Summary of NP action in the skeletal muscle in healthy individuals (A) and obese individuals with diabetes (B). NPs circulate in reduced concentrations in obese individuals with diabetes compared with the levels in healthy individuals. Furthermore, expression of NPRA, which binds NPs and activates intracellular signaling events, is reduced, while expression of NPRC, which clears NPs in tissues, is increased in obesity and T2D. In healthy individuals, generation of cGMP from guanosine triphosphate (GTP) by the guanylyl cyclase activity of NPRA activates a signaling pathway resulting in the phosphorylation (P) and activation of p38 mitogen-activated protein kinase (p38 MAPK) and the increased transcription of peroxisome proliferator–activated receptor coactivator γ-1α (PGC1α). This is associated with mitochondrial biogenesis and oxidation of lipids, including the lipotoxic diacylglycerols (DAGs) and ceramides. In obese individuals, NP signaling from NPRA is attenuated, predisposing to DAG and ceramide accumulation in the muscle and thus IR, characterized by inhibition of insulin signaling via Akt and impaired glucose disposal.
Natriuretic peptide receptors proposed as new target for metabolic disorders. A new study has revealed an important relationship between proteins secreted by the heart and obesity, glucose intolerance, and insulin resistance. The findings offer a new approach to treating metabolic disorders, including type 2 diabetes, by targeting the pathway that controls the proteins’ concentration in the blood.
“Our results illustrate how the regulation of cardiac natriuretic peptides (NPs) is altered in obesity, insulin resistance, and type 2 diabetes,” said Prof. Sheila Collins, Ph.D. “When we examined fat (adipose) tissue from patients with these metabolic conditions, we found higher levels of the receptor that clears NPs from circulation, suggesting that if we can boost NP levels and/or reduce the level of its clearance receptor, we may be able to correct some of these conditions.”
NPs are hormones produced by the heart that are primarily known for their ability to influence BP. When the heart senses elevated pressure, it releases NPs, which go to the kidneys, triggering the body to release salt and water from the bloodstream to lower blood pressure. NPs prompt the response to blood pressure by signaling through an active receptor (NPRA), and are removed from the blood by a clearance receptor (NPRC). Both receptors contribute to the level of NP activity.
Almost 2 decades ago, NP receptors were unexpectedly found in human adipose tissue, suggesting that NP levels may play an additional role in metabolism and obesity. Subsequent studies showed circulating NP levels are lower in obese individuals and those with metabolic risk factors, including high glucose levels. More recently, research has shown obese individuals have higher levels of clearance receptor in adipose tissue.
“We examined levels of NPRA and NPRC in adipose and skeletal tissue in individuals with a range of body mass index (BMI) values and insulin sensitivity,” said Richard Pratley, M.D. “We found that higher BMI values are associated with elevated levels of the clearance receptor in adipose tissue. “We also looked at NP receptor levels in patients with type 2 diabetes after taking pioglitazone, a drug used to improve insulin sensitivity and control blood sugar in patients with type 2 diabetes. Interestingly, we found that these patients had a significant reduction in the level of the clearance receptor in adipose tissue, further reinforcing the link between NPs, insulin resistance, and obesity”.
“Overall, our results suggest that drugs that target the pathway(s) that lead to ncreased NP levels may be a new way to treat metabolic disorders, including obesity, insulin resistance, and potentially type 2 diabetes. “Since we already have access to FDA-approved drugs to control blood sugar, and we know that these drugs impact NP levels, we may be able to redesign these drugs to specifically target other metabolic conditions including obesity,” said Collins.
“This project is a great example of taking research from bench to beside, and highlights the strength of the partnership between SBP and TRI–a partnership that accelerates the delivery of lab discoveries to the clinic,” added Pratley. http://beaker.sbpdiscovery.org/2016/02/new-links-between-heart-hormones-obesity-and-diabetes/
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