Review articleEffects of leptin on cardiovascular physiology
Introduction
The discovery of leptin synthesis and secretion from adipose tissue was a result of studies to understand the genetic basis for obesity in the ob/ob mouse.1 Shortly after the identification of leptin as a secretory product of adipose tissue a number of laboratories demonstrated that administration of the exogenous hormone resulted in inhibition of food intake and weight loss in mice.2 The leptin receptor was then identified as a hypothalamic protein, and a point mutation within the gene implicated as the defect resulting in obesity in db/db mice.3, 4 Taken together these observations, as well as numerous other related findings, established a central role for leptin in regulation of body weight. However, the demonstration of elevated leptin in obese humans and animals, and that the leptin receptor point mutation in the db/db mouse was not present in the human leptin receptor, suggested that most human obesity was not the result of single gene mutations identified in these mouse obesity models. Thus, in analogy to the concept of insulin resistance, it was suggested that obese humans were resistant to the weight-reducing effects of leptin.2, 5 Further, findings from a number of laboratories suggest that the hyperleptinemia resulting from the inability of leptin to reduce adipose tissue mass in obesity may have pathologic consequences, particularly on the cardiovascular system. In this article the cellular and neural mechanisms through which the leptin signal is propagated are reviewed with respect to the development of leptin resistance. Deleterious effects of hyperleptinemia on cardiovascular physiology are then evaluated in the context of whole body physiology and with attention to differences between physiologic and pharmacologic effects.
Section snippets
Leptin Receptors and Leptin Signaling
The leptin receptor is present in almost all tissues examined. The best-studied isoform, the hypothalamic leptin receptor Ob-Rb, is a class I cytokine receptor.6 Upon leptin binding, activation of Ob-Rb promotes janus kinase (JAK)-dependent signaling through signal transducer and activator of transcription (STAT) proteins, primarily STAT-3.7 This leptin receptor has also been observed to activate phosphoinositol-3 kinase and phosphodiesterase 3B signaling pathways in the hypothalamus,8, 9
Leptin Resistance
The concept of leptin resistance was originally proposed to explain the observation that elevated levels of the hormone did not reduce food intake or prevent body weight gain in obese humans.5, 18 Subsequently several molecular possibilities have been put forth to explain the mechanism of leptin resistance. Feeding a high fat diet decreases the effectiveness of peripherally injected leptin to induce weight loss in rodents.19, 20 As previously described, Ob-Ra is present on cerebral microvessels
Effects of Leptin on Cardiovascular Physiology
Elevated serum leptin has been associated with cardiovascular disease including stroke, chronic heart failure, acute myocardial infarction, coronary heart disease, and left cardiac hypertrophy.23, 24 Many of these studies suggest that the effect of leptin is independent of adiposity, although correction for measures of adiposity may not be sufficient if body fat distribution is not also taken into account. For example, a recent report adjusting for body fat distribution and insulin levels
Conclusions
The discovery of leptin 13 years ago1 began a new era of research that recognized adipose tissue as an active endocrine organ rather than just a passive reservoir for storage of fatty acids. An extensive amount of work since that time has established that leptin influences many physiological processes in addition to body weight homeostasis. However, hyperleptinemia resulting from resistance to the weight-reducing effects of leptin can result in pathology. In particular, the evidence is fairly
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Cardiovascular consequences of metabolic syndrome
2017, Translational ResearchCitation Excerpt :Chronic increases in body weight and adiposity can lead to significant neurohormonal changes and adaptations in the cardiovascular system.18,20 These alterations include activation of the renin-angiotensin-aldosterone system,21,22 altered levels of adipocytokines,23-27 and proinflammatory cytokines,28,29 and activation of the sympathetic nervous system.30-33 Sympathetic nervous system activation can contribute to commonly described increases in heart rate, renal sodium retention, circulating blood volume, ventricular end-diastolic volume (preload), cardiac output, and/or blood pressure.18,30,34
Obesity hypertension: Pathophysiological role of leptin in neuroendocrine dysregulation
2014, American Journal of the Medical SciencesCitation Excerpt :From these findings, the concept of “selective leptin resistance” as a mechanism for the development of hypertension in obesity has emerged.18 The precise factors behind this selectivity are yet to be fully defined but may involve alterations in the suppressor of cytokine signaling protein-3 signaling pathway or insulin receptor substrate-1 serine residue phosphorylation.17,20 Independent of the possibility of selective leptin resistance in obesity, studies in normal rats have demonstrated that chronic hyperleptinemia leads to a persistent elevation in MAP, and this hypertensive effect is rapidly reversed upon cessation of the hormone administration.21
Postnatal Development of Hypothalamic Leptin Receptors
2010, Vitamins and HormonesCitation Excerpt :Discovered in 1994 (Zhang et al., 1994), leptin was initially thought to act only as a satiety factor, signaling to the brain the repletion of body fat stores. Since this time, however, leptin receptors (ObRs) have been identified in essentially every tissue, and leptin has been shown to play a role in a diverse range of physiological systems, including reproduction, immunity, cardiovascular function, and cognition (Ahima and Flier, 2000; Harvey et al., 2005; La Cava and Matarese, 2004; Tune and Considine, 2007). In terms of body weight regulation, leptin promotes negative energy balance by inhibiting feeding and stimulating energy expenditure, acting primarily through central nervous system (CNS) ObRs.
TSP-1 (Thrombospondin-1) Deficiency Protects ApoE<sup>-/-</sup>Mice Against Leptin-Induced Atherosclerosis
2021, Arteriosclerosis, Thrombosis, and Vascular BiologyBetween inflammation and autophagy: The role of leptin-adiponectin axis in cardiac remodeling
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2020, Acta Pharmacologica Sinica
This study has been supported by National Institutes of Health Grants DK51140 (R.V.C.) and HL67804 (J.D.T.) and a grant from the American Diabetes Association (R.V.C.).
Conflict of interest: none.