(Hypertension. 1997;30:619.)
© 1997 American Heart Association, Inc.
Articles |
Sympathetic and Cardiorenal Actions of Leptin
From the Hypertension Genetics Specialized Center of Research, Cardiovascular Center, Diabetes Endocrine Research Center, and Department of Internal Medicine, University of Iowa College of Medicine and Veterans Affairs Medical Center (Iowa City).
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Abstract |
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 Top Abstract IntroductionRegulation of Body FatLeptin BiologyLeptin and the Sympathetic...Leptin and KidneyLeptin and Insulin SensitivityClinical Relevance of LeptinReferences |
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Abstract Body weight is tightly regulated physiologically. The recent discovery of the peptide hormone leptin has permitted more detailed evaluation of the mechanisms responsible for control of body fat. Leptin is almost exclusively produced by adipose tissue and acts in the CNS through a specific receptor and multiple neuropeptide pathways to decrease appetite and increase energy expenditure. Leptin thus functions as the afferent component of a negative feedback mechanism to control adipose tissue mass. Increasing evidence suggests that leptin may have wider actions influencing autonomic, cardiovascular, and endocrine function. Intravenous leptin increases norepinephrine turnover and sympathetic nerve activity to thermogenic brown adipose tissue. Studies from our laboratory suggest that leptin also increases sympathetic nerve activity to kidney, hindlimb, and adrenal gland. However, systemic administration of leptin does not acutely increase arterial pressure or heart rate in anesthetized animals. Thus, longer-term exposure to hyperleptinemia may be necessary for full expression of the expected pressor effect of renal sympathoexcitation. Alternatively, leptin may have additional cardiovascular actions to oppose sympathetically mediated vasoconstriction. Leptin in high doses increases renal sodium and water excretion, apparently through a direct tubular action. In addition, leptin appears to increase systemic insulin sensitivity, even in the absence of weight loss. Although we are at an early stage of understanding, we speculate that abnormalities in the actions of leptin may have implications for the sympathetic, cardiovascular, and renal changes associated with obesity.
Key Words: obesity • adipose tissue • autonomic nervous system • kidney • blood pressure
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Introduction |
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TopAbstractIntroductionRegulation of Body FatLeptin BiologyLeptin and the Sympathetic...Leptin and KidneyLeptin and Insulin SensitivityClinical Relevance of LeptinReferences |
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Obesity is associated with increased incidence of hypertension and cardiovascular mortality.1 2 3 4 5 6 These complications have been attributed in the past to insulin resistance and hyperinsulinemia, but there is evidence that these factors cannot entirely explain obesity-induced hypertension.7 Animal models suggest that the sympathetic nervous system may be involved in obesity-related hypertension.8 In the last few years, there have been dramatic advances in understanding of the factors that regulate appetite, energy expenditure, and adiposity. This includes the discovery of leptin9 and increasing insight into the roles of neuropeptide Y (NPY),10 11 melanocortins,12 13 and corticotrophin-releasing factor11 in the hypothalamus, and into the function of the ß3-adrenergic receptor14 and uncoupling proteins15 16 in peripheral tissues. We briefly review intriguing evidence that leptin exerts sympathetic, renal, and metabolic effects that could potentially contribute to altered cardiovascular regulation in obesity.
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Regulation of Body Fat |
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TopAbstractIntroductionRegulation of Body FatLeptin BiologyLeptin and the Sympathetic...Leptin and KidneyLeptin and Insulin SensitivityClinical Relevance of LeptinReferences |
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Tight regulation of body fat stores is important to maintain energy reserves and to prevent excessive changes in body weight that might impair survival. Regulation of adipose tissue size is achieved through several mechanisms that form a negative feedback "lipostat"; changes in adipose tissue mass are signaled to central nervous system (CNS) centers that control both appetite and energy expenditure. A central tenet of the lipostat hypothesis is that there is a signal from adipose tissue to the CNS that completes the feedback loop. More than 20 years ago, Coleman17 demonstrated in parabiosis experiments that obesity in ob mice was due to lack of a circulating factor that acted to decrease body weight, whereas obesity in db mice was due to insensitivity to this same substance. In 1994, Friedman’s group (Zhang et al9 ) used positional cloning to identify the mutated gene responsible for obesity in the ob mouse strain. The product of this gene, named leptin from the Greek leptos for "thin," appears to constitute the signal from adipose tissue that acts in the CNS to complete the feedback loop regulating appetite and energy expenditure.
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Leptin Biology |
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TopAbstractIntroductionRegulation of Body FatLeptin BiologyLeptin and the Sympathetic...Leptin and KidneyLeptin and Insulin SensitivityClinical Relevance of LeptinReferences |
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Leptin is a 167 amino acid that is expressed and secreted exclusively from adipocytes.9 Leptin circulates in blood at low levels (
5 to 15 ng/mL) in lean subjects, with about
50% of leptin as the free form and the remainder attached to binding
proteins.18 Leptin expression and plasma concentrations
are proportional to adipose tissue mass in genetic models of obesity
(other than ob mouse), as well as in experimentally induced
obesity.19 Decreases in adipose tissue mass in obesity are
associated with decreases in leptin concentrations.19 Food
intake, insulin, and corticosteroids increase leptin
expression.20 21 22 Cold temperature and
catecholamines decrease adipocyte expression of
leptin.23 Leptin is too large to readily penetrate the
blood-brain barrier by passive diffusion. Entry of leptin into
cerebrospinal fluid appears to occur via a saturable specific transport
mechanism24 25 26 that mediates binding and endocytosis of
leptin by brain capillaries.27 The work of Coleman predicted that the db mouse should possess a mutation in a gene encoding for the leptin receptor. This has been confirmed by a number of investigators.28 29 30 The full leptin receptor (Ob-Rb) is a protein containing a single transmembrane domain with similarities to the class I cytokine receptors. It possesses two peptide motifs in a long intracellular carboxy terminal tail that interact with specific kinases to promote transcription through the STAT pathway.30 31 The gene for the leptin receptor appears to encode for at least six alternatively spiced variants of the receptor.30 The Ob-Rb form encodes for the full receptor, including a long intracellular tail. Ob-Ra, Ob-Rc, and Ob-Rd have premature terminations with resulting short intracellular tails, and they may act to transport leptin across the blood-brain barrier. Interestingly, mRNA for the leptin receptor is expressed not only in the hypothalamus but also in the choroid plexus, a plausible site for transport into the cerebrospinal fluid. The Ob-Re form lacks the transmembrane domain and, therefore, may be secreted as a soluble receptor, perhaps contributing to binding and inactivation of circulating leptin. In addition to the CNS, leptin receptor mRNA is expressed in adipose tissue, heart, kidney, liver, spleen, pancreatic islets, and testis,30 32 although the presence of the full-length receptor splice variant (Ob-Rb) has not been demonstrated in all of these tissues. Leptin appears to exert its effects on body fat stores through a number of hypothalamic mediators. These include NPY, which acts to increase body fat and is suppressed by leptin,10 11 and melanocortins12 13 and corticotrophin-releasing factor,11 which act to decrease body fat stores and are stimulated by leptin.
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Leptin and the Sympathetic Nervous System |
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TopAbstractIntroductionRegulation of Body FatLeptin BiologyLeptin and the Sympathetic...Leptin and KidneyLeptin and Insulin SensitivityClinical Relevance of LeptinReferences |
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Leptin acts to decrease weight and adipose tissue mass through decreases in appetite and food intake.33 34 35 However, leptin-treated mice lose more weight than pair-fed vehicle-treated animals, implying that leptin also increases energy expenditure.34 In addition, leptin-treated animals have higher core temperatures and metabolic rates than controls.33 Leptin has been shown to increase norepinephrine turnover in interscapular brown adipose tissue, suggesting increased sympathetic outflow to this thermogenic organ (Fig 1).36
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We have recently examined the effects of leptin on directly measured
sympathetic nerve activity to brown adipose tissue in lean
Sprague-Dawley rats.37 Because of lack of available
recombinant rat leptin, these studies were performed with recombinant
murine leptin. We first demonstrated that continuous subcutaneous
infusion of murine leptin (0.1 to 1 µg/h) for 5 days by
osmotic minipump decreased body weight by 5% in conscious rats,
thus confirming biological activity (Fig 2). Leptin administered
intravenously at a dose of 1000 µg/kg over 3 hours
caused a substantial, yet slow-onset, increase in sympathetic nerve
activity to brown adipose tissue of almost 300% (Fig 3). This effect of leptin on sympathetic
nerve activity to a thermogenic tissue was not unexpected.
Surprisingly, leptin also increased sympathetic nerve activity to
kidney, hindlimb, and adrenal gland (Fig 3). As with sympathetic nerve
activity to brown adipose tissue, sympathoactivation to leptin in these
other tissues was slow in onset, taking more than 2 hours to
reach maximal. The effect of leptin on sympathetic nerve activity was
dose-dependent, with a threshold dose of 100 µg/kg (plasma
concentration 5 ng/mL). Leptin-induced
sympathoactivation was still apparent after transection of sympathetic
nerves distal to the recording site, implying that the increase
in activity was from efferent, not afferent, nerves. This was confirmed
by the disappearance of sympathetic activity after ganglion blockade
with intravenous chlorisondamine (30 mg/kg). Leptin
did not cause sympathoactivation in obese Zucker rats, which are known
to possess a mutation in the gene for the leptin
receptor38 (Fig 4). Thus,
the sympathetic actions of leptin appear to require the presence of an
intact leptin receptor. Circulating immunoreactive leptin
concentrations between 10 and 200 ng/mL were produced by
infusion of leptin at doses above 100 µg/kg. However, unlike
the sympathoactivation, which was delayed, elevations in plasma leptin
were rapid in onset. Interestingly, arterial pressure and
heart rate were unaffected by leptin.
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These results demonstrating sympathoactivation to leptin have several implications. First, there was a dissociation between the time course of plasma leptin concentrations and sympathetic nerve activity during infusion of leptin, with delayed increases in sympathetic nerve activity. The implication of these data is that plasma leptin concentrations do not closely track concentrations at the site where leptin activates sympathetic nerve activity. Given that leptin is transported into cerebrospinal fluid by a saturable specific transport system,24 25 26 27 the CNS is a plausible site for the actions of leptin on sympathetic nerve traffic. Second, because the threshold concentration was only 5 ng/mL, it appears likely that physiological increases in plasma leptin may affect sympathetic nerve activity. Third, the effect of leptin on sympathetic nerve activity to kidney, a tissue not normally considered thermogenic, is unexpected. Sympathetically mediated thermogenesis in brown adipose tissue is dependent on activation of an uncoupling protein (UCP), which generates heat by creating a pathway that allows dissipation of the proton electrochemical gradient across the inner mitochondrial membrane.15 However, UCP is expressed only in brown adipose tissue. The recent discovery of a novel uncoupling protein that is expressed in most human tissues (UCP-2) could theoretically support a metabolic effect of renal sympathoactivation to leptin.16 Alternatively, sympathoactivation to leptin may reflect a wider role for leptin in control of autonomic function. Finally, it is of interest that acute leptin infusion did not alter arterial pressure or heart rate despite marked increases in renal, hindlimb, and adrenal sympathetic nerve activity, perhaps because the rats were anesthetized or because the degree or duration of sympathoexcitation was insufficient to acutely increase pressure. Alternatively, the lack of a pressor effect of leptin may indicate other actions that oppose sympathetically mediated vasoconstriction. Such actions might include vasodilatation or effects on cardiac and renal function. Indeed, there is preliminary evidence to support a direct renal effect of leptin.
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Leptin and Kidney |
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TopAbstractIntroductionRegulation of Body FatLeptin BiologyLeptin and the Sympathetic...Leptin and KidneyLeptin and Insulin SensitivityClinical Relevance of LeptinReferences |
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The kidney has been shown to express mRNA for the full-length Ob-Rb leptin receptor, suggesting that leptin may exert functional effects in this organ.32 Jackson and Li39 reported that leptin acts on the renal tubules to promote natriuresis and diuresis. Acute infusion of human leptin (0.3 to 30 µg/min) into a renal artery in anesthetized rats produced an ipsilateral increase in sodium excretion and urine volume without significant effects on renal blood flow or glomerular filtration rate39 (Fig 5). This diuretic and natriuretic effect of leptin was slow in onset and apparent at calculated local concentrations about 10-fold higher than the physiological range. The maximum increase in sodium excretion was approximately threefold and was confined to the infused kidney, suggesting a direct local effect. These results have been confirmed in studies using systemic intravenous administration of leptin (400 µg/kg), in which leptin caused an
400% increase in sodium excretion and an 50% increase in
urine volume.40 Given that the doses of leptin used in
these studies likely achieved supraphysiological
concentrations, it would be of interest to know whether lower doses
given chronically could achieve the same effects on renal water and
sodium excretion. Interestingly, the diuretic and
natriuretic effects of intravenous leptin
appear to be absent in spontaneously hypertensive rats
(SHR).40 Whether the lack of effect of leptin in SHR is
due to true leptin resistance or merely reflects the known impairment
of renal tubular sodium transport in this model must await further
studies. Given that SHR tend to be leaner than their normotensive
counterparts, any leptin resistance would presumably have to be
selective in nature.
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Leptin and Insulin Sensitivity |
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TopAbstractIntroductionRegulation of Body FatLeptin BiologyLeptin and the Sympathetic...Leptin and KidneyLeptin and Insulin SensitivityClinical Relevance of LeptinReferences |
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Leptin inhibits glucose-mediated insulin secretion in a perfused pancreas model.32 In lean Wistar rats, administration of an adenovirus containing cDNA for rat leptin increased plasma leptin concentrations to
8 ng/mL.41 Such gene therapy
with leptin for 28 days decreased body adipose mass substantially and
decreased plasma insulin concentrations without altering plasma glucose
concentrations.41 The finding that glucose levels did not
rise suggests that in addition to inhibiting insulin secretion, leptin
may act to increase insulin sensitivity. This hypothesis is supported
by the fact that insulin concentrations in genetically hyperleptinemic
animals were also lower than in pair-fed control animals of similar
weight, albeit with higher adipose mass.41 To investigate
the effects of leptin on insulin sensitivity without the potential
confounding effects of changes in adipose mass or alterations in
endogenous insulin secretion, we have performed studies
using a hyperinsulinemic, euglycemic clamp
to directly measure the effects of leptin on insulin sensitivity.
Murine leptin infused at a dose of 1000 µg/kg over 3 hours to
anesthetized Sprague-Dawley rats increased overall glucose
disposal rates by 30%.42 This effect occurred in the
absence of endogenous insulin secretion, as evidenced by
suppression of plasma C-peptide concentrations. Thus, leptin may
acutely increase insulin sensitivity, even in the absence of changes in
endogenous insulin secretion, adiposity, or weight. |
Clinical Relevance of Leptin |
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TopAbstractIntroductionRegulation of Body FatLeptin BiologyLeptin and the Sympathetic...Leptin and KidneyLeptin and Insulin SensitivityClinical Relevance of LeptinReferences |
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The majority of obese human subjects have high circulating concentrations of leptin.43 Some obese subjects have leptin concentrations within the normal range; these subjects may be more likely to gain weight subsequently.44 However, for most obese humans, inadequate leptin production does not appear to underlie obesity. Circulating hyperleptinemia suggests that leptin resistance may contribute to obesity. However, poor transport across the blood-brain barrier may also play a role in some subjects.24 25 26 Indeed, it has been shown that development of diet-induced obesity in rodents, a model with pathophysiologic similarities to human obesity, is associated with the development of impaired transport of leptin across the blood-brain barrier.45 To a large degree, the pathophysiologic relevance of the effects of leptin on sympathetic nerve activity, insulin sensitivity, and renal function depends on the degree and sites of leptin resistance in obese human subjects. Resistance to the neural effects of leptin on thermogenic sympathetic nerve activity would tend to decrease energy expenditure and thus promote adiposity. Alternatively, if hyperleptinemia merely reflects a compensatory mechanism for other, as yet unknown, pathophysiologic processes that contribute to obesity, then leptin-induced sympathoexcitation might act to increase thermogenesis, but it might also contribute to the sympathetically mediated renal sodium retention and hypertension of obesity.8 Resistance to the facilitatory effects of leptin on insulin sensitivity and renal sodium excretion might explain why insulin resistance and sodium sensitivity of blood pressure are frequent accompaniments of obesity. On the other hand, if obesity in some subjects is related to poor transport of leptin into the brain, then effects of leptin that are not mediated centrally, such as natriuresis, would be preserved.
Thus, leptin has multiple actions that are potentially relevant not only to control of body fat but also to cardiovascular regulation. Such actions include sympathetic activation, renal sodium excretion, and increased insulin sensitivity (Fig 6). For some of these actions, leptin may act as a signaling mechanism to activate compensatory mechanisms for the potentially deleterious effects of increases in adipose mass. This would apply to the effects of leptin on thermogenic sympathetic nerve traffic, insulin sensitivity, and renal sodium excretion. However, it is difficult to use this rationale for the renal sympathoactivation that leptin causes, unless these sympathetic effects mediate a metabolic function. The autonomic, renal, and endocrine effects of leptin warrant further investigation to address these possibilities.
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Acknowledgments |
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This research was supported by grants HL44546, HL43514, and HL55006-02 from the National Heart, Lung, and Blood Institute; by grant DK25295 from the National Institute of Diabetes, Digestive, and Kidney Diseases; and by funds from the Department of Veterans Affairs. William G. Haynes was the recipient of a Wellcome Trust Advanced Training Fellowship (No. 04215/114).
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Footnotes |
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Reprint requests to William G. Haynes, MD, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242.
Received May 8, 1997; first decision May 21, 1997; accepted June 2, 1997.
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E. Lambert, N. Straznicky, M. Schlaich, M. Esler, T. Dawood, E. Hotchkin, and G. Lambert Differing Pattern of Sympathoexcitation in Normal-Weight and Obesity-Related Hypertension Hypertension, November 1, 2007; 50(5): 862 - 868. [Abstract] [Full Text] [PDF]
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 I. Levinger, C. Goodman, D. L. Hare, G. Jerums, and S. Selig The Effect of Resistance Training on Functional Capacity and Quality of Life in Individuals with High and Low Numbers of Metabolic Risk Factors Diabetes Care, September 1, 2007; 30(9): 2205 - 2210. [Abstract] [Full Text] [PDF]
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 B. E. Levin Why some of us get fat and what we can do about it J. Physiol., September 1, 2007; 583(2): 425 - 430. [Abstract] [Full Text] [PDF]
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 J. D. Knudson, G. M. Dick, and J. D. Tune Adipokines and Coronary Vasomotor Dysfunction Experimental Biology and Medicine, June 1, 2007; 232(6): 727 - 736. [Abstract] [Full Text] [PDF]
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J. N. Gorski, A. A. Dunn-Meynell, and B. E. Levin Maternal obesity increases hypothalamic leptin receptor expression and sensitivity in juvenile obesity-prone rats Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2007; 292(5): R1782 - R1791. [Abstract] [Full Text] [PDF]
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D. M. Penn, L. C. Jordan, E. W. Kelso, J. E. Davenport, and R. B. S. Harris Effects of central or peripheral leptin administration on norepinephrine turnover in defined fat depots Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2006; 291(6): R1613 - R1621. [Abstract] [Full Text] [PDF]
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A. A. da Silva, L. S. Tallam, J. Liu, and J. E. Hall Chronic antidiabetic and cardiovascular actions of leptin: role of CNS and increased adrenergic activity Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2006; 291(5): R1275 - R1282. [Abstract] [Full Text] [PDF]
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M. Esler, N. Straznicky, N. Eikelis, K. Masuo, G. Lambert, and E. Lambert Mechanisms of Sympathetic Activation in Obesity-Related Hypertension Hypertension, November 1, 2006; 48(5): 787 - 796. [Full Text] [PDF]
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 P. Trayhurn and C. Bing Appetite and energy balance signals from adipocytes Phil Trans R Soc B, July 29, 2006; 361(1471): 1237 - 1249. [Abstract] [Full Text] [PDF]
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B. Wagoner, D. B. Hausman, and R. B. S. Harris Direct and indirect effects of leptin on preadipocyte proliferation and differentiation Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2006; 290(6): R1557 - R1564. [Abstract] [Full Text] [PDF]
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 S. V. Y. Raju, M. Zheng, K. H. Schuleri, A. C. Phan, D. Bedja, R. M. Saraiva, O. Yiginer, K. Vandegaer, K. L. Gabrielson, C. P. O'Donnell, et al. Activation of the cardiac ciliary neurotrophic factor receptor reverses left ventricular hypertrophy in leptin-deficient and leptin-resistant obesity. PNAS, March 14, 2006; 103(11): 4222 - 4227. [Abstract] [Full Text] [PDF]
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A. A. da Silva, J. J. Kuo, L. S. Tallam, J. Liu, and J. E. Hall Does Obesity Induce Resistance to the Long-Term Cardiovascular and Metabolic Actions of Melanocortin 3/4 Receptor Activation? Hypertension, February 1, 2006; 47(2): 259 - 264. [Abstract] [Full Text] [PDF]
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 M. Esler and N. Eikelis Is obstructive sleep apnea the cause of sympathetic nervous activation in human obesity? J Appl Physiol, January 1, 2006; 100(1): 11 - 12. [Full Text] [PDF]
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 N. E. Straznicky, E. A. Lambert, G. W. Lambert, K. Masuo, M. D. Esler, and P. J. Nestel Effects of Dietary Weight Loss on Sympathetic Activity and Cardiac Risk Factors Associated with the Metabolic Syndrome J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 5998 - 6005. [Abstract] [Full Text] [PDF]
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 Y. Zhang, G. E Kilroy, T. M. Henagan, V. Prpic-Uhing, W. G. Richards, A. W. Bannon, R. L. Mynatt, and T. W. Gettys Targeted deletion of melanocortin receptor subtypes 3 and 4, but not CART, alters nutrient partitioning and compromises behavioral and metabolic responses to leptin FASEB J, September 1, 2005; 19(11): 1482 - 1491. [Abstract] [Full Text] [PDF]
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J. D. Knudson, U. D. Dincer, C. Zhang, A. N. Swafford Jr., R. Koshida, A. Picchi, M. Focardi, G. M. Dick, and J. D. Tune Leptin receptors are expressed in coronary arteries, and hyperleptinemia causes significant coronary endothelial dysfunction Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H48 - H56. [Abstract] [Full Text] [PDF]
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K. M. Minhas, S. A. Khan, S. V. Y. Raju, A. C. Phan, D. R. Gonzalez, M. W. Skaf, K. Lee, A. D. Tejani, A. P. Saliaris, L. A. Barouch, et al. Leptin repletion restores depressed {beta}-adrenergic contractility in ob/ob mice independently of cardiac hypertrophy J. Physiol., June 1, 2005; 565(2): 463 - 474. [Abstract] [Full Text] [PDF]
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 M. R. Peeraully, J. R. Jenkins, and P. Trayhurn NGF gene expression and secretion in white adipose tissue: regulation in 3T3-L1 adipocytes by hormones and inflammatory cytokines Am J Physiol Endocrinol Metab, August 1, 2004; 287(2): E331 - E339. [Abstract] [Full Text] [PDF]
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 L. Fu, L. M. John, S. H. Adams, X. X. Yu, E. Tomlinson, M. Renz, P. M. Williams, R. Soriano, R. Corpuz, B. Moffat, et al. Fibroblast Growth Factor 19 Increases Metabolic Rate and Reverses Dietary and Leptin-Deficient Diabetes Endocrinology, June 1, 2004; 145(6): 2594 - 2603. [Abstract] [Full Text] [PDF]
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A. A. da Silva, J. J. Kuo, and J. E. Hall Role of Hypothalamic Melanocortin 3/4-Receptors in Mediating Chronic Cardiovascular, Renal, and Metabolic Actions of Leptin Hypertension, June 1, 2004; 43(6): 1312 - 1317. [Abstract] [Full Text] [PDF]
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N. Eikelis, G. Lambert, G. Wiesner, D. Kaye, M. Schlaich, M. Morris, J. Hastings, F. Socratous, and M. Esler Extra-adipocyte leptin release in human obesity and its relation to sympathoadrenal function Am J Physiol Endocrinol Metab, May 1, 2004; 286(5): E744 - E752. [Abstract] [Full Text] [PDF]
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T. L. Goodfriend and D. A. Calhoun Resistant Hypertension, Obesity, Sleep Apnea, and Aldosterone: Theory and Therapy Hypertension, March 1, 2004; 43(3): 518 - 524. [Abstract] [Full Text] [PDF]
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 A. Aneja, F. El-Atat, S. I. McFarlane, and J. R. Sowers Hypertension and Obesity Recent Prog. Horm. Res., January 1, 2004; 59(1): 169 - 205. [Abstract] [Full Text]
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 C. Plut, C. Ribiere, Y. Giudicelli, and J.-P. Dausse Hypothalamic Leptin Receptor and Signaling Molecule Expressions in Cafeteria Diet-Fed Rats J. Pharmacol. Exp. Ther., November 1, 2003; 307(2): 544 - 549. [Abstract] [Full Text] [PDF]
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M. Esler and D. Kaye Is Very High Sympathetic Tone in Heart Failure a Result of Keeping Bad Company? Hypertension, November 1, 2003; 42(5): 870 - 872. [Full Text] [PDF]
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 A. D. Dobrian, S. D. Schriver, T. Lynch, and R. L. Prewitt Effect of salt on hypertension and oxidative stress in a rat model of diet-induced obesity Am J Physiol Renal Physiol, October 1, 2003; 285(4): F619 - F628. [Abstract] [Full Text] [PDF]
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C. Vecchione, A. Aretini, A. Maffei, G. Marino, G. Selvetella, R. Poulet, V. Trimarco, G. Frati, and G. Lembo Cooperation Between Insulin and Leptin in the Modulation of Vascular Tone Hypertension, August 1, 2003; 42(2): 166 - 170. [Abstract] [Full Text] [PDF]
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N. Eikelis, M. Schlaich, A. Aggarwal, D. Kaye, and M. Esler Interactions Between Leptin and the Human Sympathetic Nervous System Hypertension, May 1, 2003; 41(5): 1072 - 1079. [Abstract] [Full Text] [PDF]
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G. Coatmellec-Taglioni, J.-P. Dausse, Y. Giudicelli, and C. Ribiere Sexual Dimorphism in Cafeteria Diet-Induced Hypertension Is Associated with Gender-Related Difference in Renal Leptin Receptor Down-Regulation J. Pharmacol. Exp. Ther., April 1, 2003; 305(1): 362 - 367. [Abstract] [Full Text]
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J. E. Hall The Kidney, Hypertension, and Obesity Hypertension, March 1, 2003; 41(3): 625 - 633. [Abstract] [Full Text] [PDF]
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 C.A Glader, L.S Birgander, S Soderberg, H.P Ildgruben, P Saikku, A Waldenstrom, and G.H Dahlen Lipoprotein(a), Chlamydia pneumoniae, leptin and tissue plasminogen activator as risk markers for valvular aortic stenosis Eur. Heart J., January 2, 2003; 24(2): 198 - 208. [Abstract] [Full Text] [PDF]
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K. Matsumura, T. Tsuchihashi, K. Fujii, I. Abe, and M. Iida Central Ghrelin Modulates Sympathetic Activity in Conscious Rabbits Hypertension, November 1, 2002; 40(5): 694 - 699. [Abstract] [Full Text] [PDF]
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A. Fortuno, A. Rodriguez, J. Gomez-Ambrosi, P. Muniz, J. Salvador, J. Diez, and G. Fruhbeck Leptin Inhibits Angiotensin II-Induced Intracellular Calcium Increase and Vasoconstriction in the Rat Aorta Endocrinology, September 1, 2002; 143(9): 3555 - 3560. [Abstract] [Full Text] [PDF]
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M. Hausberg, D. A. Morgan, J. L. Mitchell, W. I. Sivitz, A. L. Mark, and W. G. Haynes Leptin Potentiates Thermogenic Sympathetic Responses to Hypothermia: A Receptor-Mediated Effect Diabetes, August 1, 2002; 51(8): 2434 - 2440. [Abstract] [Full Text] [PDF]
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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]
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M. Carlyle, O. B. Jones, J. J. Kuo, and J. E. Hall Chronic Cardiovascular and Renal Actions of Leptin: Role of Adrenergic Activity Hypertension, February 1, 2002; 39(2): 496 - 501. [Abstract] [Full Text] [PDF]
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C. Vecchione, A. Maffei, S. Colella, A. Aretini, R. Poulet, G. Frati, M. T. Gentile, L. Fratta, V. Trimarco, B. Trimarco, et al. Leptin Effect on Endothelial Nitric Oxide Is Mediated Through Akt-Endothelial Nitric Oxide Synthase Phosphorylation Pathway Diabetes, January 1, 2002; 51(1): 168 - 173. [Abstract] [Full Text] [PDF]
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K. Matsumura, T. Tsuchihashi, and I. Abe Central Human Cocaine- and Amphetamine-Regulated Transcript Peptide 55-102 Increases Arterial Pressure in Conscious Rabbits Hypertension, November 1, 2001; 38(5): 1096 - 1100. [Abstract] [Full Text] [PDF]
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 A. Sonmez, U. Kisa, G. Uckaya, T. Eyileten, B. Comert, B. Koc, F. Kocabalkan, and M. Ozata Effects of losartan treatment on T-cell activities and plasma leptin concentrations in primary hypertension Journal of Renin-Angiotensin-Aldosterone System, June 1, 2001; 2(2): 112 - 116. [Abstract] [PDF]
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K. Matsumura, T. Tsuchihashi, and I. Abe Central Orexin-A Augments Sympathoadrenal Outflow in Conscious Rabbits Hypertension, June 1, 2001; 37(6): 1382 - 1387. [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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J. J. Kuo, O. B. Jones, and J. E. Hall Inhibition of NO Synthesis Enhances Chronic Cardiovascular and Renal Actions of Leptin Hypertension, February 1, 2001; 37(2): 670 - 676. [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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K. Matsumura, T. Tsuchihashi, and I. Abe Central Cardiovascular Action of Neuropeptide Y in Conscious Rabbits Hypertension, December 1, 2000; 36(6): 1040 - 1044. [Abstract] [Full Text] [PDF]
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J. A. Harrold, P. S. Widdowson, J. C. Clapham, and G. Williams Individual severity of dietary obesity in unselected Wistar rats: relationship with hyperphagia Am J Physiol Endocrinol Metab, August 1, 2000; 279(2): E340 - E347. [Abstract] [Full Text] [PDF]
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M. B. HORLICK, M. ROSENBAUM, M. NICOLSON, L. S. LEVINE, B. FEDUN, J. WANG, R. N. PIERSON Jr., and R. L. LEIBEL Effect of Puberty on the Relationship between Circulating Leptin and Body Composition J. Clin. Endocrinol. Metab., July 1, 2000; 85(7): 2509 - 2518. [Abstract] [Full Text]
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G. Paolisso, D. Manzella, N. Montano, A. Gambardella, and M. Varricchio Plasma Leptin Concentrations and Cardiac Autonomic Nervous System in Healthy Subjects with Different Body Weights J. Clin. Endocrinol. Metab., May 1, 2000; 85(5): 1810 - 1814. [Abstract] [Full Text]
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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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G. Uckaya, M. Ozata, A. Sonmez, C. Kinalp, T. Eyileten, N. Bingol, B. Koc, F. Kocabalkan, and I. C. Ozdemir Is Leptin Associated with Hypertensive Retinopathy? J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 683 - 687. [Abstract] [Full Text]
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B. E. Levin and A. A. Dunn-Meynell Defense of body weight against chronic caloric restriction in obesity-prone and -resistant rats Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2000; 278(1): R231 - R237. [Abstract] [Full Text] [PDF]
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T. D. Williams, J. B. Chambers, O. L. May, R. P. Henderson, M. E. Rashotte, and J. M. Overton Concurrent reductions in blood pressure and metabolic rate during fasting in the unrestrained SHR Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2000; 278(1): R255 - R262. [Abstract] [Full Text] [PDF]
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 A. Cittadini, C. S. Mantzoros, T. G. Hampton, K. E. Travers, S. E. Katz, J. P. Morgan, J. S. Flier, and P. S. Douglas Cardiovascular Abnormalities in Transgenic Mice With Reduced Brown Fat : An Animal Model of Human Obesity Circulation, November 23, 1999; 100(21): 2177 - 2183. [Abstract] [Full Text] [PDF]
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G. Paolisso, M. R. Tagliamonte, M. Galderisi, G. A. Zito, A. Petrocelli, C. Carella, O. de Divitiis, and M. Varricchio Plasma Leptin Level Is Associated With Myocardial Wall Thickness in Hypertensive Insulin-Resistant Men Hypertension, November 1, 1999; 34(5): 1047 - 1052. [Abstract] [Full Text] [PDF]
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S. P. Commins, D. J. Marsh, S. A. Thomas, P. M. Watson, M. A. Padgett, R. Palmiter, and T. W. Gettys Norepinephrine Is Required for Leptin Effects on Gene Expression in Brown and White Adipose Tissue Endocrinology, October 1, 1999; 140(10): 4772 - 4778. [Abstract] [Full Text]
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M. S. Blumberg, K. Deaver, and R. F. Kirby Leptin disinhibits nonshivering thermogenesis in infants after maternal separation Am J Physiol Regulatory Integrative Comp Physiol, February 1, 1999; 276(2): R606 - R610. [Abstract] [Full Text] [PDF]
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 S. Soderberg, B. Ahren, B. Stegmayr, O. Johnson, P.-G. Wiklund, L. Weinehall, G. Hallmans, and T. Olsson Leptin Is a Risk Marker for First-Ever Hemorrhagic Stroke in a Population-Based Cohort Stroke, February 1, 1999; 30(2): 328 - 337. [Abstract] [Full Text] [PDF]
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A. Glasow, A. Haidan, U. Hilbers, M. Breidert, J. Gillespie, W. A. Scherbaum, G. P. Chrousos, and S. R. Bornstein Expression of Ob Receptor in Normal Human Adrenals: Differential Regulation of Adrenocortical and Adrenomedullary Function by Leptin J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4459 - 4466. [Abstract] [Full Text]
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D. Villarreal, G. Reams, R. H. Freeman, and A. Taraben Renal effects of leptin in normotensive, hypertensive, and obese rats Am J Physiol Regulatory Integrative Comp Physiol, December 1, 1998; 275(6): R2056 - R2060. [Abstract] [Full Text] [PDF]
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J. S. Flier What's in a Name? In Search of Leptin's Physiologic Role J. Clin. Endocrinol. Metab., May 1, 1998; 83(5): 1407 - 1413. [Full Text]
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