean healthy subjects, physiological changes in glycemia and insulinemia significantly alter plasma FFA and leptin concentrations. The increases in leptin concentrations demonstrate dose-dependent relationships that appear to relate to changes in FFA levels as well as to changes in glycemia/insulinemia.
LEPTIN, THE ob gene product, is secreted from adipose tissue and is a component of a regulatory loop linking the regulation of feeding with energy expenditure and/or fat storage (1, 2, 3). Elevated levels of leptin and ob gene mRNA have been reported in obese subjects, and this elevation in leptin levels is closely related to level of body adiposity. Expression of the obese gene is subject to acute nutritional regulation in rodents, because levels of its mRNA fall during the fasting state and rise immediately with refeeding, whereas overfeeding augments adipose tissue ob gene expression. Ingesting chow, total parenteral nutrition, or iv glucose have all been shown to increase levels of leptin mRNA and circulating hormone in animal studies. Similarly, leptin secretion was shown to be reduced in fasting in a number of human studies, whereas glucose and/or insulin elevate plasma leptin levels. In addition, leptin concentrations and ob mRNA are reduced by diet-induced weight loss. That a diurnal variation in plasma leptin is entrained to meal pattern in healthy young men (4) further suggests acute nutritional regulation of leptin expression, in addition to presumably longer term regulation by changes in body fat stores.
A considerable body of evidence suggests that the prevailing insulin concentration contributes to this regulation. Insulin directly regulates ob gene expression, and changes in plasma insulin levels under different physiological states have resulted in positively correlated changes in leptin concentrations. A number of animal and in vitro studies suggest that insulin stimulates leptin production and release, thereby contributing to the regulation of starvation- and meal-induced modulations of leptin levels. That insulin participates in the acute regulation of leptin levels in humans is less obvious, however. Hyperinsulinemia induced by clamp studies results in increased leptin concentrations only over the course of longer studies (5, 6, 7, 8, 9), but not in the short term (10, 11, 12, 13, 14).
Glucose has also been shown to influence leptin levels. Indeed, several recent reports indicate that glucose and/or alterations in glucose metabolism may be the sole determinant of leptin secretion. Mueller and co-workers (15) demonstrated that glucose metabolism is necessary for leptin release from cultured adipocytes, suggesting that circulating leptin may be regulated by insulin- and glucose-mediated changes in glucose utilization. Leptin gene expression was found to be better correlated with plasma glucose than with plasma insulin in mice injected with glucose (16). Klein et al. (17) demonstrated a down-regulation of human adipose tissue leptin production occurring early in starvation, probably resulting from alterations in glucose metabolism. In that study euglycemia was maintained by continuous low glucose infusion, removing changes in insulinemia as a possible regulatory factor. More recently, Wellhoener et al. (18) provided evidence that the effects of glucose on serum leptin concentrations could be explained by insulin- and glucose-stimulated glucose uptake.
The role of FFA in the regulation of leptin concentrations is less clear. Although reductions in leptin concentrations after incubation with FFA have been demonstrated in isolated cells (19, 20), other studies have failed to demonstrate any direct short-term influence of circulating FFA on leptin levels in humans (21, 22). On the other hand, it is difficult to rule out any contribution of FFA to leptin levels. Fisher et al. (23) demonstrated an inverse relationship between insulin-induced changes in leptin and the degree of lipolysis in abdominal sc adipose tissue during a euglycemic clamp procedure, suggesting acute regulation of leptin secretion by pathways regulating lipolysis. In addition, polyunsaturated fatty acids have been reported to inhibit glucose/insulin stimulation of leptin gene transcription in transfected rat tissues (24). A recent study has demonstrated reduced leptin mRNA levels and promoter activity by n-3 polyunsaturated fatty acids in transfected BeWo cells (25), suggesting a regulation of leptin transcription by at least certain forms of dietary fatty acids. This study also demonstrated a negative relationship between plasma leptin concentration and dietary intake of polyunsaturated fatty acids as well as a reduction in leptin mRNA expression in fat tissue from rats fed an n-3 fatty acid-enriched diet relative to those fed a diet rich in lard.
It is uncertain how these factors directly contribute to and interact in the acute regulation of leptin secretion. The aim of the present study was to investigate the effects of insulin and glucose in lean healthy volunteers with regard to both short- and longer-term responses. We have attempted to represent the physiological states of normoglycemia as well as fasting and feeding states. In this regard we have studied this cohort of individuals during fasting and at three different physiological levels of glycemia/insulinemia. We also examined plasma FFA to clarify relationships between lipid turnover and plasma leptin concentrations.
Subjects and Methods
Study subjects
Nine nonobese normal subjects (six females and three males) between 21–46 yr of age (mean ± SEM, 29.2 ± 2.8 yr) participated in the study. Their weights were normal (body mass index, 23.1 ± 0.7 kg/m2; range, 19.5–26.1) and had been stable for at least 2 months before the study. Subjects were healthy without evidence suggestive of diabetes mellitus or other endocrine diseases, hypertension, or heart disease. These disorders were excluded by history, physical examination, and electrocardiogram. The absence of diabetes mellitus or impaired glucose tolerance was confirmed by a normal glucose tolerance test, evaluated according to the National Diabetes Data Group criteria. Normal kidney, liver, and thyroid functions were ascertained by laboratory tests. Subjects participating in either dietary or excessive exercise programs or taking any drugs known to influence weight or carbohydrate or lipid metabolism were not included.
The study protocol was approved by the Human Research Review Committee of the Medical College of Wisconsin. Written consent was obtained before the studies after thorough explanation of the nature of the study and the details of all procedures involved. Each volunteer was informed that the study would not provide direct benefit to him/her, although all data would be made available and explained upon request. Investigations were conducted at the General Clinical Research Center at the Medical College of Wisconsin.
Experimental protocols
The subjects were admitted to the General Clinical Research Center on the evening before studies were to begin. Each subject participated in all four parts of the study. In randomized order, they received either continuous saline infusion or one of three constant rates of iv glucose infusion. The effect of prolonged fasting on plasma concentrations of leptin, glucose, and insulin was evaluated over 16-h periods. After an initial 10-h fast, an 18-gauge catheter for infusion was inserted into an antecubital vein. Normal saline was administered via a Harvard infusion pump (model 915, Harvard Apparatus, Inc., South Natick, MA). Arterialized venous blood samples were drawn from a dorsal hand vein with the subject’s forearm placed into a heating pad maintaining a constant temperature of 65 C throughout the study. Samples were obtained at both -15 and 0 min for subsequent measurements of baseline glucose, insulin, FFA, and leptin. The beginning of all infusions represents time zero of the sampling schedule (this was always between 0900–1000 h). Blood samples were obtained at 4, 8, 12, and 16 h after the beginning of the infusion. At each time three samples (2.5 ml each) were withdrawn over consecutive 10-min periods. Tubes were immediately placed on ice and centrifuged, and aliquots for leptin, insulin, and glucose determinations were stored at -20 C until assayed. Throughout the entire study, subjects were resting in a supine position and were not allowed any food or beverages except water.
The effects of stepwise increases in glucose on plasma concentrations of leptin, glucose, and insulin were evaluated using continuous iv glucose infusions at three different rates over the 16-h period. Infusions were prepared to contain 20% dextrose and 40 mEq potassium/liter infusate. Infusions were delivered using programmable Harvard infusion pumps (model 44). The glucose infusions were prepared to deliver 2.5, 5.0, or 7.5 mg/kg·min. Blood sampling procedures and sample processing are described above.
Assays
RIA of leptin was performed using a specific antibody to human leptin (human leptin RIA, Linco Research, Inc., St. Charles, MO). A solid phase RIA (INCSTAR Corp., St. Paul, MN) was used for the determination of plasma insulin. Quality controls were performed to assure the stability and reliability of the assays. Five pool sera of increasing peptide concentrations were used to evaluate the intra- and interassay coefficients of variance (CVs). For leptin the intraassay CV ranged between 3.4–6.6%, and the interassay CV between 7.1–9.3% over the concentration range of 2–185 ng/ml. For insulin the intraassay CV ranged between 5.6–7.5%, and the interassay CV between 7.5–12.2% over the concentration range of 12–1200 pmol/liter. Plasma glucose concentrations were measured by the glucose oxidase method, using Glucose Analyzer 2 (Beckman Coulter, Inc., Brea, CA). Plasma FFA were measured colorimetrically using enzymatic, end-point kits (NEFA C) obtained from Wako Chemicals USA, Inc. (Richmond, VA).
Statistical analyses
Concentrations derived from the three blood samples obtained were averaged to represent the respective data at 0, 4, 8, 12, and 16 h after beginning infusions. Results are given as the mean ± SEM. A two-factor (infusion level by time), within-persons, repeated measures ANOVA was used to compare the glucose, insulin, FFA, and leptin responses over time (26). Relationships between leptin and FFA at each level of glycemia/insulinemia were examined using multiple regression analyses. Comparisons of the joint variation in glucose, insulin, FFA, and leptin were made using Pearson correlations. Adjusted correlations were obtained using partial correlations. A normalizing z-transform was used in the comparisons of Pearson correlations between infusion levels (27).
Results
Extended fasting
Subjects were evaluated after a 10-h overnight fast. Over a
subsequent 16-h period, short- and longer-term effects of fasting were
observed on plasma concentrations of glucose, insulin, FFA, and leptin
(Table 1
and Fig. 1). The mean plasma
leptin concentration was 8.3 ± 1.6
ng/ml in the morning at time zero and declined steadily to 3.6 ±
0.5 ng/ml by 16 h, a 57% reduction over the course of the study.
This decline was significant at time points as early as 4 h
(P < 0.05; at later points, P <
0.001). There was no change in the mean plasma glucose concentration
throughout the fasting period. The mean plasma insulin level was
45.4 ± 7.8 pmol/liter at time zero and remained unchanged at 4
and 8 h, but decreased significantly thereafter to 30.4 ±
3.5 pmol/liter by 16 h (P < 0.01). The reduction
in plasma leptin concentrations over the entire 16-h period was
correlated with the decline in insulin (r = 0.32;
P < 0.05). Plasma FFA levels increased steadily over
the entire fasting period, tripling from a baseline value of 115
± 17 to 339 ± 25 mg/liter at 16 h (P <
0.001). Changes in leptin during extended fasting (saline infusion)
were highly correlated inversely with the changes in FFA over the 16-h
period (P < 0.0001).
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The dose-response effects of graded insulinemia, resulting
from stepwise glucose infusions, on plasma leptin levels were also
evaluated. During these infusions, plasma insulin levels were increased
by 4 h in a dose-dependent manner, as shown in Table 1
and Fig. 1.
At all levels of glycemia, plasma insulin levels had reached steady
state by 4 h. Plasma glucose levels, unchanged during the fasting
period, were similarly increased during the higher glucose infusion
protocols, to steady state levels between 5.8–6.5 mmol/liter (2.5
mg/kg·min), 7.0–7.4 mmol/liter (5.0 mg/kg·min), and 7.9–8.7
mmol/liter (7.5 mg/kg·min). Like insulin, plasma glucose levels
reached steady state by 4 h at the higher levels of glucose
infusion. At the two highest concentrations of glucose, FFA levels were
significantly reduced by 4 h (P < 0.001) and
dropped slowly thereafter. There were no differences in FFA levels
between the 5 and 7.5 mg/kg·min infusions. The 2.5 mg/kg·min
glucose infusion did not significantly affect plasma FFA, whose levels
remained constant throughout the infusion period.
Plasma leptin concentrations were also examined during these glucose infusions. During the 2.5 mg/kg·min glucose infusion, leptin levels, like FFA concentrations, were virtually unchanged, ranging between 7.6–8.2 ng/ml over the course of the study. In the 5.0 mg/kg·min protocol, there was no change in leptin levels over the first 8 h (7.9–8.6 ng/ml), but leptin increased significantly over the subsequent 8 h to 9.8 ± 1.3 ng/ml (P < 0.001). In contrast, leptin levels were significantly increased by 4 h during the 7.5 mg/kg·min protocol (P < 0.05), followed by a 58% increase (relative to baseline) during the course of the protocol (to 12.8 ± 2.5 ng/ml).
Pearson correlation analysis, based upon 145 observations, was used to examine the correlations of leptin with FFA (r = -0.24; P < 0.005), glucose (r = 0.21; P < 0.01), and insulin (r = 0.15; P = 0.065) over the course of each study. Changes in plasma leptin levels were significantly correlated with both FFA and glucose.
Relationships of leptin with glucose, insulin, and FFA
As these parameters are closely interrelated, we examined their interdependence using partial correlation analysis. When the partial correlation of leptin and glucose is adjusted for FFA, the partial correlation coefficient is 0.10 (P = 0.25; n = 45 observations), whereas the partial correlation coefficient of leptin and FFA adjusted for glucose is -0.14 (P = 0.10), indicating that the correlation between leptin and glucose is substantially explained by leptin, whereas a portion of the FFA relationship with leptin is not explained by glucose.
When the partial correlation of leptin and insulin is adjusted for FFA, the partial correlation coefficient is 0.028 (P = 0.74), whereas the partial correlation coefficient of leptin and FFA adjusted for insulin is -0.18 (P = 0.024), indicating that the correlation between leptin and insulin is entirely explained by leptin, whereas a significant portion of the FFA relationship with leptin is not explained by insulin.
When the partial correlation of FFA is adjusted for both insulin and glucose, its correlation with FFA is -0.15 (P = 0.08), indicating that the combination of insulin and glucose predicts no more of the relationship between FFA and leptin than glucose alone. These results indicate that the effects of glucose and insulin are important in the regulation of plasma leptin levels and suggest that FFA may influence plasma leptin concentration through glucose and insulin.
Relative changes
Because women have higher circulating levels of plasma leptin than
men, we examined proportional changes in plasma leptin to normalize
possible gender effects. In Fig. 2, the
changes in plasma leptin during extended fasting and graded glycemia
are expressed as percentages of the 0 h points. After normalizing
the data, relative changes in plasma leptin levels exhibit similar
responses to fasting and graded glycemia as the absolute values shown
in Fig. 1.
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Although leptin secretion is acutely regulated by nutritional
factors, it has been difficult to distinguish their individual
contributions. Indeed, glucose, insulin, and FFA might act in a
concerted manner to regulate plasma leptin concentrations. We have
examined the effects of insulin/glucose and FFA on leptin
concentrations under the physiological conditions of fasting, mild,
moderate, and elevated glycemia/insulinemia. Our results demonstrate
clear relationships of leptin levels with both glucose/insulin and FFA
concentrations in lean individuals, with steady state plasma leptin
being achieved and maintained at concentrations of glucose between
4.7–5.8 mg/dl (infusion rate, 2.5 mg/kg·min) at insulin
concentrations between 41.5–45.4 pmol/liter, and FFA concentrations
between 104–123 mg/liter. This physiological steady state achieved by
low levels of glucose infusion suggests an equilibrium between leptin
production/release and clearance, whereas deviations from
normoglycemia shift this equilibrium in either direction. Thus,
extending the overnight fast by additional 16 h in these lean
individuals resulted in a significant decline in plasma leptin
concentration. Boden et al. (28), Kolaczynski
et al. (29), and Stefan et al.
(30) all reported reductions in serum leptin levels during
fasting, and Dubuc et al. (31) found a similar
decline during prolonged energy restriction. Part of this decline may
result from a reduction in transcription, as ob mRNA levels
are known to be decreased during fasting (29, 32). The
decline in plasma insulin concentration during the fasting period was
not seen before 12 h (Table 1), unlike leptin, which already
demonstrated a decline by 4 h. This suggests that other mediators
may be involved in this down-regulation of leptin levels with fasting.
On the other hand, changes in leptin levels demonstrate inverse
correlations with ambient FFA concentrations at all time points
(Pearson correlation coefficient = -0.235; P <
0.005).
Increasing glycemia/insulinemia results in increased leptin levels and decreased concentrations of FFA. At the 5.0 mg/kg·min glucose infusion (plasma glucose levels of 7.0–7.4 mmol/liter), there was no change in plasma leptin during the first 8 h. More prolonged exposure to glucose and/or insulin, however, was associated with a significant increase in leptin levels above baseline. Plasma glucose and insulin levels increased more quickly in response to the highest glucose infusion (7.5 mg/kg·min, resulting in glucose levels of 7.9–8.7 mg/dl), followed by significant increases in plasma leptin, even at 4 h. At the levels of glycemia and insulinemia achieved, there was an immediate and higher increase in plasma leptin levels than observed with the other protocols. By 16 h the increase in leptin concentration was correlated with changes in plasma levels of glucose and insulin (P < 0.05 for glucose and P < 0.0001 for insulin). As seen with fasting values, plasma FFA levels were strongly and negatively correlated with changes in plasma leptin and glucose/insulin (P < 0.001 at the higher glucose infusion rate). The strong negative relationship demonstrated between levels of leptin and FFA between all time points is seen with neither glucose nor insulin, whose concentrations are near maximal by 4 h.
Although leptin concentrations are highly correlated with body mass
index, it is clear that leptin secretion is acutely regulated by more
than the amount of energy stored in adipose tissue. Plasma leptin
homeostasis appears to be a highly complex phenomenon, undergoing both
acute and chronic regulation by a number of hormones and nutritional
factors (1, 2, 3); their plasma levels and interactions among
them appear integral to the regulatory process. Clearly, leptin levels
are increased by insulin/glucose, and some studies suggest that they
may also be reduced by elevations in FFA, but because plasma glucose,
FFA, and leptin levels all contribute to the regulation of insulin
concentrations and are, in turn, regulated by insulin, it has been
difficult to distinguish individual contributions of these factors to
leptin levels. Our results support an inhibitory role for FFA in the
regulation of plasma leptin levels. As shown in Fig. 1, FFA
concentrations behave in a reciprocal manner from those seen for leptin
in each protocol. These results agree with those showing that 1 wk of
energy restriction in men similarly results in an increase in FFA
concentrations that is significantly correlated with a sharp decline in
plasma leptin levels (32). Our results also agree with
findings reported by Fisher et al. (23) of an
inverse relationship between the lipolytic status of abdominal sc fat
and changes in plasma leptin levels and lend credence to their
hypothesis that leptin secretion may be related to the pathways that
regulate lipolysis. On the other hand, a study comparing effects of 2-h
hyperglycemic clamps (after 12- and 36-h fasts, with and without
Intralipid) vs. saline controls in groups of lean
volunteers demonstrated an elevation in plasma leptin levels under
conditions of high FFA, glucose, and insulin (30),
suggesting that under certain conditions FFA may increase plasma leptin
levels.
The actual role of FFA in the regulation of leptin levels in humans is uncertain, as a number of studies have failed to demonstrate any direct influence of leptin level by FFA, either in vivo (9, 21, 22, 33) or after high fat meals (34). In this last study, which accounted for the diurnal leptin rhythm, Havel et al. (4) examined the 24-h leptin pattern of subjects who ate isocaloric low or high fat meals and noted larger increases in leptin after high carbohydrate meals. This study did not evaluate a possible inhibitory or attenuating role for FFA in this regulation, however. We have previously addressed this question as well, examining plasma leptin concentrations during hyperglycemic clamping (plasma glucose levels to 11 mmol/liter) in lean Caucasian women whose plasma FFA levels were elevated with Intralipid (9). Combined hyperglycemia/hyperinsulinemia did not influence plasma leptin levels in proportion with the changes in FFA or glucose/insulin concentrations, which suggested that leptin levels are probably not regulated by FFA. However, the glucose level in that study may have been too high to clearly demonstrate this relationship. Another confounder is the possibility that only certain types of FFA influence leptin levels. A recent report showing that n-3 polyunsaturated fatty acids reduce leptin promoter activity, in contrast to saturated or monounsaturated fatty acids (25), suggests a very specific regulatory action of FFA. In addition, it may be that the FFA actions on leptin secretion are too slow to be noted in that short-term study. The decline in FFA levels seen in this study appears to be maximal at glucose levels near 7.4 mmol/liter, and hormonal and other nutritional factors may play more important roles in leptin dynamics at this higher level of glycemia. The present study, performed under far more physiological conditions, suggests a possible role for FFA in the regulation of leptin secretion.
It has been proposed that leptin production may be coordinated with both de novo cholesterol synthesis (4) and triglyceride synthesis (4, 35). Several recent studies have provided evidence to support a relationship between leptin production and lipogenesis (22, 32). Insulin stimulates lipogenesis, both directly and indirectly through stimulating glucose uptake into fat tissue. This suggests that our results could represent the effects of insulin-mediated changes in FFA (and glucose) concentrations, and even that FFA levels may be incidental to leptin concentrations and play no actual role in its regulation. However, insulin also functions to inhibit lipolysis, reducing levels of FFA that would otherwise inhibit leptin production and thereby contribute to elevations in leptin levels. It is therefore difficult to conclude that FFA plays no role in this regulatory process. More directly, evidence is provided by two recent studies pointing to inactivation of the leptin gene by polyunsaturated fatty acids (24, 25), suggesting that FFA could either directly inhibit leptin transcription or attenuate glucose/insulin stimulation of leptin biosynthesis. Component contributions to leptin production may ultimately be delineated through further examination of its promoter region.
Statistical analysis from this study suggests that the relationship of leptin levels with FFA is stronger than that for glucose, but the dataset is too small to try to draw this conclusion. Although these preliminary data are insufficient to distinguish direct from indirect actions of FFA on leptin dynamics or to determine which of these nutritional factors is involved in its acute regulation, we can nonetheless make several inferences from these results. Although plasma leptin concentrations demonstrate clear dose-dependent relationships with physiological levels of glycemia and insulinemia, FFA are also strongly and negatively correlated with changes in leptin during fasting and glucose infusion. Both glucose and insulin levels reach equilibrium points at 4 h, whereas FFA levels continue to fall as leptin levels are continuously elevated throughout the course of the 16-h study. Moreover, FFA is at least as highly correlated with leptin levels as glucose. These results suggest a potential role for FFA in the regulation of leptin concentrations. However, the lack of a true time and concentration dependence for either glucose, insulin, or FFA on plasma leptin levels suggests a far more complex mode of short-term nutritional regulation.
Acknowledgments
We greatly appreciate the skillful assistance of the General Clinical Research Center nurses and the General Clinical Research Center nutrition, data management, and laboratory staff.
Footnotes
This work was supported by Grants DK-45949 (to G.E.S.) and General Clinical Research Center Program Grant RR-00058 from the NIH.
Abbreviations: CV, Coefficient of variance.
Received October 30, 2000.
Accepted July 13, 2001.
References
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),
2.5 mg/kg·min glucose infusion (
), 5 mg/kg·min glucose infusion
(
), and 7.5 mg/kg·min glucose infusion (
) plotted as a function
of time. *, Significant difference from baseline value at
P < 0.01; 
, significant difference from baseline
(time zero) value at P < 0.001.