Marcelo L. G. Correia

Selective leptin resistance: a new concept in leptin physiology with cardiovascular implications

Leptin, an adipocyte secreted hormone, acts in the hypothalamus to inhibit appetite and promote thermogenic metabolism, thereby reducing adiposity and body weight. Leptin has multiple autonomic and cardiovascular actions, including sympathetic activation, increases in endothelium derived nitric oxide (NO), and angiogenesis. The predominant cardiovascular effect of chronic hyperleptinemia is a pressor effect mediated by increased sympathetic activity. The sympathetic and cardiovascular actions of leptin are discussed and evidence derived from studies of obese mice for the novel concept of selective leptin resistance is reviewed. This concept holds that in some obese states, there is preservation of the sympathoexcitatory actions of leptin despite resistance to the satiety and weight-reducing actions of the hormone. Selective leptin resistance might explain how hyperleptinemia could contribute to increases in sympathetic activity and arterial pressure in obese states where there is resistance to the metabolic (satiety and weight-reducing) actions of leptin. It is speculated here, that this concept may have potential implications for human obesity, which is often associated with elevated plasma leptin and partial resistance to the satiety effects of leptin. If selective leptin resistance occurs in obese humans, then leptin could contribute to the sympathetic overactivity and hypertension despite resistance to its metabolic actions.

Contrasting blood pressure effects of obesity in leptin-deficient ob/ob mice and agouti yellow obese mice.

OBJECTIVE Recent advances in understanding the neuroendocrine pathways regulating appetite, metabolism and body weight afford an opportunity to explore further the mechanisms by which obesity influences arterial pressure. ob/ob(Lep(ob)/Lep(ob)) mice have a mutation in the ob gene and are leptin-deficient. Leptin possesses pressor actions and has been shown to increase arterial pressure when infused chronically or over-expressed transgenically. In contrast, agouti yellow obese(Ay) mice have overexpression of an agouti peptide that blocks melanocortin receptors. Stimulation of melanocortin receptors by alpha-melanocyte-stimulating hormone decreases arterial pressure. DESIGN AND METHODS This study measured arterial pressure in leptin-deficient ob/ob mice, agouti yellow obese mice and their lean controls to test the hypothesis that the effects of obesity on arterial pressure are importantly influenced by the genetic and neuroendocrine mechanisms causing the obesity. We measured arterial pressure directly in conscious ob/ob mice (n = 14), agouti yellow obese mice (n = 6) and the same number of lean littermates. RESULTS Body weight was nearly twice as high in ob/ob mice as in their lean controls, but mean arterial pressure was significantly lower in ob/ob mice (92+/-3 mmHg) compared with their lean controls (106+/-2 mmHg; P = 0.00017). In contrast, mean arterial pressure was significantly higher in agouti yellow obese mice (124+/-3 mmHg) than in their lean controls (99+/-1 mmHg; P = 0.000002) despite the fact that the agouti mice had milder obesity. CONCLUSIONS This study prompts three conclusions: (1) leptin-deficient ob/ob mice and agouti yellow obese mice have contrasting blood pressure responses to obesity, (2) obesity does not invariably increase arterial pressure in mice, and (3) the arterial pressure response to obesity may depend critically on the underlying genetic and neuroendocrine mechanisms.

Role of leptin in the cardiovascular and endocrine complications of metabolic syndrome

Aim:  To review the potential role of leptin, hyperleptinaemia and leptin resistance in the cardiovascular and endocrine complications of metabolic syndrome.

Impaired skeletal muscle and skin microcirculatory function in human obesity.

Background Obesity is associated with exaggerated blood pressure and systemic vascular resistance responses to mental stress. Objective To test the hypothesis that skin and muscle microvascular dilatation in response to mental stress is blunted in obesity. Design and methods Blood pressure, heart rate and forearm and skin blood flow responses to mental stress were compared in 23 obese and 23 age- and sex-matched lean normotensive individuals. Results Blood pressure was almost identical in both obese (mean 94 ± 1 mmHg) and lean (93 ± 2 mmHg) individuals. The increase in blood pressure during mental stress was similar in obese and lean individuals (2.0 ± 0.9% compared with 3.1 ± 4.0%;P = 0.8). Forearm vascular resistance decreased during mental stress in both groups, but this decrease was significantly blunted in obese individuals compared with controls (decreases of 14 ± 4% and 26 ± 3%;P < 0.01). Skin microcirculatory dilatation was also significantly blunted in obese individuals compared with controls (decreases of 5 ± 2 and 17 ± 4%;P = 0.02). Conclusions Normotensive obese individuals exhibit markedly impaired muscle and skin microcirculatory responses to mental stress. The increased propensity of obese individuals to develop hypertension under conditions of chronic psychosocial stress may underlie obesity-related hypertension and cardiovascular disease.

Loss of leptin actions in obesity: two concepts with cardiovascular implications.

Obesity is associated with increased risk of hypertension and heart disease. Leptin has recently been linked to increased risk of cardiovascular disease. We review briefly here two concepts regarding loss of leptin actions that have potential implications for cardiovascular disease. These are: 1. the concept of selective leptin resistance; and 2. the concept that loss of leptin action results in lipid accumulation and lipotoxicity of skeletal muscle, pancreatic islet cells, and heart and, thereby, promotes insulin resistance, insulin deficiency and cardiac dysfunction, respectively.

A Role for Plasminogen Activator Inhibitor-1 in Obesity: From Pie to PAI?

The regulation of fibrinolysis depends on the interaction of plasma fibrinolytic and anti-fibrinolytic proteins. Fibrinolysis depends on the enzymatic conversion of plasminogen to plasmin. This process is mediated by tissue-type and urokinase-type plasminogen activators (t & uPAs, respectively). See page 2209 Plasma antifibrinolytic activity is primarily regulated by plasminogen-activator inhibitors (PAIs).1 Four PAIs have been described: PAIs-1 through 3 and protease nexin. Importantly, PAI-1 is the main antagonist of t & uPAs, accounting for approximately 60% of the inhibition of plasminogen activators. PAI-2 mostly inhibits urokinase plasminogen activator (uPA), whereas protease nexin antagonizes plasmin, thrombin, and uPA. The antifibrinolytic activity of PAI-3 is uncertain. These molecules and others are also collectively known as serine protease inhibitors or “serpins”. PAI-1 is a single chain 45-kDa glycoprotein that contains from 379 to 381 amino acids. Endothelial and vascular smooth muscle cells are presumably the main sources of PAI-1 but other cells, such as platelets, hepatocytes, mesangial cells, fibroblasts, monocytes, macrophages, adipocytes, and stromal cells permeating the adipose tissue, have also been shown to secrete the serpin. The gene for PAI-1 is located on chromosome 7q21.3-q22, and its expression is mainly regulated at the transcriptional level through the action of several hormones [eg, renin-angiotensin-aldostrerone system (RAAS)], cytokines [eg, tumor necrosis factor (TNF) α], lipoproteins (eg, VLDL), glucose, and endotoxin.1 Polymorphisms that influence PAI-1 gene expression have been described. The single 4/5 guanine polymorphism (4G/5G) in the promoter region of PAI-1 gene is widespread and has been associated with variable plasma PAI-1 activity and antigen levels.1 Indeed, plasma expression of PAI-1 antigen and activity are augmented in homozygous subjects for the 4G allele but decreased in 5G allele homozygous. This polymorphism may have important implications for human cardiovascular disease as suggested by case–control studies showing a higher prevalence of the 4G …

Vascular smooth muscle function is associated with initiation and processing speed in patients with atherosclerotic vascular disease

We previously reported a relationship between forearm resistance vessel function and global neuropsychological performance in patients with atherosclerotic vascular disease (AVD). This study was conducted to determine the relationships among vascular smooth muscle function, endothelial function, and initiation and processing speed in this sample. Participants were 80 individuals with AVD. Resistance vessel function was measured before and after infusion of vasoactive agents. Neuropsychological assessment included measures of estimated premorbid cognitive function, current global cognitive function, initiation, and processing speed. Vascular smooth muscle function was significantly associated with the initiation/processing speed composite score [R-Square Change = .152; F Change (1,71) = 16.61; p < .001], above and beyond the variance accounted for by age, education, premorbid cognitive function, and endothelium-dependent vascular function. This relationship remained significant when controlling for current level of global cognitive functioning and 10 vascular risk factors. Endothelium-dependent vascular function was not significantly associated with test performance. Decreased vascular smooth muscle function in forearm resistance vessels was significantly associated with relatively poor initiation and processing speed in individuals with AVD. With additional research, measures of vascular function might become useful in the early identification of those individuals at greatest risk for vascular-related cognitive dysfunction.

Emerging drugs for obesity: linking novel biological mechanisms to pharmaceutical pipelines.

Obesity is associated with hypertension, diabetes, dyslipidaemias and metabolic syndrome, and causes substantial morbidity and mortality from cardiovascular and other diseases. The cost to treat obesity and its complications in the US has increased steeply and is currently estimated to be US

The Concept of Selective Leptin Resistance: Evidence From Agouti Yellow Obese Mice

100 billion. Current therapy for obesity is mainly based on changes in lifestyle that often fail. Existing pharmacological treatment is marginally efficient and poorly tolerated. The discovery of leptin and related neural mechanisms of energy metabolism regulation has opened the doors to potential targets for new antiobesity drugs. In this review, new pharmacological targets are discussed and an update on the development of emerging antiobesity drugs is provided. Despite intense investigation, the pipelines for antiobesity drugs in late stages of development are relatively empty. Breakthrough treatments for obesity may take some years to emerge. Clinical trials will be necessary to clarify the impact of new antiobesity drugs on hard cardiovascular and metabolic end points.