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The dramatic increase in the prevalence of obesity and its strong association with cardiovascular disease have resulted in unprecedented interest in understanding the effects of obesity on the cardiovascular system. A consistent, but puzzling clinical observation is that obesity confers an increased susceptibility to the development of cardiac disease, while at the same time affording protection against subsequent mortality (termed the obesity paradox). In this review we focus on evidence available from human and animal model studies and summarize the ways in which obesity can influence structure and function of the heart. We also review current hypotheses regarding mechanisms linking obesity and various aspects of cardiac remodeling. There is currently great interest in the role of adipokines, factors secreted from adipose tissue, and their role in the numerous cardiovascular complications of obesity. Here we focus on the role of leptin and the emerging promise of adiponectin as a cardioprotective agent. The challenge of understanding the association between obesity and heart failure is complicated by the multifaceted interplay between various hemodynamic, metabolic, and other physiological factors that ultimately impact the myocardium. Furthermore, the end result of obesity-associated changes in the myocardial structure and function may vary at distinct stages in the progression of remodeling, may depend on the individual pathophysiology of heart failure, and may even remain undetected for decades before clinical manifestation. Here we summarize our current knowledge of this complex yet intriguing topic.

Background: Lipocalin-2, a 25-kDa secreted glycoprotein, is a useful biomarker for early detection of various renal injuries. Because lipocalin-2 is abundantly expressed in adipose tissue and liver, we investigated its relevance to obesity-related pathologies. Methods: We used real-time PCR and in-house immunoassays to quantify the mRNA and serum concentrations of lipocalin-2 in C57BL/KsJ db/db obese mice and their age-and sex-matched lean littermates. We analyzed the association between serum lipocalin-2 concentrations and various metabolic and inflammatory variables in 229 persons (121 men and 108 women) recruited from a previous cross-sectional study, and we evaluated the effect of the insulin-sensitizing drug rosiglitazone on serum lipocalin-2 concentrations in 32 diabetic patients (21 men and 11 women). Results: Compared with the lean littermates, lipocalin-2 mRNA expression in adipose tissue and liver and its circulating concentrations were significantly increased in db/db diabetic/obese mice (P <0.001). These changes were normalized after rosiglitazone treatment. In humans, circulating lipocalin-2 concentrations were positively correlated (P <0.005) with adiposity, hypertriglyceridemia, hyperglycemia, and the insulin resistance index, but negatively correlated (P ‫؍‬ 0.002) with HDL cholesterol. There was also a strong positive association

The precise mechanisms underlying insulin-stimulated glucose transport still require investigation. Here we assessed the effect of SB203580, an inhibitor of the p38 MAP kinase family, on insulin-stimulated glucose transport in 3T3-L1 adipocytes and L6 myotubes. We found that SB203580, but not its inactive analogue (SB202474), prevented insulin-stimulated glucose transport in both cell types with an IC 50 similar to that for inhibition of p38 MAP kinase (0.6 M). Basal glucose uptake was not affected. Moreover, SB203580 added only during the transport assay did not inhibit basal or insulin-stimulated transport. SB203580 did not inhibit insulin-stimulated translocation of the glucose transporters GLUT1 or GLUT4 in 3T3-L1 adipocytes as assessed by immunoblotting of subcellular fractions or by immunofluorescence of membrane lawns. L6 muscle cells expressing GLUT4 tagged on an extracellular domain with a Myc epitope (GLUT4myc) were used to assess the functional insertion of GLUT4 into the plasma membrane. SB203580 did not affect the insulin-induced gain in GLUT4myc exposure at the cell surface but largely reduced the stimulation of glucose uptake. SB203580 had no effect on insulin-dependent insulin receptor substrate-1 phosphorylation, association of the p85 subunit of phosphatidylinositol 3-kinase with insulin receptor substrate-1, nor on phosphatidylinositol 3-kinase, Akt1, Akt2, or Akt3 activities in 3T3-L1 adipocytes. In conclusion, in the presence of SB203580, insulin caused normal translocation and cell surface membrane insertion of glucose transporters without stimulating glucose transport. We propose that insulin stimulates two independent signals contributing to stimulation of glucose transport: phosphatidylinositol 3-kinase leads to glucose transporter translocation and a pathway involving p38 MAP kinase leads to activation of the recruited glucose transporter at the membrane.

The identification of leptin as the product of the obesity (ob) gene has been followed by extensive research identifying a wide spectrum of physiological effects elicited by this adipose-derived hormone. These effects are mediated via a family of cytokine-like receptor isoforms distributed in both the central nervous system and periphery. The signal transduction pathways regulated by leptin are diverse and include those characteristic of both cytokine and growth factor receptor signalling. This review describes the structure and function of leptin receptors and summarizes recent progress that has been made in characterizing the increasing number of signal transduction pathways regulated by leptin.

OBJECTIVEThe proinflammatory cytokines/adipokines produced from adipose tissue act in an autocrine and/or endocrine manner to perpetuate local inflammation and to induce peripheral insulin resistance. The present study investigates whether lipocalin-2 deficiency or replenishment with this adipokine has any impact on systemic insulin sensitivity and the underlying mechanisms.METHODS AND RESULTSUnder conditions of aging or dietary-/genetic-induced obesity, lipocalin-2 knockout (Lcn2-KO) mice show significantly decreased fasting glucose and insulin levels and improved insulin sensitivity compared with their wild-type littermates. Despite enlarged fat mass, inflammation and the accumulation of lipid peroxidation products are significantly attenuated in the adipose tissues of Lcn2-KO mice. Adipose fatty acid composition of these mice varies significantly from that in wild-type animals. The amounts of arachidonic acid (C20:4 n6) are elevated by aging and obesity and are paradoxically further increased in adipose tissue, but not skeletal muscle and liver of Lcn2-KO mice. On the other hand, the expression and activity of 12-lipoxygenase, an enzyme responsible for metabolizing arachidonic acid, and the production of tumor necrosis factor-α (TNF-α), a critical insulin resistance–inducing factor, are largely inhibited by lipocalin-2 deficiency. Lipocalin-2 stimulates the expression and activity of 12-lipoxygenase and TNF-α production in fat tissues. Cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC), an arachidonate lipoxygenase inhibitor, prevents TNF-α expression induced by lipocalin-2. Moreover, treatment with TNF-α neutralization antibody or CDC significantly attenuated the differences of insulin sensitivity between wild-type and Lcn2-KO mice.CONCLUSIONSLipocalin-2 deficiency protects mice from developing aging- and obesity-induced insulin resistance largely by modulating 12-lipoxygenase and TNF-α levels in adipose tissue.

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Obesity is commonly associated with the development of insulin resistance and diabetes in humans and rodents. Insulin resistance and diabetes are observed in lipoatrophic individuals or rodent models of lipoatrophy. Here we focus on the role of leptin, the product of the obesity (ob) gene, in the development of insulin resistance and diabetes associated with obesity and lipoatrophy. We review the reported effects of leptin on whole body glucose metabolism and compare and contrast these with direct effects on skeletal muscle, fat and liver. This summary of paradoxical observations on the effects of leptin on glucose homeostasis and the ability of leptin to induce or improve insulin resistance suggests that a complex interplay exists between direct peripheral and centrally mediated effects of the hormone. Evidence suggesting that leptin acts as a mediator of insulin release from pancreatic beta cells is reviewed. Finally, intracellular signaling mechanisms stimulated by both leptin and insulin are discussed, with potential points of cross-talk suggested.