Natriuretic peptides in the control of lipid metabolism and insulin sensitivity.

Natriuretic peptides have long been known for their cardiovascular function. However, a growing body of evidence emphasizes the role of natriuretic peptides in human substrate and energy metabolism, thereby connecting the heart with several insulin-sensitive organs like adipose tissue, skeletal muscle and liver. Obesity may be associated with an impaired regulation of the natriuretic peptide system, also indicated as a natriuretic handicap. Evidence points towards a contribution of this natriuretic handicap to the development of obesity, type 2 diabetes mellitus and cardiometabolic complications, although the causal relationship is not fully understood. Nevertheless, targeting the natriuretic peptide pathway may improve metabolic health in obesity and type 2 diabetes mellitus. This review will focus on current literature regarding the metabolic roles of natriuretic peptides with emphasis on lipid metabolism and insulin sensitivity. Furthermore, it will be discussed how exercise and lifestyle intervention may modulate the natriuretic peptide-related metabolic effects.

Natriuretic peptides, obesity and cardiovascular diseases.

Obesity, hypertension and heart failure are conditions commonly associated with each other. Recent investigations have demonstrated that low plasmatic levels of natriuretic peptides are linked with obesity. Thus, knowing the actions of these hormones in water and salt homeostasis, it is possible to establish that low levels of natriuretic peptides may be the common denominator among obesity, hypertension and heart failure. Knowledge on this topic is crucial to develop further investigation for definitive conclusions.

Natriuretic peptides, obesity and cardiovascular diseases / Peptídeos natriuréticos, obesidade e doenças cardiovasculares

Obesity, hypertension and heart failure are conditions commonly associated with each other. Recent investigations have demonstrated that low plasmatic levels of natriuretic peptides are linked with obesity. Thus, knowing the actions of these hormones in water and salt homeostasis, it is possible to establish that low levels of natriuretic peptides may be the common denominator among obesity, hypertension and heart failure. Knowledge on this topic is crucial to develop further investigation for definitive conclusions.

Rationale and therapeutic opportunities for natriuretic peptide system augmentation in heart failure.

The natriuretic peptide system (NPS) is intimately involved in cardiorenal homeostasis in health, and dysregulation of the NPS plays an important role in the pathophysiology of heart failure (HF). Indeed, the diuretic, vasorelaxation, beneficial remodeling, and potent neurohumoral inhibition of the NPS support the therapeutic development of chronic augmentation of the NPS in symptomatic HF. Further, chronic augmentation of the protective NPS and in early stages of HF may ultimately prevent the progression of HF and reduced subsequent morbidity and mortality. In the current manuscript, we review the rationale for as well as previous and current efforts aimed at chronic therapeutic augmentation of the NPS in HF.

Natriuretic peptides and fat metabolism.

PURPOSE OF REVIEW: Cardiac natriuretic peptides have emerged as potent metabolic hormones during the past decade. We here discuss recent work highlighting the potential importance of these hormones in metabolic physiology and diseases. RECENT FINDINGS: Natriuretic peptides signal through a cyclic guanosine monophosphate pathway to convey their biological effects at the cell level. Similarly to cyclic adenosine monophosphate, activation of cyclic guanosine monophosphate signaling induces a browning of white fat and thermogenesis. Natriuretic peptides also enhance oxidative capacity and fat oxidation in skeletal muscle of mice and humans. The molecular mechanism involves an upregulation of mitochondrial fat oxidative capacity and respiration. This may be particularly relevant to relay the physiological adaptations of chronic exercise. Population-based studies indicate that circulating natriuretic peptides are lowered in obesity and predict type 2 diabetes. Recent work also directly link natriuretic peptides with type 2 diabetes through a gut-heart axis. SUMMARY: Natriuretic peptides exhibit a wide range of biological actions to control metabolic homeostasis. Natriuretic peptides deficiency in obesity may trigger metabolic dysfunction and lead to type 2 diabetes. Increasing circulating natriuretic peptides level and tissue signaling may help to fight against metabolic complications of obesity.

Involvement of guanylin and GC-C in rat mesenteric macrophages in resistance to a high-fat diet.

A high-fat diet (HFD) is a well-known contributing factor in the development of obesity. Most rats fed HFDs become obese. Those that avoid obesity when fed HFDs are considered diet resistant (DR). We performed a microarray screen to identify genes specific to the mesenteric fat of DR rats and revealed high expression of guanylin and guanylyl cyclase C (GC-C) in some subjects. Our histologic studies revealed that the cellular source of guanylin and GC-C is macrophages. Therefore, we developed double-transgenic (Tg) rats overexpressing guanylin and GC-C in macrophages and found that they were resistant to the effects of HFDs. In the mesenteric fat of HFD-fed Tg rats, Fas and perilipin mRNAs were downregulated, and those of genes involved in fatty acid oxidation were upregulated, compared with the levels in HFD-fed wild-type rats. In vitro studies demonstrated that lipid accumulation was markedly inhibited in adipocytes cocultured with macrophages expressing guanylin and GC-C and that this inhibition was reduced after treatment with guanylin- and GC-C-specific siRNAs. Our results suggest that the macrophagic guanylin-GC-C system contributes to the altered expression of genes involved in lipid metabolism, leading to resistance to obesity.

Corin: new insights into the natriuretic peptide system.

Natriuretic peptides are important in regulating salt and body-fluid balance. In cells, these peptides are made as precursor forms that are converted to active forms by proteolyic processing. Corin is a transmembrane serine protease identified in the heart. Corin converts pro-atrial natriuretic peptide (pro-ANP) to active ANP in a sequence-specific manner. In mice, lack of corin prevents the conversion of pro-ANP to ANP and causes salt-sensitive hypertension. The hypertensive phenotype is exacerbated when the mice become pregnant. In humans, single nucleotide polymorphisms in the corin gene have been identified in African Americans with hypertension and cardiac hypertrophy. These data indicate that corin is important in maintaining normal blood pressure in vivo and that corin deficiency may contribute to hypertension and heart disease in patients.

Novel therapeutic directions for the natriuretic peptides in cardiovascular diseases: what's on the horizon.

Remarkable advances have occurred since the discovery of ANP. The field of the natriuretic peptides has moved beyond their role as regulators of renal function. Growing evidence has now established the natriuretic peptides as regulators of myocardial structure and function as well as in cardiovascular regulation. Further, they emerge as being products not only of the cardiomyocyte but also of the cardiac fibroblast. Studies in vitro and in vivo have clearly established these cardiac hormones as antihypertrophic and antifibrotic. Further, indications such as cardioprotection for acute myocardial infarction, chronic therapy with oral BNP for hypertension and next generation peptides such as DNP-like peptides for acute heart failure may be in the near future. Novel therapeutic strategies to be tested in clinical trials in humans with cardiovascular disease are clearly on the horizon.